Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability.

PubMed

Beckley, Ethan H; Scibelli, Angela C; Finn, Deborah A

2011-07-01

Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

Parental emotion socialization in clinically depressed adolescents: Enhancing, and dampening positive affect

PubMed Central

Katz, Lynn Fainsilber; Shortt, Joann Wu; Allen, Nicholas B.; Davis, Betsy; Hunter, Erin; Leve, Craig; Sheeber, Lisa

2013-01-01

This study compared parental socialization of adolescent positive affect in families of depressed and healthy adolescents. Participants were 107 adolescents (42 boys) aged 14 - 18 years and their parents. Half of the participants met criteria for major depressive disorder and the others were demographically matched adolescents without emotional or behavioral disorders. Results based on multi-source questionnaire and interview data indicated that mothers and fathers of depressed adolescents were less accepting of adolescents’ positive affect and more likely to use strategies that dampen adolescents’ positive affect than were parents of healthy adolescents. Additionally, fathers of depressed adolescents exhibited fewer responses likely to enhance the adolescents’ positive affect than were fathers of healthy adolescents. These findings build on those of previous work in examining parental responses to adolescent emotions, focusing on positive emotions and including both mothers and fathers. PMID:23942826

Transient Anosmia Induces Depressive-like and Anxiolytic-like Behavior and Reduces Amygdalar Corticotropin-Releasing Hormone in a ZnSO4-Induced Mouse Model.

PubMed

Ahn, Sangzin; Choi, Mooseok; Kim, Hyunju; Yang, Eun-Jeong; Mahmood, Usman; Kang, Seong-Il; Shin, Hyun-Woo; Kim, Dae Woo; Kim, Hye-Sun

2018-04-23

Olfactory loss is known to affect both mood and quality of life. Transient anosmia was induced in mice to study the resulting changes in mood, behavior, and on a molecular level. Transient anosmia was induced by a single intranasal instillation of ZnSO4 in BALB/c mice. Hematoxylin and eosin (HE) staining, and potato chip finding test were performed to confirm olfactory loss. Tail suspension, forced swim, and splash tests were performed to evaluate depression-related behavior; while the open field, and elevated plus maze tests were used to evaluate anxiety-related behavior. The mRNA levels of amygdalar corticotropin-releasing hormone (CRH) and hypothalamic glucocorticoid receptor (GR) were quantified using real-time PCR to confirm relevant molecular change. Olfactory loss was confirmed 1-2.5 weeks after induction, and this loss was subsequently reversed over time. The results of the behavioral tests indicated increased depression-like and reduced anxiety-like behavior at week 1. Accordingly, PCR data identified decreased amygdalar CRH expression at week 1. These results suggest that transient anosmia induces both depressive and anxiolytic behavior as a result of decreased amygdalar CRH in a mouse model of anosmia.

Immune malfunction in the GPR39 zinc receptor of knockout mice: Its relationship to depressive disorder.

PubMed

Młyniec, Katarzyna; Trojan, Ewa; Ślusarczyk, Joanna; Głombik, Katarzyna; Basta-Kaim, Agnieszka; Budziszewska, Bogusława; Skrzeszewski, Jakub; Siwek, Agata; Holst, Birgitte; Nowak, Gabriel

2016-02-15

Depression is a serious psychiatric disorder affecting not only the monaminergic, glutamatergic, and GABAergic neurosystems, but also the immune system. Patients suffering from depression show disturbance in the immune parameters as well as increased susceptibility to infections. Zinc is well known as an anti-inflammatory agent, and its link with depression has been proved, zinc deficiency causing depression- and anxiety-like behavior with immune malfunction. It has been discovered that trace-element zinc acts as a neurotransmitter in the central nervous system via zinc receptor GPR39. In this study we investigated whether GPR39 knockout would cause depressive-like behavior as measured by the forced swim test, and whether these changes would coexist with immune malfunction. In GPR39 knockout mice versus a wild-type control we found: i) depressive-like behavior; ii) significantly reduced thymus weight; (iii) reduced cell viability of splenocytes; iv) reduced proliferative response of splenocytes; and v) increased IL-6 production of splenocytes after ConA stimulation and decreased IL-1b and IL-6 release after LPS stimulation. The results indicate depressive-like behavior in GPR39 KO animals with an immune response similar to that observed in depressive disorder. Here for the first time we show immunological changes under GPR39-deficient conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

Chronic exercise improves repeated restraint stress-induced anxiety and depression through 5HT1A receptor and cAMP signaling in hippocampus.

PubMed

Kim, Mun Hee; Leem, Yea Hyun

2014-03-01

Mood disorders such as anxiety and depression are prevalent psychiatric illness, but the role of 5HT1A in the anti-depressive effects of exercise has been rarely known yet. We investigated whether long-term exercise affected a depressive-like behavior and a hippocampal 5HT1A receptor-mediated cAMP/PKA/CREB signaling in depression mice model. To induce depressive behaviors, mice were subjected to 14 consecutive days of restraint stress (2 hours/day). Depression-like behaviors were measured by forced swimming test (TST), and anxiety-like behavior was assessed by elevated plus maze (EPM). Treadmill exercise was performed with 19 m/min for 60 min/day, 5 days/week from weeks 0 to 8. Restraint stress was started at week 6 week and ended at week 8. To elucidate the role of 5HT1A in depression, the immunoreactivities of 5HT1A were detected in hippocampus using immunohistochemical technique. Chronic/repeated restraint stress induced behavioral anxiety and depression, such as reduced time and entries in open arms in EPM and enhanced immobility time in FST. These anxiety and depressive behaviors were ameliorated by chronic exercise. Also, these behavioral changes were concurrent with the deficit of 5HT1A and cAMP/PKA/CREB cascade in hippocampus, which was coped with chronic exercise. These results suggest that chronic exercise may improve the disturbance of hippocampal 5HT1A-regulated cAMP/PKA/CREB signaling in a depressed brain, thereby exerting an antidepressive action.

A Single Sub-anesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

PubMed Central

Wang, Jing; Goffer, Yossef; Xu, Duo; Tukey, David S.; Shamir, D. B.; Eberle, Sarah E.; Zou, Anthony H.; Blanck, Thomas J.J.; Ziff, Edward B.

2011-01-01

Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its anti-nociceptive properties. Methods We examined whether the spared nerve injury (SNI) model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats SNI-induced depression. Results SNI-treated rats, compared with control, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10mg/kg) did not alter SNI-induced hypersensitivity; however, it treated SNI-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain. PMID:21934410

Behavioral and Neurobiological Effects of Deep Brain Stimulation in a Mouse Model of High Anxiety- and Depression-Like Behavior

PubMed Central

Schmuckermair, Claudia; Gaburro, Stefano; Sah, Anupam; Landgraf, Rainer; Sartori, Simone B; Singewald, Nicolas

2013-01-01

Increasing evidence suggests that high-frequency deep brain stimulation of the nucleus accumbens (NAcb-DBS) may represent a novel therapeutic strategy for individuals suffering from treatment-resistant depression, although the underlying mechanisms of action remain largely unknown. In this study, using a unique mouse model of enhanced depression- and anxiety-like behavior (HAB), we investigated behavioral and neurobiological effects of NAcb-DBS. HAB mice either underwent chronic treatment with one of three different selective serotonin reuptake inhibitors (SSRIs) or received NAcb-DBS for 1 h per day for 7 consecutive days. Animals were tested in established paradigms revealing depression- and anxiety-related behaviors. The enhanced depression-like behavior of HAB mice was not influenced by chronic SSRI treatment. In contrast, repeated, but not single, NAcb-DBS induced robust antidepressant and anxiolytic responses in HAB animals, while these behaviors remained unaffected in normal depression/anxiety animals (NAB), suggesting a preferential effect of NAcb-DBS on pathophysiologically deranged systems. NAcb-DBS caused a modulation of challenge-induced activity in various stress- and depression-related brain regions, including an increase in c-Fos expression in the dentate gyrus of the hippocampus and enhanced hippocampal neurogenesis in HABs. Taken together, these findings show that the normalization of the pathophysiologically enhanced, SSRI-insensitive depression-like behavior by repeated NAcb-DBS was associated with the reversal of reported aberrant brain activity and impaired adult neurogenesis in HAB mice, indicating that NAcb-DBS affects neuronal activity as well as plasticity in a defined, mood-associated network. Thus, HAB mice may represent a clinically relevant model for elucidating the neurobiological correlates of NAcb-DBS. PMID:23325324

An investigation into the effects of antenatal stressors on the postpartum neuroimmune profile and depressive-like behaviors

PubMed Central

Posillico, Caitlin K.; Schwarz, Jaclyn M.

2015-01-01

Postpartum depression is a specific type of depression that affects approximately 10-15% of mothers (Wisner et al., 2013). While many have attributed the etiology of postpartum depression to the dramatic change in hormone levels that occurs immediately postpartum, the exact causes are not well-understood. It is well-known; however, that pregnancy induces a number of dramatic changes in the peripheral immune system that foster the development of the growing fetus. It is also well-known that changes in immune function, specifically within the brain, have been linked to several neuropsychiatric disorders including depression. Thus, we sought to determine whether pregnancy induces significant neuroimmune changes postpartum and whether stress or immune activation during pregnancy induce a unique neuroimmune profile that may be associated with depressive-like behaviors postpartum. We used late-gestation sub-chronic stress and late-gestation acute immune activation to examine the postpartum expression of depressive-like behaviors, microglial activation markers, and inflammatory cytokines within the medial prefrontal cortex (mPFC) and the hippocampus (HP). The expression of many immune molecules was significantly altered in the brain postpartum, and postpartum females also showed significant anhedonia, both independently of stress. Following late-gestation immune activation, we found a unique set of changes in neuroimmune gene expression immediately postpartum. Thus, our data indicate that even in the absence of additional stressors, postpartum females exhibit significant changes in the expression of cytokines within the brain that are associated with depressive-like behavior. Additionally, different forms of antenatal stress produce varying profiles of postpartum neuroimmune gene expression and associated depressive-like behaviors. PMID:26589802

Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression.

PubMed

Andersen, Susan L

2015-05-01

The relationship between developmental exposure to adversity and affective disorders is reviewed. Adversity discussed herein includes physical and sexual abuse, neglect, or loss of a caregiver in humans. While these stressors can occur at any point during development, the unique temporal relationship to specific depressive symptoms was the focus of discussion. Further influences of stress exposure during sensitive periods can vary by gender and duration of abuse as well. Data from animal studies are presented to provide greater translational and causal understanding of how sensitive periods, different types of psychosocial stressors, and sex interact to produce depressive-like behaviors. Findings from maternal separation, isolation rearing, chronic variable stress, and peer-peer rearing paradigms clarify interpretation about how various depressive behaviors are influenced by age of exposure. Depressive behaviors are broken down into the following categories: mood and affect, anhedonia, energy, working memory, sleep-wake, appetite changes, suicide, and general malaise. Cross-species evidence from humans, nonhuman primates, rats, and mice within each of these categories is discussed. In conclusion, sensitive periods for affective-related behaviors (anxiety, mood, and controllability) occur earlier in life, while other aspects of depression are associated with adversity later during adolescence.

Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions.

PubMed

Vilar-Pereira, Glaucia; Silva, Andrea Alice da; Pereira, Isabela Resende; Silva, Rafael Rodrigues; Moreira, Otacílio Cruz; de Almeida, Luciana Rodrigues; de Souza, Amanda Santos; Rocha, Monica Santos; Lannes-Vieira, Joseli

2012-10-01

Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosoma cruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T. cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian-infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T. cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive-like behavior was triggered only by the type I Colombian T. cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite-induced immune dysregulation may contribute to chronic depressive disorder in T. cruzi infection, which opens a new therapeutic pathway to be explored. Copyright © 2012 Elsevier Inc. All rights reserved.

Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression.

PubMed

Malatynska, Ewa; Steinbusch, Harry W M; Redkozubova, Olga; Bolkunov, Alexei; Kubatiev, Aslan; Yeritsyan, Naira B; Vignisse, Julie; Bachurin, Sergei; Strekalova, Tatyana

2012-08-01

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced sensitivity to reward, which is listed as a core feature of major depression in the DSM-IVR, can be measured by a decrease in intake of and preference for sweet solutions. Here, sucrose intake, forced swimming, immobility in the modified tail suspension test, novelty exploration, grooming, anxiety and locomotor activity were compared in naïve 3- and 18-month-old male C57BL/6 mice. The absolute amounts and the ratio of consumed 1% sucrose solution to water intake was significantly smaller in 18-month-old mice than in 3-month-old mice. The consumption of 5%-sucrose solution requiring high levels of drinking effort, novelty exploration in two setups and grooming behavior in the splash test were reduced in older animals. Analysis of other behaviors suggested that the above-mentioned signs of anhedonic-like traits were unlikely to be attributable to the potential effect of aging on metabolic needs for water, taste perception, motor capabilities or the induction of essential anxiety and neophobia. A 4-week treatment with the antidepressant imipramine (7mg/kg/day) or dimebon, a compound with suggested neuroprotective proneurogenic properties (1mg/kg/day) restored sucrose intake and preference in 18-month-old mice. Meanwhile, young and old mice showed no differences in the parameters of behavioral despair evaluated in the forced swim and modified tail suspension tests. Thus, the behavioral profile of aged mice parallels that of humans with elderly depression, in whom the symptoms of hedonic deficits typically outweigh affective disturbances. The assessment of anhedonic-like traits with the sucrose preference test in 18-month-old mice will be useful in preclinical studies of elderly depression. Copyright © 2012 Elsevier Inc. All rights reserved.

Depressive-like behavior is elevated among offspring of parents exposed to dim light at night prior to mating.

PubMed

Cissé, Yasmine M; Russart, Kathryn L G; Nelson, Randy J

2017-09-01

Rates of major depressive disorder (MDD) have steadily increased over the past 50 years. Many factors have been implicated in the etiology of depressive disorders and environmental influences are being increasingly recognized. The increase in depression rates has coincided with increased artificial nighttime lighting. Exposure to light at night (LAN) has been associated with increased depressive-like behavior in rodents and decreased mood in humans. However, relatively little is known on the multigenerational effects of dLAN on affect. In this study, we exposed adult male and female Siberian hamsters (Phodopus sungorus) to either DARK (0lx) or dim LAN (5lx) for 9 weeks, then paired animals in a full factorial design; all animals were thereafter housed in dark nights. Offspring were gestated and reared in dark nights, then tested in adulthood for depressive-like behaviors and hippocampal expression of glucocorticoid (GR) and melatonin (MT1) receptor expression. Maternal exposure to dLAN decreased sucrose preference, time to first float bout in the Porsolt swim test, and GR expression in the hippocampus. Paternal exposure to dLAN increased time spent floating, and increased hippocampal GR expression. Overall, our results suggest that chronic exposure of parents to light at night has multigenerational effects on offspring depressive-like behavior. If these results pertain to humans, then our data suggest that LAN may contribute to the rapidly rising rates of major depressive disorder in industrialized and developing countries. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adolescent chronic restraint stress (aCRS) elicits robust depressive-like behavior in freely cycling, adult female rats without increasing anxiety-like behaviors.

PubMed

Hibicke, Meghan; Graham, Martha A; Hayslett, Renée L

2017-04-01

Stress during times of rapid development is a risk factor for Major Depressive Disorder, a mood disorder that disproportionately affects women. We developed an adolescent chronic restraint stress (aCRS) protocol using female rats to address the impact of adolescent stress on female adult depressive-like behavior. Animals were divided into 4 treatment groups: not restrained:saline (NRSAL), not restrained:desipramine (NRDES), restrained:saline (RSAL), and restrained:desipramine (RDES). NRSAL and NRDES rats were housed in a separate colony room from RSAL and RDES rats. All animals were weighed and handled daily. Beginning postnatal day (PND) 34(±1), RSAL and RDES rats were restrained for 1 hour daily for 14 consecutive days. Beginning PND 55(±1), NRDES and RDES rats were given subcutaneous desipramine (5 mg/kg), which served as a positive control, daily for 14 consecutive days. During that same time period, NRSAL and RSAL rats were given subcutaneous saline daily. aCRS (RSAL and RDES) rats showed significantly attenuated weight gain compared with nonrestrained (NRSAL and NRDES) rats during the restraint period. Weight gain normalized after the final restraint session. Behavioral testing took place PND 68-69(±1), and included open field testing, the elevated plus maze, locomotor activity, and the forced swim test (FST). RSAL rats showed significantly more immobility in the FST versus all other groups, indicating depressive-like behavior. No differences between groups were observed in the other behavioral measures. These results indicate that aCRS elicits depressive-like behavioral characteristics in adult female rats without increasing anxiety-like behaviors. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Activation of GABA-A receptors during postnatal brain development increases anxiety- and depression-related behaviors in a time- and dose-dependent manner in adult mice.

PubMed

Salari, Ali-Akbar; Bakhtiari, Amir; Homberg, Judith R

2015-08-01

Disturbances of the gamma-amino butyric acid-ergic (GABAergic) system during postnatal development can have long-lasting consequences for later life behavior, like the individual's response to stress. However, it is unclear which postnatal windows of sensitivity to GABA-ergic modulations are associated with what later-life behavioral outcomes. Therefore, we sought to determine whether neonatal activation of the GABA-A receptor during two postnatal periods, an early window (postnatal day 3-5) and a late window (postnatal day 14-16), can affect anxiety- and depression-related behaviors in male mice in later life. To this end, mice were treated with either saline or muscimol (50, 100, 200, 300 and 500μg/kg) during the early and late postnatal periods. An additional group of mice was treated with the GABA-A receptor antagonist bicuculline+muscimol. When grown to adulthood male mice were exposed to behavioral tests to measure anxiety- and depression-related behaviors. Baseline and stress-induced corticosterone (CORT) levels were also measured. The results indicate that early postnatal and to a lesser extent later postnatal exposure to the GABA-A receptor agonist muscimol increased anxiety-like behavior and stress-induced CORT levels in adults. Moreover, the early postnatal treatment with muscimol increased depression-like behavior with increasing baseline CORT levels. The anxiogenic and depression-like later-life consequences could be antagonized by bicuculline. Our findings suggest that GABA-A receptor signaling during early-life can influence anxiety- and depression-related behaviors in a time- and dose-dependent manner in later life. Our findings help to increase insight in the developmental mechanisms contributing to stress-related disorders. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

PubMed

Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Young-Adult Male Rats' Vulnerability to Chronic Mild Stress Is Reflected by Anxious-Like instead of Depressive-Like Behaviors.

PubMed

José Jaime, Herrera-Pérez; Venus, Benítez-Coronel; Graciela, Jiménez-Rubio; Tania, Hernández-Hernández Olivia; Lucía, Martínez-Mota

2016-01-01

In a previous study, we found that chronic mild stress (CMS) paradigm did not induce anhedonia in young-adult male rats but it reduced their body weight gain. These contrasting results encouraged us to explore other indicators of animal's vulnerability to stress such as anxious-like behaviors, since stress is an etiologic factor also for anxiety. Thus, in this study, we evaluated the vulnerability of these animals to CMS using behavioral tests of depression or anxiety and measuring serum corticosterone. Male Wistar rats were exposed to four weeks of CMS; the animals' body weight and sucrose preference (indicator of anhedonia) were assessed after three weeks, and, after the fourth week, some animals were evaluated in a behavioral battery (elevated plus maze, defensive burying behavior, and forced swimming tests); meanwhile, others were used to measure serum corticosterone. We found that CMS (1) did not affect sucrose preference, immobility behavior in the forced swimming test, or serum corticosterone; (2) decreased body weight gain; and (3) increased the rat's entries into closed arms of the plus maze and the cumulative burying behavior. These data indicate that young male rats' vulnerability to CMS is reflected as poor body weight gain and anxious-like instead of depressive-like behaviors.

Young-Adult Male Rats' Vulnerability to Chronic Mild Stress Is Reflected by Anxious-Like instead of Depressive-Like Behaviors

PubMed Central

José Jaime, Herrera-Pérez; Venus, Benítez-Coronel; Graciela, Jiménez-Rubio; Tania, Hernández-Hernández Olivia

2016-01-01

In a previous study, we found that chronic mild stress (CMS) paradigm did not induce anhedonia in young-adult male rats but it reduced their body weight gain. These contrasting results encouraged us to explore other indicators of animal's vulnerability to stress such as anxious-like behaviors, since stress is an etiologic factor also for anxiety. Thus, in this study, we evaluated the vulnerability of these animals to CMS using behavioral tests of depression or anxiety and measuring serum corticosterone. Male Wistar rats were exposed to four weeks of CMS; the animals' body weight and sucrose preference (indicator of anhedonia) were assessed after three weeks, and, after the fourth week, some animals were evaluated in a behavioral battery (elevated plus maze, defensive burying behavior, and forced swimming tests); meanwhile, others were used to measure serum corticosterone. We found that CMS (1) did not affect sucrose preference, immobility behavior in the forced swimming test, or serum corticosterone; (2) decreased body weight gain; and (3) increased the rat's entries into closed arms of the plus maze and the cumulative burying behavior. These data indicate that young male rats' vulnerability to CMS is reflected as poor body weight gain and anxious-like instead of depressive-like behaviors. PMID:27433469

Effects of prenatal stress on anxiety- and depressive-like behaviors are sex-specific in prepubertal rats.

PubMed

Iturra-Mena, Ann Mary; Arriagada-Solimano, Marcia; Luttecke-Anders, Ariane; Dagnino-Subiabre, Alexies

2018-05-17

The fetal brain is highly susceptible to stress in late pregnancy, with lifelong effects of stress on physiology and behavior. The aim of this study was to determine the physiological and behavioral effects of prenatal stress during the prepubertal period of female and male rats. We subjected pregnant Sprague-Dawley rats to a restraint stress protocol from gestational day 14 until 21, a critical period for fetal brain susceptibility to stress effects. Male and female offspring were subsequently assessed at postnatal day 24 for anxiety- and depressive-like behaviors, and spontaneous social interaction. We also assessed maternal behaviors and two stress markers: basal vs. acute-evoked stress levels of serum corticosterone and body weight gain. Prenatal stress did not affect the maternal behavior, while both female and male offspring had higher body weight gain. On the other hand, lower levels of corticosterone after acute stress stimulation as well as anxiety- and depressive-like behaviors were only evident in stressed males compared to control males. These results suggest that prenatal stress induced sex-specific effects on the hypothalamus-pituitary-adrenal (HPA) axis activity and on behavior during prepuberty. The HPA axis of prenatally stressed male rats was less active compared to control males, as well as they were more anxious and experienced depressive-like behaviors. Our results can be useful to study the neurobiological basis of childhood depression at a pre-clinical level. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Lipopolysaccharide-induced brain activation of the indoleamine 2,3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome.

PubMed

Dinel, Anne-Laure; André, Caroline; Aubert, Agnès; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie

2014-02-01

Although peripheral low-grade inflammation has been associated with a high incidence of mood symptoms in patients with metabolic syndrome (MetS), much less is known about the potential involvement of brain activation of cytokines in that context. Recently we showed in a mouse model of MetS, namely the db/db mice, an enhanced hippocampal inflammation associated with increased anxiety-like behavior (Dinel et al., 2011). However, depressive-like behavior was not affected in db/db mice. Based on the strong association between depressive-like behavior and cytokine-induced brain activation of indoleamine 2,3-dioxygenase (IDO), the enzyme that metabolizes tryptophan along the kynurenine pathway, these results may suggest an impairment of brain IDO activation in db/db mice. To test this hypothesis, we measured the ability of db/db mice and their healthy db/+ littermates to enhance brain IDO activity and depressive-like behavior after a systemic immune challenge with lipopolysaccharide (LPS). Here we show that LPS (5 μg/mouse) significantly increased depressive-like behavior (increased immobility time in a forced-swim test, FST) 24h after treatment in db/+ mice, but not in db/db mice. Interestingly, db/db mice also displayed after LPS treatment blunted increase of brain kynurenine/tryptophan ratio compared to their db/+ counterparts, despite enhanced induction of hippocampal cytokine expression (interleukin-1β, tumor necrosis factor-α). Moreover, this was associated with an impaired effect of LPS on hippocampal expression of the brain-derived neurotrophic factor (BDNF) that contributes to mood regulation, including under inflammatory conditions. Collectively, these data indicate that the rise in brain tryptophan catabolism and depressive-like behavior induced by innate immune system activation is impaired in db/db mice. These findings could have relevance in improving the management and treatment of inflammation-related complications in MetS. Copyright © 2013 Elsevier Ltd. All rights reserved.

Learned helplessness and social avoidance in the Wistar-Kyoto rat

PubMed Central

Nam, Hyungwoo; Clinton, Sarah M.; Jackson, Nateka L.; Kerman, Ilan A.

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague–Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression. PMID:24744709

Learned helplessness and social avoidance in the Wistar-Kyoto rat.

PubMed

Nam, Hyungwoo; Clinton, Sarah M; Jackson, Nateka L; Kerman, Ilan A

2014-01-01

The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague-Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression.

Adolescent recognition of parental affect: influence of depressive symptoms.

PubMed

Ehrmantrout, Nikki; Allen, Nicholas B; Leve, Craig; Davis, Betsy; Sheeber, Lisa

2011-08-01

This study examined depressive biases in adolescents' labeling of parental affect. Adolescents (151 girls; 82 boys) and their parents engaged in videotaped problem-solving interactions. Adolescents then participated in a video-mediated recall procedure in which they watched the videotaped interaction and indicated how they thought their parents were feeling. Indices of parents' affect during the problem-solving interactions were also provided by parent self-report and behavioral observations. Adolescent depressive symptoms were associated with overreporting of parental aggressive affect and underreporting of parental happy and neutral affects, relative to both directly observed and self-reported parental affect. Depressive symptoms were not associated with overreporting of parental dysphoric affect. Given the importance of accurately reading affective cues for negotiating interpersonal interactions, these findings likely have implications for understanding processes that contribute to adverse relationships among the families of adolescents with depressive symptoms. © 2011 American Psychological Association

Neonatal blockade of GABA-A receptors alters behavioral and physiological phenotypes in adult mice.

PubMed

Salari, Ali-Akbar; Amani, Mohammad

2017-04-01

Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Impairments in the Initiation of Maternal Behavior in Oxytocin Receptor Knockout Mice

PubMed Central

Rich, Megan E.; deCárdenas, Emily J.; Lee, Heon-Jin; Caldwell, Heather K.

2014-01-01

Oxytocin (Oxt) acting through its single receptor subtype, the Oxtr, is important for the coordination of physiology and behavior associated with parturition and maternal care. Knockout mouse models have been helpful in exploring the contributions of Oxt to maternal behavior, including total body Oxt knockout (Oxt −/−) mice, forebrain conditional Oxtr knockout (Oxtr FB/FB) mice, and total body Oxtr knockout (Oxtr −/−) mice. Since Oxtr −/− mice are unable to lactate, maternal behavior has only been examined in virgin females, or in dams within a few hours of parturition, and there have been no studies that have examined their anxiety-like and depression-like behavior following parturition. To improve our understanding of how the absence of Oxt signaling affects maternal behavior, mood and anxiety, we designed a study using Oxtr −/− mice that separated nursing behavior from other aspects of maternal care, such as licking and grooming by thelectomizing (i.e. removing the nipples) of Oxtr +/+ mice and sham-thelectomizing Oxtr −/− mice, and pairing both genotypes with a wet nurse. We then measured pup abandonment, maternal behavior, and postpartum anxiety-like and depression-like behaviors. We hypothesized that genetic disruption of the Oxtr would impact maternal care, mood and anxiety. Specifically, we predicted that Oxtr −/− dams would have impaired maternal care and increased anxiety-like and depression-like behaviors in the postpartum period. We found that Oxtr −/− dams had significantly higher levels of pup abandonment compared to controls, which is consistent with previous work in Oxtr FB/FB mice. Interestingly, Oxtr −/− dams that initiated maternal care did not differ from wildtype controls in measures of maternal behavior. We also did not find any evidence of altered anxiety-like or depressive-like behavior in the postpartum period of Oxtr −/− dams. Thus, our data suggest that Oxt lowers the threshold for the initiation of maternal behavior. PMID:24892749

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats.

PubMed

Zhang, Xiaosong; Wang, Qi; Wang, Yan; Hu, Jingmin; Jiang, Han; Cheng, Wenwen; Ma, Yuchao; Liu, Mengxi; Sun, Anji; Zhang, Xinxin; Li, Xiaobai

2016-12-01

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Loss of Ahi1 Impairs Neurotransmitter Release and Causes Depressive Behaviors in Mice

PubMed Central

Zhai, Lijing; Sun, Miao; Miao, Zhigang; Li, Jizhen; Xu, Xingshun

2014-01-01

Major depression is becoming one of the most prevalent forms of psychiatric disorders. However, the mechanisms of major depression are still not well-understood. Most antidepressants are only effective in some patients and produce some serious side effects. Animal models of depression are therefore essential to unravel the mechanisms of depression and to develop novel therapeutic strategies. Our previous studies showed that Abelson helper integration site-1 (Ahi1) deficiency causes depression-like behaviors in mice. In this study, we characterized the biochemical and behavioral changes in Ahi1 knockout (KO) mice. In Ahi1 KO mice, neurotransmitters including serotonin and dopamine were significantly decreased in different brain regions. However, glutamate and GABA levels were not affected by Ahi1 deficiency. The antidepressant imipramine attenuated depressive behaviors and partially restored brain serotonin level in Ahi1 KO mice. Our findings suggest that Ahi1 KO mice can be used for studying the mechanisms of depression and screening therapeutic targets. PMID:24691070

Depression and substance use comorbidity: What we have learned from animal studies.

PubMed

Ng, Enoch; Browne, Caleb J; Samsom, James N; Wong, Albert H C

2017-07-01

Depression and substance use disorders are often comorbid, but the reasons for this are unclear. In human studies, it is difficult to determine how one disorder may affect predisposition to the other and what the underlying mechanisms might be. Instead, animal studies allow experimental induction of behaviors relevant to depression and drug-taking, and permit direct interrogation of changes to neural circuits and molecular pathways. While this field is still new, here we review animal studies that investigate whether depression-like states increase vulnerability to drug-taking behaviors. Since chronic psychosocial stress can precipitate or predispose to depression in humans, we review studies that use psychosocial stressors to produce depression-like phenotypes in animals. Specifically, we describe how postweaning isolation stress, repeated social defeat stress, and chronic mild (or unpredictable) stress affect behaviors relevant to substance abuse, especially operant self-administration. Potential brain changes mediating these effects are also discussed where available, with an emphasis on mesocorticolimbic dopamine circuits. Postweaning isolation stress and repeated social defeat generally increase acquisition or maintenance of drug self-administration, and alter dopamine sensitivity in various brain regions. However, the effects of chronic mild stress on drug-taking have been much less studied. Future studies should consider standardizing stress-induction protocols, including female subjects, and using multi-hit models (e.g. genetic vulnerabilities and environmental stress).

Suicidal behavior, negative affect, gender, and self-reported delinquency in college students.

PubMed

Langhinrichsen-Rohling, Jennifer; Arata, Catalina; Bowers, David; O'Brien, Natalie; Morgan, Allen

2004-01-01

The associations among suicidal behavior, negative affect, and delinquency were assessed via an anonymous self-report survey administered to male and female college students ( N = 383). Contrary to our hypothesized results, there were no gender differences in rates of suicidal ideation and attempts. Confirming our hypotheses about gender differences, college men did report significantly more delinquent behavior than college women. College men also scored higher on the suicide-proneness scale, which contained a mixture of death-related, risk-related, and negative self- and health-related items. Furthermore, as predicted, college students with a history of depression, suicide ideation, and/or suicide attempts all reported significantly more delinquent behavior. Self-reported delinquency and current levels of depressive symptomology emerged as significant predictors of suicide-prone behavior for both college men and women, explaining 34% of the variance for women and 17% for men. Levels of engagement in suicide-prone behavior and feelings of depression were elevated in college students with any type of juvenile arrest history. Students with an arrest history were also more likely to have had a diagnosis of depression and to have engaged in suicide ideation in their past. These findings suggest there are complex links between depression, delinquency, and suicidal behavior in college men and women.

Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.

PubMed

Zhang, Zhuan; Hong, Juan; Zhang, Suyun; Zhang, Tingting; Sha, Sha; Yang, Rong; Qian, Yanning; Chen, Ling

2016-04-01

Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Intranasal Immune Challenge Induces Sex-Dependent Depressive-Like Behavior and Cytokine Expression in the Brain

PubMed Central

Tonelli, Leonardo H; Holmes, Andrew; Postolache, Teodor T

2007-01-01

The association between activation of the immune system and mood disorders has been reported by several studies. However, the mechanisms by which the immune system affects mood are only partially understood. In the present study, we detected depressive-like behavior in a rat animal model which involves the induction of inflammation in the nasal cavities by intranasal (i.n.) instillation of bacterial lipopolysaccharides (LPS). Female rats showed depressive-like behavior as evidenced by the forced swim test after repeated i.n. administration of LPS. These responses were not paralleled by alterations in motor activity as measured by the open field test. In the same animals, corticosterone responses after the swimming sessions were the highest of all the groups evaluated. Real-time RT PCR was used to analyze the transcriptional regulation of the cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 in several brain regions. Increased tumor necrosis factor-α was detected in the hippocampus and brainstem of female rats challenged with i.n. LPS. These results suggest that peripheral inflammation in the upper respiratory tract is an immune challenge capable of inducing depressive-like behavior, promoting exaggerated glucocorticoid responses to stress, and increasing cytokine transcription in the brain. These results further our understanding of the role that the immune system may play in the pathophysiology of depression. PMID:17593929

Induction of innate immune genes in brain create the neurobiology of addiction.

PubMed

Crews, F T; Zou, Jian; Qin, Liya

2011-06-01

Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy. Copyright © 2011 Elsevier Inc. All rights reserved.

Induction of Innate Immune Genes in Brain Create the Neurobiology of Addiction

PubMed Central

Crews, FT; Zou, Jian; Qin, Liya

2013-01-01

Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy. PMID:21402143

Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice.

PubMed

Cheng, Jie; Dong, Shuqi; Yi, Litao; Geng, Di; Liu, Qing

2018-06-01

Magnolol, the main constituent of Magnolia officinalis, has been shown to produce antidepressant-like effect in rodents. Growing evidence shows that neuroinflammation, oxidative stress and neuroendocrine contribute to the pathogenesis of major depression. Here, the aim of this present study was to determine whether magnolol affected these systems in mice exposed to chronic mild stress (CMS). The ameliorative effect of magnolol on depressive-like symptoms was investigated through behavioral tests, including the classical sucrose preference and forced swimming tests. The behavioral evaluation showed that magnolol reversed the depressive-like deficits both in sucrose preference test and forced swimming test. The elevation of prefrontal cortex pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was decreased by magnolol. Consistently, the microglia activation by CMS was also alleviated by magnolol. In addition, the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CMS was attenuated by magnolol. Moreover, the increased lipid peroxidation such as malonaldehyde (MDA) and decreased antioxidant defense enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) induced by CMS were also reversed by magnolol. These findings suggest that administration of magnolol could alleviate depressive-like behaviors in CMS mice that are mediated by suppressing neuroinflammation and oxidative stress in the prefrontal cortex. Copyright © 2018 Elsevier B.V. All rights reserved.

The effects of central pro-and anti-inflammatory immune challenges on depressive-like behavior induced by chronic forced swim stress in rats.

PubMed

Pan, Yuqin; Lin, Wenjuan; Wang, Weiwen; Qi, Xiaoli; Wang, Donglin; Tang, Mingming

2013-06-15

Although increasing evidence demonstrates that both chronic stressors and inflammatory immune activation contribute to pathophysiology and behavioral alterations associated with major depression, little is known about the interaction effect of central inflammatory immune activation and stress on depressive-like behavior. Our previous work has shown that 14-day chronic forced swim stress induces significant depressive-like behavior. The present investigation assessed whether pro-inflammatory cytokine and anti-inflammatory cytokine challenges have differential interaction effect on depressive-like behavior induced by chronic forced swim stress in rats. The pro-inflammatory and anti-inflammatory immune challenges were achieved respectively by central administration of lipopolysaccharide (LPS), a pro-inflammatory cytokine inducer, and interleukin-10 (IL-10), an anti-inflammatory cytokine. It was found that either central LPS treatment alone or chronic forced swim stress alone significantly induced depressive-like behavior, including reduced body weight gain, reduced saccharin preference and reduced locomotor activity. However, there was no significant synergistic or additive effect of central LPS treatment and stress on depressive-like behavior. LPS treatment did not exacerbate the depressive-like behavior induced by forced swim stress. Nevertheless, IL-10 reversed depressive-like behavior induced by forced swim stress, a finding indicating that IL-10 has antidepressant effect on behavioral depression induced by stress. The present findings provide new insight into the complexity of the immunity-inflammation hypothesis of depression. Copyright © 2013 Elsevier B.V. All rights reserved.

Baicalin Modulates APPL2/Glucocorticoid Receptor Signaling Cascade, Promotes Neurogenesis, and Attenuates Emotional and Olfactory Dysfunctions in Chronic Corticosterone-Induced Depression.

PubMed

Gao, Chong; Du, Qiaohui; Li, Wenting; Deng, Ruixia; Wang, Qi; Xu, Aimin; Shen, Jiangang

2018-04-19

Olfactory dysfunction is often accompanied with anxiety- and depressive-like behaviors in depressive patients. Impaired neurogenesis in hippocampus and subventricular zone (SVZ)-olfactory bulb (OB) contribute to anxiety- and depressive-like behaviors and olfactory dysfunctions. However, the underlying mechanisms of olfactory dysfunction remain unclear. Our previous study indicates that adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2 (APPL2), could affect the activity and sensitivity of glucocorticoid receptor (GR) and mediate impaired hippocampal neurogenesis, which contribute the development of depression. In the present study, we further identified the roles of APPL2 in olfactory functions. APPL2 Tg mice displayed higher GR activity and less capacity of neurogenesis at olfactory system with less olfactory sensitivity than WT mice, indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits. We then studied the effects of baicalin, a medicinal herbal compound, on modulating APPL2/GR signaling pathway for promoting neurogenesis and antidepressant as well as improving olfactory functions. Baicalin treatment inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ, OB, and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model. Behavioral tests revealed that baicalin attenuated depressive- and anxiety-like behaviors and improve olfactory functions in the chronic depression mouse model and APPL2 Tg mice. Taken together, APPL2 could be a novel therapeutic target for improving depressant-related olfactory dysfunctions and baicalin could inhibit APPL2-mediated GR hyperactivity and promote adult neurogenesis, subsequently releasing depressive and anxiety symptoms and improving olfactory functions for antidepressant therapy.

Edaravone abrogates LPS-induced behavioral anomalies, neuroinflammation and PARP-1.

PubMed

Sriram, Chandra Shaker; Jangra, Ashok; Gurjar, Satendra Singh; Mohan, Pritam; Bezbaruah, Babul Kumar

2016-02-01

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA nick-sensor enzyme that functions at the center of cellular stress response and affects the immune system at several key points, and thus modulates inflammatory diseases. Our previous study demonstrated that lipopolysaccharide (LPS)-induced depressive-like behavior in mice can be ameliorated by 3-aminobenzamide, which is a PARP-1 inhibitor. In the present study we've examined the effect of a free radical scavenger, edaravone pretreatment against LPS-induced anxiety and depressive-like behavior as well as various hippocampal biochemical parameters including PARP-1. Male Swiss albino mice were treated with edaravone (3 & 10mg/kgi.p.) once daily for 14days. On the 14th day 30min after edaravone treatment mice were challenged with LPS (1mg/kgi.p.). After 3h and 24h of LPS administration we've tested mice for anxiety and depressive-like behaviors respectively. Western blotting analysis of PARP-1 in hippocampus was carried out after 12h of LPS administration. Moreover, after 24h of LPS administration serum corticosterone, hippocampal BDNF, oxido-nitrosative stress and pro-inflammatory cytokines were estimated by ELISA. Results showed that pretreatment of edaravone (10mg/kg) ameliorates LPS-induced anxiety and depressive-like behavior. Western blotting analysis showed that LPS-induced anomalous expression of PARP-1 significantly reverses by the pretreatment of edaravone (10mg/kg). Biochemical analyses revealed that LPS significantly diminishes BDNF, increases pro-inflammatory cytokines and oxido-nitrosative stress in the hippocampus. However, pretreatment with edaravone (10mg/kg) prominently reversed all these biochemical alterations. Our study emphasized that edaravone pretreatment prevents LPS-induced anxiety and depressive-like behavior, mainly by impeding the inflammation, oxido-nitrosative stress and PARP-1 overexpression. Copyright © 2015. Published by Elsevier Inc.

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

PubMed Central

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID:26114099

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression.

PubMed

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan; Cheng, Tain-Junn; Chuu, Jiunn-Jye

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision.

PubMed

Bentea, Eduard; Demuyser, Thomas; Van Liefferinge, Joeri; Albertini, Giulia; Deneyer, Lauren; Nys, Julie; Merckx, Ellen; Michotte, Yvette; Sato, Hideyo; Arckens, Lutgarde; Massie, Ann; Smolders, Ilse

2015-06-03

There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical features and psychiatric comorbidities of borderline personality disorder patients with versus without a history of suicide attempt.

PubMed

Sher, Leo; Fisher, Amanda M; Kelliher, Caitlin H; Penner, Justin D; Goodman, Marianne; Koenigsberg, Harold W; New, Antonia S; Siever, Larry J; Hazlett, Erin A

2016-12-30

Patients with borderline personality disorder (BPD) are at high risk for suicidal behavior. However, many BPD patients do not engage in suicidal behavior. In this study, we compared clinical features of BPD patients with or without a history of suicide attempts and healthy volunteers. Compared with healthy volunteers, both BPD groups had higher Affective Lability Scale (ALS), ALS - Depression-Anxiety Subscale, Barratt Impulsivity Scale (BIS), and Lifetime History of Aggression (LHA) scores and were more likely to have a history of temper tantrums. BPD suicide attempters had higher ALS, ALS - Depression-Anxiety Subscale and LHA scores and were more likely to have a history of non-suicidal self-injury or temper tantrums compared to BPD non-attempters. Also, BPD suicide attempters were more likely to have a history of comorbid major depressive disorder and less likely to have comorbid narcissistic personality disorder (NPD) in comparison to BPD non-attempters. About 50% of study participants in each BPD group had a history of comorbid substance use disorder (SUD). Our study indicates that BPD patients with a history of suicide attempt are more aggressive, affectively dysregulated and less narcissistic than BPD suicide non-attempters. Published by Elsevier Ireland Ltd.

ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer's disease.

PubMed

Esmaeili, Mohammad Hossein; Bahari, Behnam; Salari, Ali-Akbar

2018-03-01

Affective disorders including depression and anxiety are among the most prevalent behavioral abnormalities in patients with Alzheimer's disease (AD), which affect the quality of life and progression of the disease. Dysregulation of the hypothalamic-pituitary-adrenal-(HPA) axis has been reported in affective disorders and AD. Recent studies revealed that current antidepressant drugs are not completely effective for treating anxiety- and depression-related disorders in people with dementia. ATP-sensitive-potassium-(K ATP ) channels are well-known to be involved in AD pathophysiology, HPA axis function and the pathogenesis of depression and anxiety-related behaviors. Thus, targeting of K ATP channel may be a potential therapeutic strategy in AD. Hence, we investigated the effects of intracerebroventricular injection of Aβ25-35 alone or in combination with glibenclamide, K ATP channel inhibitor on depression- and anxiety-related behaviors as well as HPA axis response to stress in rats. To do this, non-Aβ25-35- and Aβ25-35-treated rats were orally treated with glibenclamide, then the behavioral consequences were assessed using sucrose preference, forced swim, light-dark box and plus maze tests. Stress-induced corticosterone levels following forced swim and plus maze tests were also evaluated as indicative of abnormal HPA-axis-function. Aβ25-35 induced HPA axis hyperreactivity and increased depression- and anxiety-related symptoms in rats. Our results showed that blockade of K ATP channels with glibenclamide decreased depression- and anxiety-related behaviors by normalizing HPA axis activity in Aβ25-35-treated rats. This study provides additional evidence that Aβ administration can induce depression- and anxiety-like symptoms in rodents, and suggests that K ATP channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Depression-like behavior and stressor-induced neuroendocrine activation in female prairie voles exposed to chronic social isolation

PubMed Central

Grippo, Angela J.; Cushing, Bruce S.; Carter, C. Sue

2010-01-01

Objective Previous evidence suggests that responses to social stressors may play a mechanistic role in the behavioral and physiological changes associated with affective disorders such as depression. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that share features of social behavior with humans, and therefore might provide a useful model for examining social regulation of behaviors and physiological responses related to depression. In the present study we hypothesized that social isolation in female prairie voles would induce depression-relevant behaviors and altered neuroendocrine responses to an acute social stressor. Methods Twenty adult female prairie voles were exposed to either 60 days of social isolation or paired (control) housing, and tested for a depression-like behavior (anhedonia), numbers of corticotropin-releasing factor- and oxytocin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and circulating levels of hormones and peptide in response to an acute social stressor (resident-intruder test). Results Chronic social isolation produced anhedonia, measured by a reduction in sucrose intake and sucrose preference relative to paired animals. Compared to paired animals, isolated prairie voles displayed increased plasma hormone and peptide levels (oxytocin, arginine vasopressin, and corticosterone) following a 5-minute resident-intruder test, mirrored by an increased number of oxytocin- and corticotropin-releasing factor-immunoreactive cells in the hypothalamic paraventricular nucleus. Conclusions These findings suggest that isolation in a socially monogamous rodent model induces both behavioral and neuroendocrine changes that are relevant to depression, and may provide insight into the mechanisms that underlie the development and/or maintenance of depressive disorders in humans. PMID:17289829

Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats.

PubMed

Ferguson, Sherry A; Cisneros, F Javier; Gough, B; Hanig, Joseph P; Berry, Kimberly J

2005-10-01

Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression.

Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress.

PubMed

Azman, Khairunnuur Fairuz; Zakaria, Rahimah; AbdAziz, CheBadariah; Othman, Zahiruddin; Al-Rahbi, Badriya

2015-01-01

Recent evidence has exhibited dietary influence on the manifestation of different types of behavior induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of stress-related behaviors in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following four groups: i) nonstressed with vehicle, ii) nonstressed with Tualang honey, iii) stressed with vehicle, and iv) stressed with honey. The supplement was given once daily via oral gavage at 0.2 g/kg body weight. Two types of behavioral tests were performed, namely, the novel object recognition test to evaluate working memory and the forced swimming test to evaluate depressive-like behavior. Data were analyzed by a two-way analysis of variance (ANOVA) using IBM SPSS 18.0. It was observed that the rats subjected to noise stress expressed higher levels of depressive-like behavior and lower memory functions compared to the unexposed control rats. In addition, our results indicated that the supplementation regimen successfully counteracted the effects of noise stress. The forced swimming test indicated that climbing and swimming times were significantly increased and immobility times significantly decreased in honey-supplemented rats, thereby demonstrating an antidepressant-like effect. Furthermore, cognitive function was shown to be intensely affected by noise stress, but the effects were counteracted by the honey supplement. These findings suggest that subchronic exposure to noise stress induces depressive-like behavior and reduces cognitive functions, and that these effects can be attenuated by Tualang honey supplementation. This warrants further studies to examine the role of Tulang honey in mediating such effects.

Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress

PubMed Central

Azman, Khairunnuur Fairuz; Zakaria, Rahimah; AbdAziz, CheBadariah; Othman, Zahiruddin; Al-Rahbi, Badriya

2015-01-01

Recent evidence has exhibited dietary influence on the manifestation of different types of behavior induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of stress-related behaviors in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following four groups: i) nonstressed with vehicle, ii) nonstressed with Tualang honey, iii) stressed with vehicle, and iv) stressed with honey. The supplement was given once daily via oral gavage at 0.2 g/kg body weight. Two types of behavioral tests were performed, namely, the novel object recognition test to evaluate working memory and the forced swimming test to evaluate depressive-like behavior. Data were analyzed by a two-way analysis of variance (ANOVA) using IBM SPSS 18.0. It was observed that the rats subjected to noise stress expressed higher levels of depressive-like behavior and lower memory functions compared to the unexposed control rats. In addition, our results indicated that the supplementation regimen successfully counteracted the effects of noise stress. The forced swimming test indicated that climbing and swimming times were significantly increased and immobility times significantly decreased in honey-supplemented rats, thereby demonstrating an antidepressant-like effect. Furthermore, cognitive function was shown to be intensely affected by noise stress, but the effects were counteracted by the honey supplement. These findings suggest that subchronic exposure to noise stress induces depressive-like behavior and reduces cognitive functions, and that these effects can be attenuated by Tualang honey supplementation. This warrants further studies to examine the role of Tulang honey in mediating such effects. PMID:25774610

Resident intruder paradigm-induced aggression relieves depressive-like behaviors in male rats subjected to chronic mild stress

PubMed Central

Wei, Sheng; Ji, Xiao-wei; Wu, Chun-ling; Li, Zi-fa; Sun, Peng; Wang, Jie-qiong; Zhao, Qi-tao; Gao, Jie; Guo, Ying-hui; Sun, Shi-guang; Qiao, Ming-qi

2014-01-01

Background Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that the resident intruder paradigm (RIP) results in aggressive behavior in male rats. However, it is not known how resident intruder paradigm-induced aggression affects depressive-like behavior in isolated male rats subjected to chronic mild stress (CMS), which is an animal model of depression. Material/Methods Male Wistar rats were divided into 3 groups: non-stressed controls, isolated rats subjected to the CMS protocol, and resident intruder paradigm-exposed rats subjected to the CMS protocol. Results In the sucrose intake test, ingestion of a 1% sucrose solution by rats in the CMS group was significantly lower than in control and CMS+RIP rats after 3 weeks of stress. In the open-field test, CMS rats had significantly lower open-field scores compared to control rats. Furthermore, the total scores given the CMS group were significantly lower than in the CMS+RIP rats. In the forced swimming test (FST), the immobility times of CMS rats were significantly longer than those of the control or CMS+RIP rats. However, no differences were observed between controls and CMS+RIP rats. Conclusions Our data show that aggressive behavior evoked by the resident intruder paradigm could relieve broad-spectrum depressive-like behaviors in isolated adult male rats subjected to CMS. PMID:24911067

Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress.

PubMed

Francis, T Chase; Chandra, Ramesh; Friend, Danielle M; Finkel, Eric; Dayrit, Genesis; Miranda, Jorge; Brooks, Julie M; Iñiguez, Sergio D; O'Donnell, Patricio; Kravitz, Alexxai; Lobo, Mary Kay

2015-02-01

The nucleus accumbens is a critical mediator of depression-related outcomes to social defeat stress. Previous studies demonstrate distinct neuroplasticity adaptations in the two medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 versus dopamine receptor D2, in reward and reinforcement leading to opposing roles for these MSNs in these behaviors. However, the distinct roles of nucleus accumbens MSN subtypes, in depression, remain poorly understood. Using whole-cell patch clamp electrophysiology, we examined excitatory input to MSN subtypes and intrinsic excitability measures in D1-green fluorescent protein and D2-green fluorescent protein bacterial artificial chromosome transgenic mice that underwent chronic social defeat stress (CSDS). Optogenetic and pharmacogenetic approaches were used to bidirectionally alter firing of D1-MSNs or D2-MSNs after CSDS or before a subthreshold social defeat stress in D1-Cre or D2-Cre bacterial artificial chromosome transgenic mice. We demonstrate that the frequency of excitatory synaptic input is decreased in D1-MSNs and increased in D2-MSNs in mice displaying depression-like behaviors after CSDS. Enhancing activity in D1-MSNs results in resilient behavioral outcomes, while inhibition of these MSNs induces depression-like outcomes after CSDS. Bidirectional modulation of D2-MSNs does not alter behavioral responses to CSDS; however, repeated activation of D2-MSNs in stress naïve mice induces social avoidance following subthreshold social defeat stress. Our studies uncover novel functions of MSN subtypes in depression-like outcomes. Notably, bidirectional alteration of D1-MSN activity promotes opposite behavioral outcomes to chronic social stress. Therefore, targeting D1-MSN activity may provide novel treatment strategies for depression or other affective disorders. Copyright © 2015 Society of Biological Psychiatry. All rights reserved.

Naproxen Attenuates Sensitization of Depressive-Like Behavior and Fever during Maternal Separation

PubMed Central

Hennessy, Michael B.; Stafford, Nathan P.; Yusko-Osborne, Brittany; Schiml, Patricia A.; Xanthos, Evan D.; Deak, Terrence

2014-01-01

Early life stress can increase susceptibility for later development of depressive illness though a process thought to involve inflammatory mediators. Isolated guinea pig pups exhibit a passive, depressive-like behavioral response and fever that appear mediated by proinflammatory activity, and which sensitize with repeated separations. Treatment with an anti-inflammatory can attenuate the behavioral response during the initial separation and separation the following day. Here we used the cyclooxygenase inhibitor naproxen to examine the role of prostaglandins in mediating the depressive-like behavior and core body temperature of young guinea pigs during an initial separation, separation the next day, and separation 10 days after the first. The passive, depressive-like behavior as well as fever sensitized with repeated separation. Three days of injection with 14 mg/kg of naproxen prior to the initial separation reduced depressive-like behavior during all three separations. A 28 mg/kg dose of naproxen, however, had minimal effect on behavior. Fever during the early separations was moderated by naproxen, but only at the higher dose. These results suggest a role of prostaglandins in the behavioral and febrile response to maternal separation, and particularly in the sensitization of depressive-like behavior following repeated separation. PMID:25449392

Methyl jasmonate attenuated lipopolysaccharide-induced depressive-like behaviour in mice.

PubMed

Adebesin, Adaeze; Adeoluwa, Olusegun A; Eduviere, Anthony T; Umukoro, Solomon

2017-11-01

Depression is a recurrent neuropsychiatric disorder that affects millions of individuals worldwide and impact negatively on the patients' social functions and quality of life. Studies have shown that i.p injection of lipopolysaccharide (LPS) induces depressive-like behavior in rodents via induction of oxidative stress and neuroinflammation. Methyl jasmonate (MJ), an isolated compound from jasmine plant has gained reputation in aromatherapy for treatment of depression, nervousness and memory deficits. This study was designed to evaluate the effects of MJ on LPS-induced depressive-like behavior in mice. Mice were given MJ (5-20 mg/kg), imipramine (10 mg/kg) or vehicle (10 mL/kg) intraperitoneally for 7 consecutive days. On day 7, treatment was carried out 30 min prior to i.p injection of LPS (830 μg/kg). Twenty four hours after LPS administration, tail suspension, forced swim and sucrose preference tests were carried out. Thereafter, serum corticosterone levels were determined using ELISA. The levels of malondialdehyde (MDA), glutathione (GSH) and tumor necrosis factor-alpha (TNF-α) were determined in brain tissue homogenates. LPS significantly increased immobility time in the tail suspension and forced swim tests when compared with vehicle (p < 0.05), which indicates depressive-like syndromes. However, the increased immobility time was significantly reduced by MJ (5-20 mg/kg) when compared with LPS-treated group. LPS administration also altered the levels of MDA, GSH, corticosterone and TNF alpha in mice, which was significantly reversed by MJ. These findings suggest that attenuation of LPS-induced depressive-like behavior by MJ may be related to suppression of oxidative stress and release of TNF alpha. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early social enrichment provided by communal nest increases resilience to depression-like behavior more in female than in male mice.

PubMed

D'Andrea, Ivana; Gracci, Fiorenza; Alleva, Enrico; Branchi, Igor

2010-12-20

Early experiences produce persistent changes in behavior and brain function. Being reared in a communal nest (CN), consisting of a single nest where three mouse mothers keep their pups together and share care-giving behavior from birth to weaning, provides an highly stimulating social environment to the developing pup since both mother-offspring and peer-to-peer interactions are markedly increased. Here we show that being reared in a CN affects adult behavior of CD-1 mice in a gender-dependent fashion, with reduced depression-like responses in females and increased anxiety-like behavior in males. In particular, CN females showed higher sucrose preference at baseline condition, drinking more sweet solution compared to female mice reared in a standard laboratory condition (SN). In the isolation test, both SN and CN females showed a reduction in sucrose preference after exposure to isolation stress. However, after 24h, only CN females significantly recovered. Finally, in the forced swim test, compared to SN, CN females spent longer time floating, a behavioral response that in the CN model has been inversely associated with display of endophenotypes of depression. With regard to the emotional response, CN males displayed an increased anxiety-like behavior in comparison to SN, spending less time in the open arms and displaying reduced head-dippings in the elevated plus-maze test. No difference was found in females. Overall, our findings show that gender and early experiences interact in modulating adult behavior. In particular, we show that early experiences modified developmental trajectories shaping adult endophenotypes of depression more markedly in females than in males. Copyright 2010 Elsevier B.V. All rights reserved.

Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats

PubMed Central

Weiser, Michael J.; Wynalda, Kelly; Salem, Norman; Butt, Christopher M.

2015-01-01

DHA is an important omega-3 PUFA that confers neurodevelopmental benefits. Sufficient omega-3 PUFA intake has been associated with improved mood-associated measures in adult humans and rodents, but it is unknown whether DHA specifically influences these benefits. Furthermore, the extent to which development and puberty interact with the maternal diet and the offspring diet to affect mood-related behaviors in adolescence is poorly understood. We sought to address these questions by 1) feeding pregnant rats with diets sufficient or deficient in DHA during gestation and lactation; 2) weaning their male offspring to diets that were sufficient or deficient in DHA; and 3) assessing depression-related behaviors (forced swim test), plasma biomarkers [brain-derived neurotrophic factor (BDNF), serotonin, and melatonin], and brain biomarkers (BDNF) in the offspring before and after puberty. No dietary effects were detected when the offspring were evaluated before puberty. In contrast, after puberty depressive-like behavior and its associated biomarkers were worse in DHA-deficient offspring compared with animals with sufficient levels of DHA. The findings reported here suggest that maintaining sufficient DHA levels throughout development (both pre- and postweaning) may increase resiliency to emotional stressors and decrease susceptibility to mood disorders that commonly arise during adolescence. PMID:25411442

Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation.

PubMed

André, Caroline; Dinel, Anne-Laure; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie

2014-10-01

Obesity is associated with a high prevalence of mood symptoms and cognitive dysfunctions that emerges as significant risk factors for important health complications such as cardiovascular diseases and type 2 diabetes. It is therefore important to identify the dynamic of development and the pathophysiological mechanisms underlying these neuropsychiatric symptoms. Obesity is also associated with peripheral low-grade inflammation and increased susceptibility to immune-mediated diseases. Excessive production of proinflammatory cytokines and the resulting activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been shown to promote neurobehavioral complications, particularly depression. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations and the increased susceptibility to immune-mediated diseases displayed by obese patients, particularly through brain IDO activation. To answer these questions, we used C57Bl/6 mice exposed to standard diet or western diet (WD; consisting of palatable energy-dense food) since weaning and for 20 weeks. We then measured inflammatory and behavioral responses to a systemic immune challenge with lipopolysaccharide (LPS) in experimental conditions known to alter cognitive and emotional behaviors independently of any motor impairment. We first showed that in absence of LPS, 9 weeks of WD is sufficient to impair spatial recognition memory (in the Y-maze). On the other hand, 18 weeks of WD increased anxiety-like behavior (in the elevated plus-maze), but did not affect depressive-like behavior (in the tail-suspension and forced-swim tests). However, 20 weeks of WD altered LPS-induced depressive-like behavior compared to LPS-treated lean mice and exacerbated hippocampal and hypothalamic proinflammatory cytokine expression and brain IDO activation. Taken together, these results show that WD exposure alters cognition and anxiety in unstimulated conditions and enhances activation of neurobiological mechanisms underlying depression after immune stimulation. They suggest therefore that obesity, and possibly obesity-associated inflammatory priming, may represent a vulnerability state to immune-mediated depressive symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease

PubMed Central

Karl, Franziska; Sommer, Claudia; Üçeyler, Nurcan

2017-01-01

Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. PMID:28662189

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

PubMed Central

Notaras, M; Du, X; Gogos, J; van den Buuse, M; Hill, R A

2017-01-01

The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. PMID:28926000

Postnatal cocaine exposure: effects on behavior of rats in forced swim test.

PubMed

Magalhães, Ana; Tavares, Maria Amélia; de Sousa, Liliana

2002-06-01

Exposure to cocaine in early periods of postnatal life has adverse effects on behavior, namely, it induces the display of anxiety and fear-like behaviors that are associated with stress and depression. This study examined the effects of early developmental cocaine exposure in several categories of behavior observed in forced swim test. Male and female Wistar rats were given 15 mg/kg of cocaine hydrochloride/body weight/day, subcutaneously, in two daily doses, from postnatal day (PND) 1 to PND27. Controls were saline injected in the same protocol. In PND26-PND27, rats were placed in a swimming pool during 5 min in two sessions. The categories of behavior studied in this work included horizontal and vertical rotation, vibrissae clean, head clean, fast and slow swim, struggling, floating, sliding, diving, head-diving, and wagging head. Results showed differences in the frequencies of several behavioral categories that allowed the discrimination of the behaviors that may constitute "behavioral despair" indicators, as well as which behaviors are most affected by cocaine exposure. Cocaine groups were less active and more immobile than controls. These results suggest that postnatal exposure to cocaine can produce depression-like effects and affect the ability of these animals to cope with stress situations.

Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice

PubMed Central

Hamer, Mary; Semple, Bridgette D.; Noble-Haeusslein, Linda J.; Baghchechi, Mohsen; Hiroto, Alex; Hartman, Richard E.; Obenaus, André

2016-01-01

Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi). CCI animals showed significant motor and sensory deficits in the early (1–7 dpi) and long-term (90 dpi) stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI. PMID:26796696

Effects of adrenal cortex hormones on limbic structures: some experimental and clinical correlations related to depression.

PubMed Central

Dubrovsky, B

1993-01-01

Cushing's disorder and depression present overlapping although not identical psychological symptomatology. In turn, a subset of patients with affective disorders present with hypercortisolemia and disturbances, specifically disinhibition, of the hypothalamic hypophysio adrenal axis (HHAA). Memory disturbances, in particular, biasing toward negative contents, overlapping sleep abnormalities (marked reduction of stages 3 and 4) increased fatigue and loss of energy, attentional deficits and irritability, are just part of the common symptomatology presented by patients with both Cushing's disorder and depression. All of these behavioral manifestations are known to be affected by adrenal steroid hormones. There is consensus that hippocampal structures are a main target for adrenal steroid hormones; hence, these neural regions are some of the most likely mediators of the effects of corticoadrenal steroids on behavior. This paper proposes that an imbalance of adrenal steroids and their metabolites may play a fundamental role in the psychophysiopathology of Cushing's and depressive disorders. The imbalance of these hormones, especially at limbic sites, could distort mood and memory content affecting cognition based on recollection and present experiences. Reestablishing an adrenal balance could therefore be considered as a therapeutic aid in a subset of depressive disorders. PMID:8461280

Hippocampal structure and function are maintained despite severe innate peripheral inflammation.

PubMed

Süß, Patrick; Kalinichenko, Liubov; Baum, Wolfgang; Reichel, Martin; Kornhuber, Johannes; Loskarn, Sandra; Ettle, Benjamin; Distler, Jörg H W; Schett, Georg; Winkler, Jürgen; Müller, Christian P; Schlachetzki, Johannes C M

2015-10-01

Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1β, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1β and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1β and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

PubMed Central

Bogdanova, Olena V.; Olson, Paul R.; Sung, Young-Hoon; D'Anci, Kristen E.; Renshaw, Perry F.

2015-01-01

Abstract Kanekar, Shami, Olena V. Bogdanova, Paul R. Olson, Young-Hoon Sung, Kristen E. D'Anci, and Perry F. Renshaw. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not males. High Alt Med Biol 16:52–60, 2015—Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression-like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males. PMID:25803141

Sleep Complaints as Risk Factor for Suicidal Behavior in Severely Depressed Children and Adolescents.

PubMed

Lopes, Maria-Cecilia; Boronat, Alexandre C; Wang, Yuan-Pang; Fu-I, Lee

2016-11-01

To investigate the association between sleep complaints and suicidal behaviors among severely depressed children and adolescents. The sample was 214 youths (56.1% males, mean age 12.5 years) with diagnosis of DSM-IV major depressive disorder consecutively recruited from a university-based outpatient clinic specialized in mood disorders. The structured interview for children and adolescents was applied to participants. The Children's Depression Rating Scale-revised version-scored the severity of depression, and the Children's Global Assessment Scale assessed the global functioning. Subgroups of patients were compared for psychopathological association by means of logistic regression, in accordance with presence and absence of sleep complaints and suicidality. The frequency of sleep complaints and suicidal behaviors was, respectively, 66.4% and 52.3%, and both symptoms were observed in 37.9% of patients. Initial insomnia was the most frequent manifestation (58%), followed by night awakening (36%), daytime sleepiness (31%), and early awakening (29.9%). Significant association between sleep disturbance and suicidal behavior was found (odds ratio range of 2.3-10.8). Sleep disturbances are potential warning manifestations of suicidal behaviors in depressed youth. Possibly, the severity of the active affective episode likely underlies in both sleep complaints and suicidal behaviors among depressed underage patients. © 2016 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice

PubMed Central

Bath, Kevin G.; Chuang, Jocelyn; Spencer-Segal, Joanna L.; Amso, Dima; Altemus, Margaret; McEwen, Bruce S.; Lee, Francis S.

2012-01-01

Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans. PMID:22552045

Voluntary Wheel Running Does not Affect Lipopolysaccharide-Induced Depressive-Like Behavior in Young Adult and Aged Mice

PubMed Central

Martin, Stephen A.; Dantzer, Robert; Kelley, Keith W.; Woods, Jeffrey A.

2014-01-01

Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4-month-old and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (Voluntary Wheel Running, VWR) or no wheel (Standard) for 30 days (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective Standard control groups. VWR had no effect on LPS-induced anorexia, weight-loss, increased immobility in the tail suspension test, and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and twenty-four (aged mice) hours after injection of LPS transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. These results indicate that prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences. PMID:24281669

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration.

PubMed

Ohgi, Yuta; Futamura, Takashi; Kikuchi, Tetsuro; Hashimoto, Kenji

2013-02-01

Accumulating evidence suggests that inflammation may play a role in the pathophysiology of major depressive disorder (MDD). Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), possess anti-inflammatory effects in vitro. Here, we examined the effects of SSRIs and SNRIs on lipopolysaccharide (LPS)-induced inflammation and depressive-like behavior in male mice. A single administration of LPS (0.5mg/kg, i.p.) increased serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNFα) and the anti-inflammatory cytokine, interleukin-10 (IL-10) in mice. Pretreatment with SSRIs (fluoxetine and paroxetine), SNRIs (venlafaxine and duloxetine), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin, attenuated LPS-induced increases in TNFα, whereas it increased serum levels of IL-10, in mice treated with LPS. In the tail suspension test (TST), LPS increased the immobility time without affecting spontaneous locomotor activity, suggesting that LPS induced depressive-like behavior in mice. Treatment with fluoxetine (30 mg/kg) or paroxetine (10mg/kg) significantly shortened LPS-induced increases of immobility time. These results suggested that antidepressants exert anti-inflammatory effects in vivo, and that the serotonergic system may partially mediate these effects. In addition, the anti-inflammatory effects of antidepressants may help alleviate the symptoms of LPS-induced depression in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical profile of depressive disorder in children.

PubMed

Krishnakumar, P; Geeta, M G

2006-06-01

The aim of this retrospective study was to evaluate the risk factors, clinical features and co-morbid disorders of depressive disorder in children below the age of 12 years. Children who attended the child guidance clinic between January 2000 and December 2003 formed the subjects for the study. The diagnosis of depressive disorder was based on DSMIV diagnostic criteria for Major Depressive Disorder, Single episode. There were 26 boys and 19 girls. Stress at school and in the family was significantly associated with depressive disorder. Children with depressive disorder had significantly more family members affected with mental illnesses. The clinical features included diminished interest in play and activities, excessive tiredness, low self- esteem, problems with concentration, multiple somatic complaints, behavior symptoms like anger and aggression, recent deterioration in school performance and suicidal behavior. Majority of children had other associated psychiatric disorders which included dysthymic disorder, anxiety disorders, conduct disorder and conversion disorder.

Somatic-Affective, But Not Cognitive-Depressive Symptoms are Associated With Reduced Health-Related Quality of Life in Patients With Congestive Heart Failure.

PubMed

Patron, Elisabetta; Messerotti Benvenuti, Simone; Lopriore, Vincenzo; Aratari, Jenny; Palomba, Daniela

Depression has been associated with poor health-related quality of life (HRQoL) in patients with congestive heart failure (CHF). However, to date, whether somatic-affective and cognitive-depressive symptoms differently contribute to poor HRQoL and behavioral functional capacity in patients with CHF has yet to be investigated. To examine the differential influence of somatic-affective vs cognitive-depressive symptoms on HRQoL and behavioral functional capacity in CHF patients. Overall, 55 patients with CHF completed a psychologic evaluation, including the Minnesota Living with Heart Failure Questionnaire, the Beck Depression Inventory-II, and the Beck Anxiety Inventory for HRQoL, depressive, and anxiety symptoms, respectively. The patients completed the Instrumental Activities of Daily Living Questionnaire and the 6-minute walk test for behavioral functional capacity. Hierarchical regression analyses were used to predict HRQoL and behavioral functional capacity from Beck Depression Inventory-II and Beck Anxiety Inventory scores. Somatic-affective depressive symptoms were associated with physical (β = 0.37, p = 0.005) and emotional (β = 0.39, p = 0.008) Minnesota Living with Heart Failure Questionnaire subscale scores. Likewise, somatic-affective depressive symptoms predicted Instrumental Activities of Daily Livings Scores (β = 0.43, p = 0.004) and distance ambulated during the 6-minute walk test (β = -0.36, p = 0.029). By contrast, cognitive-depressive symptoms and anxiety were unrelated to HRQoL and behavioral functional capacity (all p > 0.05). These findings showed that somatic-affective depressive symptoms, but not cognitive-depressive symptoms and anxiety, are associated with poor HRQoL and behavioral functional capacity independent of age, clinical functional status, and medical comorbidities. This study suggests that patients with CHF with somatic-affective rather than cognitive-depressive symptoms or anxiety may be at greater risk of poor HRQoL and behavioral functional capacity. Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Mice subjected to uncontrollable electric shocks show depression-like behaviors irrespective of their state of helplessness.

PubMed

Kim, Jin Yong; Yang, Soo Hyun; Kwon, Jihyun; Lee, Hyun Woo; Kim, Hyun

2017-03-30

The unpredictable and inescapable electric shock-induced "learned helplessness" paradigm has long been used to produce an animal model of depression to identify the molecules associated with depressive symptoms or to assess the efficacy of pharmacological treatments for depression. After exposure to unpredictable and inescapable shocks (uncontrollable stress), most of mice showed defect in escape behavior in active avoidance test (learned helplessness, LH), while others did not (non-learned helplessness, NLH). Here, we investigated whether mice with LH or NLH exhibited depressive symptoms, including anhedonia, anxiety, and despair. We found that compared with control naïve mice, both uncontrollable shocks-induced LH and NLH mice showed increased anhedonia- and anxiety- but not despair-like behaviors. Notably, mice subjected to uncontrollable shocks showed similar behaviors, irrespective of whether they also showed LH or NLH. Furthermore, since both LH and NLH mice showed only anhedonia- and anxiety- but not despair-like behaviors, this model may be generally inadequate for classic depression-like behavior assessment. In conclusion, uncontrollable electric shock induces depression-like behavior, irrespective of the state of helplessness. Copyright © 2017 Elsevier B.V. All rights reserved.

Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats.

PubMed

Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Takahashi, Reinaldo N; Bertoglio, Leandro J; Cunha, Rodrigo A; Prediger, Rui D

2016-08-01

The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10 μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7 days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21 days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD.

Chronic Gestational Stress Leads to Depressive-Like Behavior and Compromises Medial Prefrontal Cortex Structure and Function during the Postpartum Period

PubMed Central

Leuner, Benedetta; Fredericks, Peter J.; Nealer, Connor; Albin-Brooks, Christopher

2014-01-01

Postpartum depression, which affects approximately 15% of new mothers, is associated with impaired mother-infant interactions and deficits in cognitive function. Exposure to stress during pregnancy is a major risk factor for postpartum depression. However, little is known about the neural consequences of gestational stress. The medial prefrontal cortex (mPFC) is a brain region that has been linked to stress, cognition, maternal care, and mood disorders including postpartum depression. Here we examined the effects of chronic gestational stress on mPFC function and whether these effects might be linked to structural modifications in the mPFC. We found that in postpartum rats, chronic gestational stress resulted in maternal care deficits, increased depressive-like behavior, and impaired performance on an attentional set shifting task that relies on the mPFC. Furthermore, exposure to chronic stress during pregnancy reduced dendritic spine density on mPFC pyramidal neurons and altered spine morphology. Taken together, these findings suggest that pregnancy stress may contribute to postpartum mental illness and its associated symptoms by compromising structural plasticity in the mPFC. PMID:24594708

Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression.

PubMed

Medel-Matus, Jesús-Servando; Shin, Don; Sankar, Raman; Mazarati, Andrey

2017-12-01

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy-PLB comorbidity. Copyright © 2017 Elsevier Inc. All rights reserved.

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

PubMed Central

Stevenson, Jennie R; Schroeder, Jason P; Nixon, Kimberly; Besheer, Joyce; Crews, Fulton T; Hodge, Clyde W

2010-01-01

Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing that abstinence from voluntary alcohol drinking leads to the emergence of depression-like behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H2O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (ie behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations. PMID:18563059

Female vulnerability to the development of depression-like behavior in a rat model of intimate partner violence is related to anxious temperament, coping responses, and amygdala vasopressin receptor 1a expression.

PubMed

Poirier, G L; Cordero, M I; Sandi, C

2013-01-01

Exposure to violence is traumatic and an important source of mental health disturbance, yet the factors associated with victimization remain incompletely understood. The aim of the present study was to investigate factors related to vulnerability to depression-like behaviors in females. An animal model of intimate partner violence, which was previously shown to produce long-lasting behavioral effects in females as a result of male partner aggression, was used. The associations among the degree of partner aggression, the long-term consequences on depressive-like behavior, and the impact of the anxious temperament of the female were examined. In a separate group, pre-selected neural markers were evaluated in the amygdala and the lateral septum of females. Expression was examined by analyses of targeted candidate genes, serotonin transporter (slc6a4), vasopressin receptor 1a, (avpr1a), and oxytocin receptor (oxtr). Structural equation modeling revealed that the female's temperament moderated depressive-like behavior that was induced by cohabitation aggression from the male partner. More specifically, increased floating in the forced swim test following male aggression was most apparent in females exhibiting more anxiety-like behavior (i.e., less open arm exploration in an elevated plus-maze) prior to the cohabitation. Aggression reduced slc6a4 levels in the lateral septum. However, the interaction between partner aggression and the anxious temperament of the female affected the expression of avpr1a in the amygdala. Although, aggression reduced levels of this marker in females with high anxiety, no such pattern was observed in females with low anxiety. These results identify important characteristics in females that moderate the impact of male aggression. Furthermore, these results provide potential therapeutic targets of interest in the amygdala and the lateral septum to help improve post-stress behavioral pathology and increase resilience to social adversity.

GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality.

PubMed

Anderberg, Rozita H; Richard, Jennifer E; Hansson, Caroline; Nissbrandt, Hans; Bergquist, Filip; Skibicka, Karolina P

2016-03-01

Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Three-Week Isolation Does Not Lead to Depressive-Like Disorders in Rats.

PubMed

Gorlova, A V; Pavlov, D A; Zubkov, E A; Morozova, A Yu; Inozemtsev, A N; Chekhonin, V P

2018-06-19

We studied the effects of social isolation for 1, 2 or 3 weeks on behavioral reactions of male rats. As social isolation is a common model for inducing depressive-like state in rodents, classical tests for depressive-like behavioral features were conducted: Porsolt forced swimming test and tests for anhedonia and social interest. None of the experimental groups showed statistically significant disorders in comparison with the control group kept under standard conditions. Thus, social isolation for up to 3 weeks did not cause behavioral abnormalities in male rats. Single housing can be used in other models of induction of depressive-like states, but the use of this paradigm as an independent model for the development of depressive-like behavior requires longer period of social isolation.

Different effects of vitamin D hormone treatment on depression-like behavior in the adult ovariectomized female rats.

PubMed

Fedotova, Julia; Dudnichenko, Tatyana; Kruzliak, Peter; Puchavskaya, Zhanna

2016-12-01

Vitamine D (VD) has important functions in the human brain and may play a role in affective-related disorders. VD receptors are expressed in multiple brain regions associated with depressive disorders. The aim of the preclinical study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0mg/kg/day,s.c., once daily, for 14days) on the depression-like behavior and corticosterone levels in the blood samples following ovariectomy in female rats. Cholecalciferol was administered to the ovariectomized (OVX) rats and OVX rats treated with 17β-estradiol (17β-E 2 , 0.5μg/rat,s.c., once daily, for 14days). Depression-like behavior and spontaneous locomotor activity were assessed in the forced swimming test (FST) and the open field test (OFT), respectively. The corticosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with cholecalciferol in high dose (5.0mg/kg/day,s.c.) significantly decreased the immobility time of OVX rats in the FST. Co-administration of cholecalciferol in high dose with 17β-E 2 exerted a markedly synergistic antidepressant-like effect in the OVX rats on the same model of depression-like behavior testing. Cholecalciferol in high dose (5.0mg/kg/day,s.c.) administered alone or together with 17β-E 2 significantly enhanced frequency of grooming for the OVX rats in the OFT. Moreover, cholecalciferol in high dose administered alone or together with 17β-E 2 significantly decreased the elevated corticosterone levels in the blood serum of OVX rats following the FST. These results indicate that Cholecalciferol in high dose has a marked antidepressant-like effect in the adult female rats with low levels of estrogen. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effects of early life abuse differ across development: Infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala

PubMed Central

Raineki, Charlis; Cortés, Millie Rincón; Belnoue, Laure; Sullivan, Regina M.

2012-01-01

Abuse during early life, especially from the caregiver, increases vulnerability to develop later life psychopathologies such as depression. Although signs of depression are typically not expressed until later life, signs of dysfunctional social behavior have been found earlier. How infant abuse alters the trajectory of brain development to produce pathways to pathology is not completely understood. Here we address this question using two different but complementary rat models of early-life abuse from postnatal days (PN) 8–12: a naturalistic paradigm, where the mother is provided with insufficient bedding for nest building and a more controlled paradigm, where infants undergo olfactory classical conditioning. Amygdala neural assessment (c-Fos), as well as social behavior and forced swim tests were performed at preweaning (PN20) and adolescence (PN45). Our results show that both models of early life abuse induce deficits in social behavior, even during the preweaning period; however, depressive-like behaviors were observed only during adolescence. Adolescent depressive-like behavior corresponds with an increase in amygdala neural activity in response to forced swim test. A causal relationship between the amygdala and depressive-like behavior was suggested through amygdala temporary deactivation (muscimol infusions), which rescued the depressive-like behavior in the forced swim test. Our results indicate that social behavior deficits in infancy could serve as an early marker for later psychopathology. Moreover, the implication of the amygdala in the ontogeny of depressive-like behaviors in infant abused animals is an important step toward understanding the underlying mechanisms of later life mental disease associated with early-life abuse. PMID:22649253

Individual and combined effects of postpartum depression in mothers and fathers on parenting behavior.

PubMed

Paulson, James F; Dauber, Sarah; Leiferman, Jenn A

2006-08-01

Pediatric anticipatory guidance has been associated with parenting behaviors that promote positive infant development. Maternal postpartum depression is known to negatively affect parenting and may prevent mothers from following anticipatory guidance. The effects of postpartum depression in fathers on parenting is understudied. Our purpose with this work was to examine the effects of maternal and paternal depression on parenting behaviors consistent with anticipatory guidance recommendations. The 9-month-old wave of data from a national study of children and their families, the Early Childhood Longitudinal Study, provided data on 5089 2-parent families. Depressive symptoms were measured with a short form of the Center for Epidemiologic Studies Depression Scale. Interviews with both parents provided data on parent health behaviors and parent-infant interactions. Logistic and linear regression models were used to estimate the association between depression in each parent and the parenting behaviors of interest. These models were adjusted for demographic and socioeconomic status indicators. In this national sample, 14% of mothers and 10% of fathers exhibited levels of depressive symptoms on the Center for Epidemiologic Studies Depression Scale that have been associated with clinical diagnoses, confirming other findings of a high prevalence of postpartum maternal depression but highlighting that postpartum depression is a significant issue for fathers as well. Mothers who were depressed were approximately 1.5 times more likely to engage in less healthy feeding and sleep practices with their infant. In both mothers and fathers, depressive symptoms were negatively associated with positive enrichment activity with the child (reading, singing songs, and telling stories). Postpartum depression is a significant problem in both mothers and fathers in the United States. It is associated with undesirable parent health behaviors and fewer positive parent-infant interactions.

The Effects of High-fat-diet Combined with Chronic Unpredictable Mild Stress on Depression-like Behavior and Leptin/LepRb in Male Rats.

PubMed

Yang, Jin Ling; Liu, De Xiang; Jiang, Hong; Pan, Fang; Ho, Cyrus Sh; Ho, Roger Cm

2016-10-14

Leptin plays a key role in the pathogenesis of obesity and depression via the long form of leptin receptor (LepRb). An animal model of comorbid obesity and depression induced by high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS) was developed to study the relationship between depression/anxiety-like behavior, levels of plasma leptin and LepRb in the brains between four groups of rats, the combined obesity and CUMS (Co) group, the obese (Ob) group, the CUMS group and controls. Our results revealed that the Co group exhibited most severe depression-like behavior in the open field test (OFT), anxiety-like behavior in elevated plus maze test (EMT) and cognitive impairment in the Morris water maze (MWM). The Ob group had the highest weight and plasma leptin levels while the Co group had the lowest levels of protein of LepRb in the hypothalamus and hippocampus. Furthermore, depressive and anxiety-like behaviors as well as cognitive impairment were positively correlated with levels of LepRb protein and mRNA in the hippocampus and hypothalamus. The down-regulation of leptin/LepRb signaling might be associated with depressive-like behavior and cognitive impairment in obese rats facing chronic mild stress.

Root bark of Morus alba ameliorates the depressive-like behaviors in diabetic rats.

PubMed

Ye, Mei; Ke, Yuting; Liu, Bingyang; Yuan, Yanyan; Wang, Fuyan; Bu, Shizhong; Zhang, Yisheng

2017-01-10

Diabetes-induced depression is one of the severe chronic complications of diabetes mellitus. Up to now, there are only a few effective medicines to prevent or manage the co-morbidity of diabetes and depression. The present study was to investigate the effect of root bark of Morus alba (RBM) on depressive-like behaviors in the diabetic rats established by a high fat diet and a low dose of streptozotocin. Depressive-like behaviors were measured by the open field test, locomotor activity test and forced swimming test. Plasma glucose and lipid parameters were also measured. Expression of Brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal-regulated kinase (ERK) and Akt in the prefrontal cortex (PFC) were assessed. The results showed that a 4-week administration of RBM (10g/kg, ig) significantly reversed the depressive-like behaviors. BDNF expression and phosphorylation of ERK and Akt were increased in the PFC following RBM treatment in the diabetic rats. The data demonstrated that RBM could improve the depressive-like behaviors induced by diabetes, suggesting a therapeutic potential of RBM for the diabetes-associated depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism.

PubMed

Shimohata, Atsushi; Ishihara, Keiichi; Hattori, Satoko; Miyamoto, Hiroyuki; Morishita, Hiromasa; Ornthanalai, Guy; Raveau, Matthieu; Ebrahim, Abdul Shukkur; Amano, Kenji; Yamada, Kazuyuki; Sago, Haruhiko; Akiba, Satoshi; Mataga, Nobuko; Murphy, Niall P; Miyakawa, Tsuyoshi; Yamakawa, Kazuhiro

2017-07-01

Ts1Cje mice have a segmental trisomy of chromosome 16 that is orthologous to human chromosome 21 and display Down syndrome-like cognitive impairments. Despite the occurrence of affective and emotional impairments in patients with Down syndrome, these parameters are poorly documented in Down syndrome mouse models, including Ts1Cje mice. Here, we conducted comprehensive behavioral analyses, including anxiety-, sociability-, and depression-related tasks, and biochemical analyses of monoamines and their metabolites in Ts1Cje mice. Ts1Cje mice showed enhanced locomotor activity in novel environments and increased social contact with unfamiliar partners when compared with wild-type littermates, but a significantly lower activity in familiar environments. Ts1Cje mice also exhibited some signs of decreased depression like-behavior. Furthermore, Ts1Cje mice showed monoamine abnormalities, including increased extracellular dopamine and serotonin, and enhanced catabolism in the striatum and ventral forebrain. This study constitutes the first report of deviated monoamine metabolism that may help explain the basis for abnormal behaviors, including the environmental stimuli-triggered hyperactivity, increased sociability and decreased depression-like behavior in Ts1Cje mice. Copyright © 2017 Elsevier Inc. All rights reserved.

A detailed analysis of open-field habituation and behavioral and neurochemical antidepressant-like effects in postweaning enriched rats.

PubMed

Brenes, Juan C; Padilla, Michael; Fornaguera, Jaime

2009-01-30

Our previous work has shown that male Sprague-Dawley rats reared in social isolation, standard housing and environmental enrichment differ in their spontaneous open-field activity and in some neurobehavioral depressive-like parameters. Here, we extended this evidence by using a shorter postweaning rearing period (1 month) and including additional evaluations. First, in order to obtain a better characterization of the exploratory strategies among rearing conditions we analyzed in detail the spontaneous activity at the first minute and during the 10-min session. Second, we asked whether the changes in open-field activity were related with basal anxiety levels in the elevated plus-maze. Third, behavior in the forced-swimming test was analyzed and afterward, the tissue levels of hippocampal norepinephrine and serotonin were assessed. The possible relationship between neurotransmitters and forced-swimming behavior were explored through correlation analyses. We found that rearing conditions (i) differed on locomotor habituation and on sensory-motor exploration at the first minute and during the 10-min session without modifying the plus-maze behavior; (ii) affected differentially the grooming time, its sequential components, and the relationship between grooming and locomotor parameters; (iii) modified forced-swimming behavior and the hippocampal concentration of norepinephrine, serotonin, and its turnover; and (iv) produced different correlation patterns between both neurotransmitters and forced-swimming behaviors. Overall, environmental enrichment accelerated open-field habituation and led to behavioral and neurochemical antidepressant-like effects. In contract, isolation rearing strongly impaired habituation and simple information processing, but showed marginal effects on depressive-like behavior and on hippocampal neurochemistry. The current results suggest that differential rearing is not only a useful procedure to study behavioral plasticity or rigidity in response to early experience, but also to modeling some developmental protective or risk factors underlying depressive disorders.

Neuropsychiatric Symptom Modeling in Male and Female C57BL/6J Mice after Experimental Traumatic Brain Injury

PubMed Central

Tucker, Laura B.; Burke, John F.; Fu, Amanda H.

2017-01-01

Abstract Psychiatric symptoms such as anxiety and depression are frequent and persistent complaints following traumatic brain injury (TBI). Modeling these symptoms in animal models of TBI affords the opportunity to determine mechanisms underlying behavioral pathologies and to test potential therapeutic agents. However, testing these symptoms in animal models of TBI has yielded inconsistent results. The goal of the current study was to employ a battery of tests to measure multiple anxiety- and depressive-like symptoms following TBI in C57BL/6J mice, and to determine if male and female mice are differentially affected by the injury. Following controlled cortical impact (CCI) at a parietal location, neither male nor female mice showed depressive-like symptoms as measured by the Porsolt forced-swim test and sucrose preference test. Conclusions regarding anxiety-like behaviors were dependent upon the assay employed; CCI-induced thigmotaxis in the open field suggested an anxiogenic effect of the injury; however, results from the elevated zero maze, light-dark box, and marble-burying tests indicated that CCI reduced anxiety-like behaviors. Fewer anxiety-like behaviors were also associated with the female sex. Increased levels of activity were also measured in female mice and injured mice in these tests, and conclusions regarding anxiety should be taken with caution when experimental manipulations induce changes in baseline activity. These results underscore the irreconcilability of results from studies attempting to model TBI-induced neuropsychiatric symptoms. Changes in injury models or better attempts to replicate the clinical syndrome may improve the translational applicability of rodent models of TBI-induced anxiety and depression. PMID:27149139

Dim light at night provokes depression-like behaviors and reduces CA1 dendritic spine density in female hamsters.

PubMed

Bedrosian, Tracy A; Fonken, Laura K; Walton, James C; Haim, Abraham; Nelson, Randy J

2011-08-01

The prevalence of major depression has increased in recent decades; however, the underlying causes of this phenomenon remain unspecified. One environmental change that has coincided with elevated rates of depression is increased exposure to artificial light at night. Shift workers and others chronically exposed to light at night are at increased risk of mood disorders, suggesting that nighttime illumination may influence brain mechanisms mediating affect. We tested the hypothesis that exposure to dim light at night may impact affective responses and alter morphology of hippocampal neurons. Ovariectomized adult female Siberian hamsters (Phodopus sungorus) were housed for 8 weeks in either a light/dark cycle (LD) or a light/dim light cycle (DM), and then behavior was assayed. DM-hamsters displayed more depression-like responses in the forced swim and the sucrose anhedonia tests compared with LD-hamsters. Conversely, in the elevated plus maze DM-hamsters reduced anxiety-like behaviors. Brains from the same animals were processed using the Golgi-Cox method and hippocampal neurons within CA1, CA3, and the dentate gyrus were analyzed for morphological characteristics. In CA1, DM-hamsters significantly reduced dendritic spine density on both apical and basilar dendrites, an effect which was not mediated by baseline cortisol, as concentrations were equivalent between groups. These results demonstrate dim light at night is sufficient to reduce synaptic spine connections to CA1. Importantly, the present results suggest that night-time low level illumination, comparable to levels that are pervasive in North America and Europe, may contribute to the increasing prevalence of mood disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Upregulation of MAOA in the hippocampus results in delayed depressive-like behaviors in burn mice.

PubMed

Wang, Zhen; Chen, Lu; Rong, Xinzhou; Wang, Xuemin

2017-04-14

To observe depressive-like behavior and hippocampus monoamine oxidase A (MAOA) changes in burned mice. We tested depression and anxiety like behaviors of burn C57 mice with the sucrose preference test, forced swimming test (FST), open field test and elevated plus maze test and then detected the MAOA content and MAOA gene transcriptional levels in the hippocampus with western blot analysis and real-time quantitative PCR analysis. We then sought to reverse depressive-like behavior of burned mice with an MAOA inhibitor. (1) Mice showed depressive and anxiety like behaviors one week after they were burned; (2) The content of MAOA in the hippocampus of burned mice was significantly higher than that in control mice (P<0.05); (3) MAOA gene transcription in the hippocampus of burned mice was significantly increased (MAOA mRNA was increased, P<0.05); (4) treatment with a MAOA inhibitor (phenelzine) significantly increased the sucrose preference rate and decreased FST immobility time in burned mice, and also decreased elevated expression of MAOA in the hippocampus of burned mice. Burned mice showed "delayed" depressive-like behavior combined with a degree of anxiety; this phenomenon is likely associated with the increase in MAOA expression in the hippocampus. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

Beneficial effects of fluoxetine, reboxetine, venlafaxine, and voluntary running exercise in stressed male rats with anxiety- and depression-like behaviors.

PubMed

Lapmanee, Sarawut; Charoenphandhu, Jantarima; Charoenphandhu, Narattaphol

2013-08-01

Rodents exposed to mild but repetitive stress may develop anxiety- and depression-like behaviors. Whether this stress response could be alleviated by pharmacological treatments or exercise interventions, such as wheel running, was unknown. Herein, we determined anxiety- and depression-like behaviors in restraint stressed rats (2h/day, 5 days/week for 4 weeks) subjected to acute diazepam treatment (30min prior to behavioral test), chronic treatment with fluoxetine, reboxetine or venlafaxine (10mg/kg/day for 4 weeks), and/or 4-week voluntary wheel running. In elevated plus-maze (EPM) and forced swimming tests (FST), stressed rats spent less time in the open arms and had less swimming duration than the control rats, respectively, indicating the presence of anxiety- and depression-like behaviors. Stressed rats also developed learned fear as evaluated by elevated T-maze test (ETM). Although wheel running could reduce anxiety-like behaviors in both EPM and ETM, only diazepam was effective in the EPM, while fluoxetine, reboxetine, and venlafaxine were effective in the ETM. Fluoxetine, reboxetine, and wheel running, but not diazepam and venlafaxine, also reduced depression-like behavior in FST. Combined pharmacological treatment and exercise did not further reduce anxiety-like behavior in stressed rats. However, stressed rats treated with wheel running plus reboxetine or venlafaxine showed an increase in climbing duration in FST. In conclusion, regular exercise (voluntary wheel running) and pharmacological treatments, especially fluoxetine and reboxetine, could alleviate anxiety- and depression-like behaviors in stressed male rats. Copyright © 2013 Elsevier B.V. All rights reserved.

Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.

PubMed

Patel, Sita Sharan; Udayabanu, Malairaman

2014-03-01

Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction.

The Effects of Early-Life Predator Stress on Anxiety- and Depression-Like Behaviors of Adult Rats

PubMed Central

Chen, Lu-jing; Shen, Bing-qing; Liu, Dan-dan; Li, Sheng-tian

2014-01-01

Childhood emotional trauma contributes significantly to certain psychopathologies, such as post-traumatic stress disorder. In experimental animals, however, whether or not early-life stress results in behavioral abnormalities in adult animals still remains controversial. Here, we investigated both short-term and long-term changes of anxiety- and depression-like behaviors of Wistar rats after being exposed to chronic feral cat stress in juvenile ages. The 2-week predator stress decreased spontaneous activities immediately following stress but did not increase depression- or anxiety-like behaviors 4 weeks after the stimulation in adulthood. Instead, juvenile predator stress had some protective effects, though not very obvious, in adulthood. We also exposed genetic depression model rats, Wistar Kyoto (WKY) rats, to the same predator stress. In WKY rats, the same early-life predator stress did not enhance anxiety- or depression-like behaviors in both the short-term and long-term. However, the stressed WKY rats showed slightly reduced depression-like behaviors in adulthood. These results indicate that in both normal Wistar rats and WKY rats, early-life predator stress led to protective, rather than negative, effects in adulthood. PMID:24839560

Nature and nurture: environmental influences on a genetic rat model of depression.

PubMed

Mehta-Raghavan, N S; Wert, S L; Morley, C; Graf, E N; Redei, E E

2016-03-29

In this study, we sought to learn whether adverse events such as chronic restraint stress (CRS), or 'nurture' in the form of environmental enrichment (EE), could modify depression-like behavior and blood biomarker transcript levels in a genetic rat model of depression. The Wistar Kyoto More Immobile (WMI) is a genetic model of depression that aided in the identification of blood transcriptomic markers, which successfully distinguished adolescent and adult subjects with major depressive disorders from their matched no-disorder controls. Here, we followed the effects of CRS and EE in adult male WMIs and their genetically similar control strain, the Wistar Kyoto Less Immobile (WLI), that does not show depression-like behavior, by measuring the levels of these transcripts in the blood and hippocampus. In WLIs, increased depression-like behavior and transcriptomic changes were present in response to CRS, but in WMIs no behavioral or additive transcriptomic changes occurred. Environmental enrichment decreased both the inherent depression-like behavior in the WMIs and the behavioral difference between WMIs and WLIs, but did not reverse basal transcript level differences between the strains. The inverse behavioral change induced by CRS and EE in the WLIs did not result in parallel inverse expression changes of the transcriptomic markers, suggesting that these behavioral responses to the environment work via separate molecular pathways. In contrast, 'trait' transcriptomic markers with expression differences inherent and unchanging between the strains regardless of the environment suggest that in our model, environmental and genetic etiologies of depression work through independent molecular mechanisms.

Post-treatment with cotinine improved memory and decreased depressive-like behavior after chemotherapy in rats.

PubMed

Iarkov, Alexandre; Appunn, Doreen; Echeverria, Valentina

2016-11-01

Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." Cotinine, the main derivative of nicotine, improved visual and spatial working memory and decreased depressive-like behavior in an animal model of chemotherapy-induced cognitive impairment. In this study, we investigated the effect of cotinine on weight gain, locomotor activity, cognitive abilities and depressive-like behavior in rats treated with the chemotherapy mix, cyclophosphamide, methotrexate and 5-fluorouracil. Locomotor activity and depressive-like behavior were assessed using the rotarod and Porsolt's tests, respectively. Changes in cognitive abilities were determined using the novel place recognition test. Female rats treated with cotinine after chemotherapy, recovered weight faster, showed superior cognitive abilities and lower levels of depressive-like behavior than chemotherapy, vehicle-treated rats. This evidence suggests that treatment with cotinine may facilitate the recovery and diminish the cognitive consequences of chemotherapy.

Repeated Short-term (2h×14d) Emotional Stress Induces Lasting Depression-like Behavior in Mice.

PubMed

Kim, Kyoung-Shim; Kwon, Hye-Joo; Baek, In-Sun; Han, Pyung-Lim

2012-03-01

Chronic behavioral stress is a risk factor for depression. To understand chronic stress effects and the mechanism underlying stress-induced emotional changes, various animals model have been developed. We recently reported that mice treated with restraints for 2 h daily for 14 consecutive days (2h-14d or 2h×14d) show lasting depression-like behavior. Restraint provokes emotional stress in the body, but the nature of stress induced by restraints is presumably more complex than emotional stress. So a question remains unsolved whether a similar procedure with "emotional" stress is sufficient to cause depression-like behavior. To address this, we examined whether "emotional" constraints in mice treated for 2h×14d by enforcing them to individually stand on a small stepping platform placed in a water bucket with a quarter full of water, and the stress evoked by this procedure was termed "water-bucket stress". The water-bucket stress activated the hypothalamus-pituitary-adrenal gland (HPA) system in a manner similar to restraint as evidenced by elevation of serum glucocorticoids. After the 2h×14d water-bucket stress, mice showed behavioral changes that were attributed to depression-like behavior, which was stably detected >3 weeks after last water-bucket stress endorsement. Administration of the anti-depressant, imipramine, for 20 days from time after the last emotional constraint completely reversed the stress-induced depression-like behavior. These results suggest that emotional stress evokes for 2h×14d in mice stably induces depression-like behavior in mice, as does the 2h×14d restraint.

The bidirectional effects of hypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats.

PubMed

Yu, Dafu; Zhou, Heng; Yang, Yuan; Jiang, Yong; Wang, Tianchao; Lv, Liang; Zhou, Qixin; Yang, Yuexiong; Dong, Xuexian; He, Jianfeng; Huang, Xiaoyan; Chen, Jijun; Wu, Kunhua; Xu, Lin; Mao, Rongrong

2015-03-01

Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using (131)iodine ((131)I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of (131)I (5mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats.

PubMed

Pudell, Claudia; Vicente, Bianca A; Delattre, Ana M; Carabelli, Bruno; Mori, Marco A; Suchecki, Deborah; Machado, Ricardo B; Zanata, Sílvio M; Visentainer, Jesuí V; de Oliveira Santos Junior, Oscar; Lima, Marcelo M S; Ferraz, Anete C

2014-01-01

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Strain-dependent effects of prenatal maternal immune activation on anxiety- and depression-like behaviors in offspring.

PubMed

Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

2014-03-01

There is converging evidence that prenatal maternal infection can increase the risk of occurrence of neuropsychiatric disorders like schizophrenia, autism, anxiety and depression in later life. Experimental studies have shown conflicting effects of prenatal maternal immune activation on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis development in offspring. We investigated the effects of maternal immune activation during pregnancy on anxiety- and depression-like behaviors in pregnant mice and their offspring to determine whether these effects are dependent on strain. NMRI and C57BL/6 pregnant mice were treated with either saline or lipopolysaccharide on gestational day 17 and then interleukin (IL)-6 and corticosterone (COR) levels; anxiety or depression in the pregnant mice and their offspring were evaluated. The results indicate that maternal inflammation increased the levels of COR and anxiety-like behavior in NMRI pregnant mice, but not in C57BL/6 dams. Our data also demonstrate that maternal inflammation elevated the levels of anxiety-and depression-like behaviors in NMRI offspring on the elevated plus-maze, elevated zero-maze, tail suspension test and forced swimming test respectively, but not in the open field and light-dark box. In addition, we did not find any significant change in anxiety- and depression-like behaviors of adult C57BL/6 offspring. Our findings suggest that prenatal maternal immune activation can alter the HPA axis activity, anxiety- and depression-like behaviors in a strain- and task-dependent manner in offspring and further comprehensive studies are needed to prove the causal relationship between the findings found here and to validate their relevance to neuropsychiatric disorders in humans. Copyright © 2013 Elsevier Inc. All rights reserved.

Agmatine abolishes restraint stress-induced depressive-like behavior and hippocampal antioxidant imbalance in mice.

PubMed

Freitas, Andiara E; Bettio, Luis E B; Neis, Vivian B; Santos, Danúbia B; Ribeiro, Camille M; Rosa, Priscila B; Farina, Marcelo; Rodrigues, Ana Lúcia S

2014-04-03

Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherapy of depression. The acute restraint stress (ARS) is an unavoidable stress situation that may cause depressive-like behavior in rodents. In this study, we investigated the potential antidepressant-like effect of agmatine (10mg/kg, administered acutely by oral route) in the forced swimming test (FST) in non-stressed mice, as well as its ability to abolish the depressive-like behavior and hippocampal antioxidant imbalance induced by ARS. Agmatine reduced the immobility time in the mouse FST (1-100mg/kg) in non-stressed mice. ARS caused an increase in the immobility time in the FST, indicative of a depressive-like behavior, as well as hippocampal lipid peroxidation, and an increase in the activity of hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, reduced catalase (CAT) activity and increased SOD/CAT ratio, an index of pro-oxidative conditions. Agmatine was effective to abolish the depressive-like behavior induced by ARS and to prevent the ARS-induced lipid peroxidation and changes in SOD, GR and CAT activities and in SOD/CAT activity ratio. Hippocampal levels of reduced glutathione (GSH) were not altered by any experimental condition. In conclusion, the present study shows that agmatine was able to abrogate the ARS-induced depressive-like behavior and the associated redox hippocampal imbalance observed in stressed restraint mice, suggesting that its antidepressant-like effect may be dependent on its ability to maintain the pro-/anti-oxidative homeostasis in the hippocampus. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of GABA microinjection into dorsal raphe nucleus on behavior and activity of lateral habenular neurons in mice.

PubMed

Xiao, Jinyu; Song, Meiying; Li, Fengdan; Liu, Xiaofeng; Anwar, Alinur; Zhao, Hua

2017-12-01

The dorsal raphe nucleus (DRN) is a key site for 5-hydroxytryptamine (5-HT) synthesis and release. DRN dysfunction has been implicated in several stress-related disorders, including depression and anxiety. The lateral habenular nucleus (LHb) has been shown to inhibit the activity of DRN 5-HT neurons, and thus the LHb-DRN pathway plays an important role in the pathogenesis of depression. Although it is known that the LHb also receives the projection from the 5-HT neuron in the DRN, whether 5-HT neurons in the DRN can influence activity of the LHb in vivo and whether this effect is related to the induced behavioral changes have not been investigated. In the current study, we determined how injecting γ-aminobutyric acid (GABA) into the DRN to inhibit 5-HT neurons affected behavior and the changes in the activity of LHb neurons in mice. We found that GABA injection into the DRN induced depression-like behavior in mice, as indicated by increased immobility time, and decreased climbing time in the forced swimming test and the tail suspension test, decreased time spent in the center and total distance moved in the open field test. Using extracellular single unit recording, we showed that the firing rate of LHb neurons decreased after GABA microinjection into the DRN. Further, c-Fos expression in LHb neurons was inhibited. Together our results indicate that inhibition of DRN 5-HT neurons can cause decreased LHb activity and depression-like behavior in mice, however this depression-like behavior could be independent of the LHb activity. The observed decrease in LHb activity is probably due to the presence of a negative feedback loop between the DRN and the LHb, which may play a role in maintaining emotional homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Deuterium content of water increases depression susceptibility: the potential role of a serotonin-related mechanism.

PubMed

Strekalova, Tatyana; Evans, Matthew; Chernopiatko, Anton; Couch, Yvonne; Costa-Nunes, João; Cespuglio, Raymond; Chesson, Lesley; Vignisse, Julie; Steinbusch, Harry W; Anthony, Daniel C; Pomytkin, Igor; Lesch, Klaus-Peter

2015-01-15

Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal SERT. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Nature and nurture: environmental influences on a genetic rat model of depression

PubMed Central

Mehta-Raghavan, N S; Wert, S L; Morley, C; Graf, E N; Redei, E E

2016-01-01

In this study, we sought to learn whether adverse events such as chronic restraint stress (CRS), or ‘nurture' in the form of environmental enrichment (EE), could modify depression-like behavior and blood biomarker transcript levels in a genetic rat model of depression. The Wistar Kyoto More Immobile (WMI) is a genetic model of depression that aided in the identification of blood transcriptomic markers, which successfully distinguished adolescent and adult subjects with major depressive disorders from their matched no-disorder controls. Here, we followed the effects of CRS and EE in adult male WMIs and their genetically similar control strain, the Wistar Kyoto Less Immobile (WLI), that does not show depression-like behavior, by measuring the levels of these transcripts in the blood and hippocampus. In WLIs, increased depression-like behavior and transcriptomic changes were present in response to CRS, but in WMIs no behavioral or additive transcriptomic changes occurred. Environmental enrichment decreased both the inherent depression-like behavior in the WMIs and the behavioral difference between WMIs and WLIs, but did not reverse basal transcript level differences between the strains. The inverse behavioral change induced by CRS and EE in the WLIs did not result in parallel inverse expression changes of the transcriptomic markers, suggesting that these behavioral responses to the environment work via separate molecular pathways. In contrast, ‘trait' transcriptomic markers with expression differences inherent and unchanging between the strains regardless of the environment suggest that in our model, environmental and genetic etiologies of depression work through independent molecular mechanisms. PMID:27023176

Fibroblast growth factor 9 is a novel modulator of negative affect

PubMed Central

Aurbach, Elyse L.; Inui, Edny Gula; Turner, Cortney A.; Hagenauer, Megan H.; Prater, Katherine E.; Li, Jun Z.; Absher, Devin; Shah, Najmul; Blandino, Peter; Bunney, William E.; Myers, Richard M.; Barchas, Jack D.; Schatzberg, Alan F.; Watson, Stanley J.; Akil, Huda

2015-01-01

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders. PMID:26351673

Is there an association between hypercholesterolemia and depression? Behavioral evidence from the LDLr(-/-) mouse experimental model.

PubMed

Engel, Daiane Fátima; de Oliveira, Jade; Lopes, Jadna Bogado; Santos, Danúbia Bonfanti; Moreira, Eduardo Luiz Gasnhar; Farina, Marcelo; Rodrigues, Ana Lúcia S; de Souza Brocardo, Patricia; de Bem, Andreza Fabro

2016-09-15

Although epidemiological studies have reported an association between hypercholesterolemia and mood disorders, there is a lack of data regarding depressive-like behavior in animal models of hypercholesterolemia. To address these questions, we assessed depressive-like behavior and hippocampal and cortical monoaminergic metabolism in three-month-old, low-density lipoprotein receptor knockout (LDLr(-/-)) and C57BL/6 wild-type mice. The LDLr(-/-) mice exhibited depressive-like behavior in the sucrose preference test, splash test, and tail suspension test. Increased monoamine oxidase (MAO) A and B activity was evidenced in the hippocampus of LDLr(-/-) mice. Furthermore, to address whether or not cholesterol modulates MAO activity, we exposed SH-SY5Y human neuroblastoma cells to human isolated low-density lipoprotein (LDL). Notably, LDL increased the activity of MAO-A and stimulated the reactive species generation in vitro. These findings indicate that depressive-like behavior in hypercholesterolemic mice is accompanied by alterations in the monoaminergic metabolism, providing new evidence about the association between hypercholesterolemia and depression. Copyright © 2016. Published by Elsevier B.V.

Affect Intensity and Phasic REM Sleep in Depressed Men before and after Treatment with Cognitive-Behavioral Therapy.

ERIC Educational Resources Information Center

Nofzinger, Eric A.; And Others

1994-01-01

Explored relationship between daytime affect and REM (rapid eye movement) sleep in 45 depressed men before and after treatment with cognitive-behavioral therapy and in control group of 43 healthy subjects. For depressed subjects only, intensity of daytime affect correlated significantly and positively with phasic REM sleep measures at pre- and…

Depression-like behaviors and heme oxygenase-1 are regulated by Lycopene in lipopolysaccharide-induced neuroinflammation.

PubMed

Zhang, Fang; Fu, Yanyan; Zhou, Xiaoyan; Pan, Wei; Shi, Yue; Wang, Mei; Zhang, Xunbao; Qi, Dashi; Li, Lei; Ma, Kai; Tang, Renxian; Zheng, Kuiyang; Song, Yuanjian

2016-09-15

Previous studies have demonstrated that lycopene possesses anti-inflammatory properties in the central nervous system. However, the potential role and the molecular mechanisms of lycopene in lipopolysaccharide (LPS)-challenge inflammation and depression-like behaviors has not been clearly investigated. The present study aimed to assess the effects and the potential mechanisms of lycopene on LPS-induced depression-like behaviors. Lycopene was orally administered (60mg/kg) every day for seven days followed by intraperitoneal LPS injection (1mg/kg). The Forced swim test and tail suspension test were used to detect changes in the depression-like behaviors. ELISA was used to measure the expression of interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α) in the plasma. Immunoblotting was performed to measure the expression of interleukin-1β (IL-1β) and heme oxygenase-1 (HO-1) in the hippocampus. The results showed that pretreatment with lycopene could ameliorate depression-like behaviors. Moreover, lycopene relieved neuronal cell injury in hippocampal CA1 regions. Furthermore, lycopene decreased LPS-induced expression of IL-1β and HO-1 in the hippocampus together with decreasing level of IL-6 and TNF-α in the plasma. Taken together, these results suggest that lycopene can attenuate LPS-induced inflammation and depression-like behaviors, which may be involved in regulating HO-1 in the hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Behavioral in-effectiveness of high frequency electromagnetic field in mice.

PubMed

Salunke, Balwant P; Umathe, Sudhir N; Chavan, Jagatpalsingh G

2015-03-01

The present investigation was carried out with an objective to study the influence of high frequency electromagnetic field (HF-EMF) on anxiety, obsessive compulsive disorder (OCD) and depression-like behavior. For exposure to HF-EMF, non-magnetic material was used to fabricate the housing. Mice were exposed to HF-EMF (2.45GHz), 60min/day for 7 or 30 or 60 or 90 or 120days. The exposure was carried out by switching-on inbuilt class-I BLUETOOTH device that operates on 2.45GHz frequency in file transfer mode at a peak density of 100mW. Mice were subjected to the assessment of anxiety, OCD and depression-like behavior for 7 or 30 or 60 or 90 or 120days of exposure. The anxiety-like behavior was assessed by elevated plus maze, open field test and social interaction test. OCD-like behavior was assessed by marble burying behavior, whereas depression-like behavior was assessed by forced swim test and tail suspension test. The present experiment demonstrates that up to 120days of exposure to HF-EMF does not produce anxiety, OCD and depression-like behavior in mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain.

PubMed

Frey, Anna; Popp, Sandy; Post, Antonia; Langer, Simon; Lehmann, Marc; Hofmann, Ulrich; Sirén, Anna-Leena; Hommers, Leif; Schmitt, Angelika; Strekalova, Tatyana; Ertl, Georg; Lesch, Klaus-Peter; Frantz, Stefan

2014-01-01

Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.

Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression.

PubMed

Qiao, Hui; An, Shu-Cheng; Xu, Chang; Ma, Xin-Ming

2017-05-15

Major depressive disorder (MDD) is one of the most common psychiatric disorder, but the underlying mechanisms are largely unknown. Increasing evidence shows that brain-derived neurotrophic factor (BDNF) plays an important role in the structural plasticity induced by depression. Considering the opposite effects of BDNF and its precursor proBDNF on neural plasticity, we hypothesized that the balance of BDNF and proBDNF plays a critical role in chronic unpredicted mild stress (CUMS)-induced depressive-like behaviors and structural plasticity in the rodent hippocampus. The aims of this study were to compare the functions of BDNF and proBDNF in the CUMS-induced depressive-like behaviors, and determine the effects of BDNF and proBDNF on expressions of kalirin-7, postsynaptic density protein 95 (PSD95) and NMDA receptor subunit NR2B in the hippocampus of stressed and naïve control rats, respectively. Our results showed that CUMS induced depressive-like behaviors, caused a decrease in the ratio of BDNF/proBDNF in the hippocampus and resulted in a reduction in spine density in hippocampal CA1 pyramidal neurons; these alterations were accompanied by a decrease in the levels of kalirin-7, PSD95 and NR2B in the hippocampus. Injection of exogenous BDNF into the CA1 area of stressed rats reversed CUMS-induced depressive-like behaviors and prevented CUMS-induced spine loss and decrease in kalirin-7, NR2B and PSD95 levels. In contrast, injection of exogenous proBDNF into the CA1 region of naïve rats caused depressive-like behavior and an accompanying decrease in both spine density and the levels of kalirin-7, NR2B and PSD95. Taken together, our results suggest that the ratio of BDNF to proBDNF in the hippocampus plays a key role in CUMS-induced depressive-like behaviors and alterations of dendritic spines in hippocampal CA1 pyramidal neurons. Kalirin-7 may play an important role during this process. Copyright © 2017 Elsevier B.V. All rights reserved.

Antidepressant Flavonoids and Their Relationship with Oxidative Stress

PubMed Central

Hritcu, Lucian; Ionita, Radu; Postu, Paula Alexandra; Gupta, Girish Kumar; Turkez, Hasan; Lima, Tamires Cardoso; Carvalho, Caroline Uchôa Souza

2017-01-01

Depression is a serious disorder that affects hundreds of millions of people around the world and causes poor quality of life, problem behaviors, and limitations in activities of daily living. Therefore, the search for new therapeutic options is of high interest and growth. Research on the relationship between depression and oxidative stress has shown important biochemical aspects in the development of this disease. Flavonoids are a class of natural products that exhibit several pharmacological properties, including antidepressant-like activity, and affects various physiological and biochemical functions in the body. Studies show the clinical potential of antioxidant flavonoids in treating depressive disorders and strongly suggest that these natural products are interesting prototype compounds in the study of new antidepressant drugs. So, this review will summarize the chemical and pharmacological perspectives related to the discovery of flavonoids with antidepressant activity. The mechanisms of action of these compounds are also discussed, including their actions on oxidative stress relating to depression. PMID:29410733

Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice.

PubMed

Ledo, Jose Henrique; Azevedo, Estefania P; Beckman, Danielle; Ribeiro, Felipe C; Santos, Luis E; Razolli, Daniela S; Kincheski, Grasielle C; Melo, Helen M; Bellio, Maria; Teixeira, Antonio L; Velloso, Licio A; Foguel, Debora; De Felice, Fernanda G; Ferreira, Sergio T

2016-11-30

Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function. Copyright © 2016 the authors 0270-6474/16/3612106-11$15.00/0.

Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

PubMed

Sarkisova, Karine Yu; Fedotova, Irina B; Surina, Natalia M; Nikolaev, Georgy M; Perepelkina, Olga V; Kostina, Zoya A; Poletaeva, Inga I

2017-03-01

Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. Copyright © 2016 Elsevier Inc. All rights reserved.

Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation.

PubMed

Amini-Khoei, Hossein; Mohammadi-Asl, Ali; Amiri, Shayan; Hosseini, Mir-Jamal; Momeny, Majid; Hassanipour, Mahsa; Rastegar, Mojgan; Haj-Mirzaian, Arya; Mirzaian, Arvin Haj-; Sanjarimoghaddam, Hossein; Mehr, Shahram Ejtemaei; Dehpour, Ahmad Reza

2017-06-02

Mother-infant contact has a critical role on brain development and behavior. Experiencing early-life adversities (such as maternal separation stress or MS in rodents) results in adaptations of neurotransmission systems, which may subsequently increase the risk of depression symptoms later in life. In this study, we show that Oxytocin (OT) exerted antioxidant and anti-inflammatory properties. Previous studies indicate that neuroinflammation and mitochondrial dysfunction are associated with the pathophysiology of depression. To investigate the antidepressant-like effects of OT, we applied MS paradigm (as a valid animal model of depression) to male mice at postnatal day (PND) 2 to PND 14 (3h daily, 9AM to 12AM) and investigated the depressive-like behaviors of these animals at PND 60 in different groups. Animals in this work were divided into 4 experimental groups: 1) saline-treated, 2) OT-treated, 3) atosiban (OT antagonist)-treated and, 4) OT+ atosiban-treated mice. We used forced swimming test (FST), splash test, sucrose preference test (SPT) and open field test (OFT) for behavioral assessment. Additionally, we used another set of animals to investigate the effects of MS and different treatments on mitochondrial function and the expression of the relevant genes for neuroinflammation. Our results showed that MS provoked depressive- like behaviors in the FST, SPT and splash test. In addition, our molecular findings revealed that MS is capable of inducing abnormal mitochondrial function and immune-inflammatory response in the hippocampus. Further, we observed that treating stressed animals with OT (intracerebroventricular, i.c.v. injection) attenuated the MS-induced depressive-like behaviors through improving mitochondrial function and decreasing the hippocampal expression of immune-inflammatory genes. In conclusion, we showed that MS-induced depressive-like behaviors in adult male mice are associated with abnormal mitochondrial function and immune-inflammatory responses in the hippocampus, and activation of OTergic system has protective effects against negative effects of MS on brain and behavior of animals. Copyright © 2017 Elsevier Inc. All rights reserved.

Inflammatory Th17 cells promote depression-like behavior in mice

PubMed Central

Beurel, Eléonore; Harrington, Laurie E.; Jope, Richard S.

2012-01-01

Background Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact CNS functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models Th17 cells promote susceptibility to depression-like behaviors. Methods Behavioral characteristics were measured in male mice administered Th17 cells, CD4+ cells, or vehicle, and in RORγT+/GFP mice or male mice treated with RORγT inhibitor or anti-IL-17A antibodies. Results Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the RORγT transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of RORγT as a potential intervention. Treatment with the RORγT inhibitor SR1001, or anti-IL-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness. Conclusions These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells. PMID:23174342

Interoceptive Dysfunction: Toward An Integrated Framework for Understanding Somatic and Affective Disturbance in Depression

PubMed Central

Harshaw, Christopher

2014-01-01

Depression is characterized by disturbed sleep and eating, a variety of other, nonspecific somatic symptoms, and significant somatic comorbidities. Why there is such close association between cognitive and somatic dysfunction in depression is nonetheless poorly understood. An explosion of research in the area of interoception—the perception and interpretation of bodily signals—over the last decade nonetheless holds promise for illuminating what have until now been obscure links between the social, cognitive-affective, and somatic features of depression. This paper reviews rapidly accumulating evidence that both somatic signaling and interoception are frequently altered in depression. This includes comparative studies showing vagus-mediated effects on depression-like behaviors in rodent models as well as studies in humans indicating both dysfunction in the neural substrates for interoception (e.g., vagus, insula, anterior cingulate cortex) and reduced sensitivity to bodily stimuli in depression. An integrative framework for organizing and interpreting this evidence is put forward which incorporates (a) multiple potential pathways to interoceptive dysfunction; (b) interaction with individual, gender, and cultural differences in interoception; and (c) a developmental psychobiological systems perspective, emphasizing likely differential susceptibility to somatic and interoceptive dysfunction across the lifespan. Combined with current theory and evidence, it is suggested that core symptoms of depression (e.g., anhedonia, social deficits) may be products of disturbed interoceptive-exteroceptive integration. More research is nonetheless needed to fully elucidate the relationship between mind, body, and social context in depression. PMID:25365763

Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats

PubMed Central

Lapmanee, Sarawut; Teerapornpuntakit, Jarinthorn; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2017-01-01

Several severe stressful situations, e.g., natural disaster, infectious disease out break, and mass casualty, are known to cause anxiety, depression and cognitive impairment, and preventive intervention for these stress complications is worth exploring. We have previously reported that the serotonin-norepinephrine-dopamine reuptake inhibitor, venlafaxine, as well as voluntary wheel running are effective in the treatment of anxiety- and depression-like behaviors in stressed rats. But whether they are able to prevent deleterious consequences of restraint stress in rats, such as anxiety/depression-like behaviors and memory impairment that occur afterward, was not known. Herein, male Wistar rats were pre-treated for 4 weeks with anti-anxiety/anti-depressive drugs, agomelatine and venlafaxine, or voluntary wheel running, followed by 4 weeks of restraint-induced stress. During the stress period, rats received neither drug nor exercise intervention. Our results showed that restraint stress induced mixed anxiety- and depression-like behaviors, and memory impairment as determined by elevated plus-maze, elevated T-maze, open field test (OFT), forced swimming test (FST), and Morris water maze (MWM). Both pharmacological pre-treatments and running successfully prevented the anxiety-like behavior, especially learned fear, in stressed rats. MWM test suggested that agomelatine, venlafaxine, and running could prevent stress-induced memory impairment, but only pharmacological treatments led to better novel object recognition behavior and positive outcome in FST. Moreover, western blot analysis demonstrated that venlafaxine and running exercise upregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. In conclusion, agomelatine, venlafaxine as well as voluntary wheel running had beneficial effects, i.e., preventing the restraint stress-induced anxiety/depression-like behaviors and memory impairment. PMID:29099859

Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats.

PubMed

Lapmanee, Sarawut; Charoenphandhu, Jantarima; Teerapornpuntakit, Jarinthorn; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2017-01-01

Several severe stressful situations, e.g., natural disaster, infectious disease out break, and mass casualty, are known to cause anxiety, depression and cognitive impairment, and preventive intervention for these stress complications is worth exploring. We have previously reported that the serotonin-norepinephrine-dopamine reuptake inhibitor, venlafaxine, as well as voluntary wheel running are effective in the treatment of anxiety- and depression-like behaviors in stressed rats. But whether they are able to prevent deleterious consequences of restraint stress in rats, such as anxiety/depression-like behaviors and memory impairment that occur afterward, was not known. Herein, male Wistar rats were pre-treated for 4 weeks with anti-anxiety/anti-depressive drugs, agomelatine and venlafaxine, or voluntary wheel running, followed by 4 weeks of restraint-induced stress. During the stress period, rats received neither drug nor exercise intervention. Our results showed that restraint stress induced mixed anxiety- and depression-like behaviors, and memory impairment as determined by elevated plus-maze, elevated T-maze, open field test (OFT), forced swimming test (FST), and Morris water maze (MWM). Both pharmacological pre-treatments and running successfully prevented the anxiety-like behavior, especially learned fear, in stressed rats. MWM test suggested that agomelatine, venlafaxine, and running could prevent stress-induced memory impairment, but only pharmacological treatments led to better novel object recognition behavior and positive outcome in FST. Moreover, western blot analysis demonstrated that venlafaxine and running exercise upregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. In conclusion, agomelatine, venlafaxine as well as voluntary wheel running had beneficial effects, i.e., preventing the restraint stress-induced anxiety/depression-like behaviors and memory impairment.

TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury.

PubMed

Karpova, Nina N; Lindholm, Jesse Saku Olavi; Kulesskaya, Natalia; Onishchenko, Natalia; Vahter, Marie; Popova, Dina; Ceccatelli, Sandra; Castrén, Eero

2014-01-01

Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure.

TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury

PubMed Central

Karpova, Nina N.; Lindholm, Jesse Saku Olavi; Kulesskaya, Natalia; Onishchenko, Natalia; Vahter, Marie; Popova, Dina; Ceccatelli, Sandra; Castrén, Eero

2014-01-01

Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure. PMID:25309367

Interplay between Marital Attributions and Conflict Behavior in Predicting Depressive Symptoms

PubMed Central

Ellison, Jenna K.; Kouros, Chrystyna D.; Papp, Lauren M.; Cummings, E. Mark

2015-01-01

Marital attributions--i.e., causal inferences and explanations spouses make about their partners’ behavior--have been implicated as predictors of relationship functioning. Extending previous work, we examined marital attributions as a moderator of the link between marital conflict and depressive symptoms one year later. Participants were 284 couples who reported on marital attributions and depressive symptoms. Couples also engaged in a videotaped marital conflict interaction, which was later coded for specific conflict behaviors. The results showed that husbands’ and wives’ marital attributions about their partner moderated relations between marital conflict behavior and later depressive symptoms, controlling for global marital sentiments. For husbands, positive behavior and affect during marital conflict predicted a decrease in depressive symptoms, but only for husbands’ who made low levels of responsibility and causal attributions about their wives. Wives’ causal attributions about their partner also moderated relations between positive behavior and affect during marital conflict and husbands’ later depressive symptoms. Reflecting an unexpected finding, negative behavior and affect during marital conflict predicted increases in wives’ depressive symptoms, but only for wives who made low levels of responsibility attributions about their partner. The findings suggest that, for husbands, low levels of negative marital attributions for spouses may be protective, strengthening the positive effect of constructive conflict behaviors for their mental health, whereas for wives low levels of responsibility attributions about their spouse may be a risk factor, exacerbating the negative effect of negative marital conflict behaviors on their later depressive symptoms. PMID:26751758

Interplay between marital attributions and conflict behavior in predicting depressive symptoms.

PubMed

Ellison, Jenna K; Kouros, Chrystyna D; Papp, Lauren M; Cummings, E Mark

2016-03-01

Marital attributions-that is, causal inferences and explanations spouses make about their partners' behavior-have been implicated as predictors of relationship functioning. Extending previous work, we examined marital attributions as a moderator of the link between marital conflict and depressive symptoms 1 year later. Participants were 284 couples who reported on marital attributions and depressive symptoms. Couples also engaged in a videotaped marital conflict interaction, which was later coded for specific conflict behaviors. The results showed that husbands' and wives' marital attributions about their partner moderated relations between marital conflict behavior and later depressive symptoms, controlling for global marital sentiments. For husbands, positive behavior and affect during marital conflict predicted a decrease in depressive symptoms, but only for husbands' who made low levels of responsibility and causal attributions about their wives. Wives' causal attributions about their partner also moderated relations between positive behavior and affect during marital conflict and husbands' later depressive symptoms. Reflecting an unexpected finding, negative behavior and affect during marital conflict predicted increases in wives' depressive symptoms, but only for wives who made low levels of responsibility attributions about their partner. The findings suggest that, for husbands, low levels of negative marital attributions for spouses may be protective, strengthening the positive effect of constructive conflict behaviors for their mental health, whereas for wives low levels of responsibility attributions about their spouse may be a risk factor, exacerbating the negative effect of negative marital conflict behaviors on their later depressive symptoms. (c) 2016 APA, all rights reserved).

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.

PubMed

Yu, Q; Teixeira, C M; Mahadevia, D; Huang, Y; Balsam, D; Mann, J J; Gingrich, J A; Ansorge, M S

2014-06-01

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.

PubMed

Norden, Diana M; Devine, Raymond; Bicer, Sabahattin; Jing, Runfeng; Reiser, Peter J; Wold, Loren E; Godbout, Jonathan P; McCarthy, Donna O

2015-03-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. Copyright © 2014 Elsevier Inc. All rights reserved.

Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice.

PubMed

Ali, Syed Hamid; Madhana, Rajaram Mohanrao; K V, Athira; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Pitta, Sathish; Mahareddy, Jalandhar Reddy; Lahkar, Mangala

2015-09-01

A mouse model of depression has been recently developed by exogenous corticosterone (CORT) administration, which has shown to mimic HPA-axis induced depression-like state in animals. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of resveratrol, a naturally occurring polyphenol of phytoalexin family, on depressive-like behavior induced by repeated corticosterone injections in mice. Mice were injected subcutaneously (s.c.) with 40mg/kg corticosterone (CORT) chronically for 21days. Resveratrol and fluoxetine were administered 30min prior to the CORT injection. After 21-days treatment with respective drugs, behavioral and biochemical parameters were estimated. Since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant activity of many drugs, we also evaluated the effect of resveratrol on BDNF in the hippocampus. Three weeks of CORT injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Further, there was a significant increase in serum corticosterone level and a significant decrease in hippocampus BDNF level in CORT-treated mice. Treatment of mice with resveratrol significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. These results suggest that resveratrol produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of hippocampal BDNF levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Assessing the relationship between quality of life and behavioral activation using the Japanese Behavioral Activation for Depression Scale-Short Form.

PubMed

Shudo, Yusuke; Yamamoto, Tatsuya

2017-01-01

Quality of life (QOL) is an important health-related concept. Identifying factors that affect QOL can help develop and improve health-promotion interventions. Previous studies suggest that behavioral activation fosters subjective QOL, including well-being. However, the mechanism by which behavioral activation improves QOL is not clear. Considering that QOL improves when depressive symptoms improve post-treatment and that behavioral activation is an effective treatment for depression, it is possible that behavioral activation affects QOL indirectly rather than directly. To clarify the mechanism of the influence of behavioral activation on QOL, it is necessary to examine the relationships between factors related to behavioral activation, depressive symptoms, and QOL. Therefore, we attempted to examine the relationship between these factors. Participants comprised 221 Japanese undergraduate students who completed questionnaires on behavioral activation, QOL, and depressive symptoms: the Japanese versions of the Behavioral Activation for Depression Scale-Short Form (BADS-SF), WHO Quality of Life-BREF (WHOQOL-26), and Center for Epidemiologic Studies Depression Scale (CES-D). The BADS-SF comprises two subscales, Activation and Avoidance, and the WHOQOL-26 measures overall QOL and four domains, Physical Health, Psychological Health, Social Relationships, and Environment. Mediation analyses were conducted with BADS-SF activation and avoidance as independent variables, CES-D as a mediator variable, and each WHO-QOL as an outcome variable. Results indicated that depression completely mediated the relationship between Avoidance and QOL, and partially mediated the relationship between Activation and QOL. In addition, analyses of each domain of QOL showed that Activation positively affected all aspects of QOL directly and indirectly, but Avoidance had a negative influence on only part of QOL mainly through depression. The present study provides behavioral activation strategies aimed at QOL enhancement.

Sex differences in depressive, anxious behaviors and hippocampal transcript levels in a genetic rat model.

PubMed

Mehta, N S; Wang, L; Redei, E E

2013-10-01

Major depressive disorder (MDD) is a common, debilitating illness with high prevalence of comorbid anxiety. The incidence of depression and of comorbid anxiety is much higher in women than in men. These gender biases appear after puberty and their etiology is mostly unknown. Selective breeding of the Wistar Kyoto (WKY) rat strain, an accepted model of adult and adolescent depression, resulted in two fully inbred substrains. Adult WKY more immobile (WMI) rats of both sexes consistently show increased depression-like behavior in the forced swim test when compared with the control WKY less immobile (WLI) strain. In contrast, here we show that while adult female WMIs and WLIs both display high anxiety-like behaviors, only WLI males, but not WMI males, show this behavior. Moreover, the behavioral profile of WMI males is consistent from early adolescence to adulthood, but the high depression- and anxiety-like behaviors of the female WMIs appear only in adulthood. These sex-specific behavioral patterns are paralleled by marked sex differences in hippocampal gene expression differences established by genome-wide transcriptional analyses of 13th generation WMIs and WLIs. Moreover, sex- and age-specific differences in transcript levels of selected genes are present in the hippocampus of the current, fully inbred WMIs and WLIs. Thus, the contribution of specific genes and/or the influence of the gonadal hormonal environment to depression- and anxiety-like behaviors may differ between male and female WMIs, resulting in their distinct behavioral and transcriptomic profiles despite shared sequences of the somatic chromosomes. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.

PubMed

Parrott, J M; Redus, L; Santana-Coelho, D; Morales, J; Gao, X; O'Connor, J C

2016-10-18

The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO -/- ) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg -1 ) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO -/- mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO -/- mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.

Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation

PubMed Central

Parrott, J M; Redus, L; Santana-Coelho, D; Morales, J; Gao, X; O'Connor, J C

2016-01-01

The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO−/−) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg−1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO−/− mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO−/− mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge. PMID:27754481

Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain

PubMed Central

Frey, Anna; Popp, Sandy; Post, Antonia; Langer, Simon; Lehmann, Marc; Hofmann, Ulrich; Sirén, Anna-Leena; Hommers, Leif; Schmitt, Angelika; Strekalova, Tatyana; Ertl, Georg; Lesch, Klaus-Peter; Frantz, Stefan

2014-01-01

Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. PMID:25400562

Increased cooperative behavior across remitted bipolar I disorder and major depression: Insights utilizing a behavioral economic trust game.

PubMed

Ong, Desmond C; Zaki, Jamil; Gruber, June

2017-01-01

Mood disorders impact social functioning, but might contribute to experiences-like affective distress-that might result in increased cooperative behavior under certain circumstances. We recruited participants with a history of bipolar I disorder (n = 28), major depressive disorder (n = 30), and healthy controls (n = 27)-to play a well-validated behavioral economic Trust Game, a task that provides a well-controlled experimental scenario, to measure cooperative behavior for the first time across both groups. Both remitted mood-disordered groups cooperated significantly more than the control group, but did not differ from one another. These results suggest that, in some contexts, a history of mood disturbance can produce enhanced cooperation, even in the absence of current mood symptoms. We discuss the clinical significance of enhanced cooperation in mood disorders and point to key directions for future research. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Maternal Depression History Moderates Parenting Responses to Compliant and Noncompliant Behaviors of Children with ADHD

PubMed Central

Thomas, Sharon R.; O’Brien, Kelly A.; Clarke, Tana L.; Liu, Yihao; Chronis-Tuscano, Andrea

2014-01-01

Maternal depression and parenting are robust predictors of developmental outcomes for children with attention-deficit/hyperactivity disorder (ADHD). However, methods commonly used to examine parent-child interactions in these families do not account for temporal associations between child and parent behavior that have been theorized to maintain negative child behavior. Moreover, studies examining associations between maternal depression and parenting in families of children with ADHD have not compared mothers who were currently depressed, remitted, and never clinically depressed. This study utilized sequential analysis to examine how maternal reinforcement of compliant and noncompliant child behavior differs as a function of maternal depression history. Within the 82 participating mother-child dyads, 21 mothers were currently depressed, 29 mothers had a lifetime history of depression but were in remission for at least 1 month, and 32 mothers had never been clinically depressed. 24 girls (29.6%) and 57 boys (70.4%) between the ages of 6–12 year old (M = 8.7, SD = 2.0) and were diagnosed with ADHD. Results indicated that all mothers were less likely to respond optimally than non-optimally to child compliant and noncompliant behaviors during observed parent-child interactions; however, currently depressed mothers were least likely to reinforce child compliance and responded most coercively to child noncompliance relative to the other groups. Remitted mothers in this sample were more coercive than never clinically depressed mothers, but were more likely to follow through with commands than never clinically depressed mothers. Implications for behavioral parent training programs aimed at skill development for depressed mothers of children with ADHD are discussed. PMID:25413021

Ovariectomy results in inbred strain-specific increases in anxiety-like behavior in mice

PubMed Central

Schoenrock, Sarah Adams; Oreper, Daniel; Young, Nancy; Ervin, Robin Betsch; Bogue, Molly A.; Valdar, William; Tarantino, Lisa M.

2017-01-01

Women are at an increased risk for developing affective disorders during times of hormonal flux, including menopause when the ovaries cease production of estrogen. However, while all women undergo menopause, not all develop an affective disorder. Increased vulnerability can result from genetic predisposition, environmental factors and gene by environment interactions. In order to investigate interactions between genetic background and estrogen depletion, we performed bilateral ovariectomy, a surgical procedure that results in estrogen depletion and is thought to model the post-menopausal state, in a genetically defined panel of 37 inbred mouse strains. Seventeen days post-ovariectomy, we assessed behavior in two standard rodent assays of anxiety- and depressive-like behavior, the open field and forced swim tests. We detected a significant interaction between ovariectomy and genetic background on anxiety-like behavior in the open field. No strain specific effects of ovariectomy were observed in the forced swim assay. However, we did observe significant strain effects for all behaviors in both the open field and forced swim tests. This study is the largest to date to look at the effects of ovariectomy on behavior and provides evidence that ovariectomy interacts with genetic background to alter anxiety-like behavior in an animal model of menopause. PMID:27693591

Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.

PubMed

Qi, Xiaoli; Lin, Wenjuan; Li, Junfa; Li, Huanhuan; Wang, Weiwen; Wang, Donglin; Sun, Meng

2008-08-01

Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.

Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

PubMed

Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

2016-02-01

Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chronic unpredictable mild stress-induced depressive-like behavior and dysregulation of brain levels of biogenic amines in Drosophila melanogaster.

PubMed

Araujo, Stífani Machado; Poetini, Marcia Rósula; Bortolotto, Vandreza Cardoso; de Freitas Couto, Shanda; Pinheiro, Franciane Cabral; Meichtry, Luana Barreto; de Almeida, Francielli Polet; Santos Musachio, Elize Aparecida; de Paula, Mariane Trindade; Prigol, Marina

2018-05-24

The etiopathogenesis of depression may involve repeated exposure to several unpredictable stressors. This study was conducted to investigate changes induced by chronic unpredictable mild stress (CUMS) and to assess behavioral and neurochemical changes that predict depressive-like behavior in Drosophila melanogaster. Male Drosophila melanogaster flies were exposed to CUMS with several stressors (cold, heat, starvation, and sleep deprivation) in an unpredictable and chronic manner for ten days. At the end of treatment, in vivo behavioral tests (open field, aggression, forced swimming, mating, light/dark box, male fertility evaluation, sucrose preference, weight evaluation) and ex vivo analyses (dopamine and serotonin levels) were performed. Using this CUMS model, we obtained results that contribute to the construction of a depressive model in Drosophila, where we reproduce some behavioral phenotypes corresponding to depressive symptoms, such as immobility in the forced swimming test, less exploration in the light/dark test, changes in mating behavior, changes in the aggressiveness test, reduced sucrose preference, and weight-loss, in addition to a significant reduction in the levels of serotonin and dopamine when compared to the control group. Fluoxetine was used in our study as a positive control to demonstrate that CUMS-induced depressive-like behaviors in flies can be reversed by antidepressants. In conclusion, male Drosophila melanogaster exposed to CUMS display a depressive-like phenotype, and, while this poses some limitations as an animal model for depression, it meets some of the criteria required to be a valid model, such as good face and construct validity. Copyright © 2018. Published by Elsevier B.V.

Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

PubMed

Chen, Jiao; Wang, Zhen-zhen; Zuo, Wei; Zhang, Shuai; Chu, Shi-feng; Chen, Nai-hong

2016-02-01

Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Depressive-like behavior induced by tumor necrosis factor-α in mice.

PubMed

Kaster, Manuella P; Gadotti, Vinícius M; Calixto, João B; Santos, Adair R S; Rodrigues, Ana Lúcia S

2012-01-01

Pro-inflammatory cytokines are implicated in the pathogenesis of depression. However, few animal models of cytokine-induced depression well characterized regarding its response to antidepressants are available. Hence, the aim of this study was to propose a model of depressive-like behavior induced by the administration of tumor necrosis factor-α (TNF-α) responsive to antidepressant treatments. TNF-α administered by i.c.v. route produced a depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1-1 fg/site and 0.001 fg/site, respectively), without altering the locomotor activity in the open-field test. In addition, anti-TNF-α antibody (0.1-1 pg/site, i.c.v.), but not the inhibitor of TNF-α synthesis thalidomide (3-30 mg/kg, s.c.) produced an antidepressant-like response in the FST. Moreover, either anti-TNF-α antibody (0.01 pg/site, i.c.v) or thalidomide (30 mg/kg, s.c.) reversed the depressive-like behavior induced by TNF- (0.1 fg/site, i.c.v.) in the FST. TNF-α receptor 1 (TNFR1) knockout mice exhibited an antidepressant-like behavior in the FST and in the TST as compared with the wild type mice. Treatment with fluoxetine (32 mg/kg, i.p), imipramine (15 mg/kg, i.p.) and desipramine (16 mg/kg, i.p) prevented the depressant-like effect induced by TNF-α (0.1 fg/site, i.c.v.) in the FST. In addition, TNF-α (0.1 fg/site, i.c.v.) administration produced an anhedonic response in a sucrose intake test, which was prevented by anti-TNF-α antibody (0.01 pg/site, i.c.v) or fluoxetine (32 mg/kg, i.p). Taken together, these results indicate that TNF-α produces a depressive-like state in mice, reinforcing the notion that an inflammatory component may play an important role in the pathophysiology of depression and suggesting that the central administration of TNF-α may be a novel approach to study the inflammatory component of depressive disorder. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Addiction, Adolescence, and Innate Immune Gene Induction

PubMed Central

Crews, Fulton T.; Vetreno, Ryan Peter

2011-01-01

Repeated drug use/abuse amplifies psychopathology, progressively reducing frontal lobe behavioral control, and cognitive flexibility while simultaneously increasing limbic temporal lobe negative emotionality. The period of adolescence is a neurodevelopmental stage characterized by poor behavioral control as well as strong limbic reward and thrill seeking. Repeated drug abuse and/or stress during this stage increase the risk of addiction and elevate activator innate immune signaling in the brain. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a key glial transcription factor that regulates proinflammatory chemokines, cytokines, oxidases, proteases, and other innate immune genes. Induction of innate brain immune gene expression (e.g., NF-κB) facilitates negative affect, depression-like behaviors, and inhibits hippocampal neurogenesis. In addition, innate immune gene induction alters cortical neurotransmission consistent with loss of behavioral control. Studies with anti-oxidant, anti-inflammatory, and anti-depressant drugs as well as opiate antagonists link persistent innate immune gene expression to key behavioral components of addiction, e.g., negative affect-anxiety and loss of frontal–cortical behavioral control. This review suggests that persistent and progressive changes in innate immune gene expression contribute to the development of addiction. Innate immune genes may represent a novel new target for addiction therapy. PMID:21629837

Particulate matter triggers depressive-like response associated with modulation of inflammatory cytokine homeostasis and brain-derived neurotrophic factor signaling pathway in mice.

PubMed

Liu, Xuemei; Qian, Xin; Xing, Jing; Wang, Jinhua; Sun, Yixuan; Wang, Qin'geng; Li, Huiming

2018-04-23

Particulate matter (PM) exposure may contribute to depressive-like response in mice. However, few studies have evaluated the adaptive impacts of long-term PM exposure on depressive-like response associated with systemic inflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. We studied the association among depressive-like behaviors, mRNA levels of pro- and anti-inflammatory cytokines, and the expression of BDNF signaling pathway in mice by long-term PM exposure. C57BL/6 male mice were exposed to ambient air alongside control mice breathing air filtered through a high-efficiency air PM (HEPA) filter. Depressive-like behaviors were assessed together with pro-inflammatory, anti-inflammatory cytokine mRNA levels and the modulation of BDNF pathway in hippocampus and olfactory-bulb of mice exposed to PM for 4, 8, and 12 weeks. Exposure to HEPA filtered air for 4 weeks may exert antidepressant like effects in mice. Pro-inflammatory cytokines were up-regulated while the expression of BDNF, its high-affinity receptor tropomyosin-related kinase B (TrkB), and the transcription factor cAMP-response-element binding protein (CREB) were down-regulated in ambient air mice. However, after 8 weeks, there was no significant difference in the rate of depressive-like behaviors between the two groups. After 12 weeks, mice exposed to ambient air again had a higher rate of depressive-like behaviors, significant up-regulation of pro-inflammatory cytokines, down-regulation of interleukin-10 (IL-10), BDNF, TrkB, and CREB than HEPA mice. Ultrafine PM in brain tissues of mice exposed to ambient air was observed. Our results suggest continuous high-level PM exposure alters the depressive-like response in mice and induces a damage-repair-imbalance reaction.

Like parent, like child: parent and child emotion dysregulation.

PubMed

Carrère, Sybil; Bowie, Bonnie H

2012-06-01

This study examined the association between children's emotion regulatory processes and parents' emotional problems. A 5-year longitudinal study of families from Northwestern United States with data collected over 3 time points. Families were recruited in an effort to oversample for multiracial and African American families because these families have historically not been well represented in research studies. Parental hostility characteristics and subclinical levels of depression were assessed in combination with teachers' reports of children's externalizing and internalizing behaviors. Ninety-one families with married parents and an elementary school-aged child participated in the study. There was a significant main effect for the association between fathers' self-reports of hostility and teacher reports of children's externalizing behaviors. Neither parental hostility nor depressive symptoms were significantly associated with the children's internalizing behaviors. The results suggest that children's externalizing behaviors are associated with their fathers' dysregulated expression of hostility. Parent-child interactions are a key component of children's emotion regulation development. Our findings may guide health care professionals in identifying and intervening in parental behaviors, particularly fathers' behaviors, that may adversely affect the healthy emotional development of their children. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute hypoglycemia causes depressive-like behaviors in mice.

PubMed

Park, Min Jung; Yoo, Samuel W; Choe, Brian S; Dantzer, Robert; Freund, Gregory G

2012-02-01

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia. Copyright © 2012 Elsevier Inc. All rights reserved.

Chronic agmatine treatment prevents behavioral manifestations of nicotine withdrawal in mice.

PubMed

Kotagale, Nandkishor R; Chopde, Chandrabhan T; Umekar, Milind J; Taksande, Brijesh G

2015-05-05

Smoking cessation exhibits an aversive withdrawal syndrome characterized by both increases in somatic signs and affective behaviors including anxiety and depression. In present study, abrupt withdrawal of daily nicotine injections (2mg/kg, s.c., four times daily, for 10 days) significantly increased somatic signs viz. rearing, grooming, jumping, genital licking, leg licking, head shakes with associated depression (increased immobility in forced swim test) as well as anxiety (decreased the number of entries and time spent in open arm in elevated plus maze) in nicotine dependent animals. The peak effect was observed at 24h time point of nicotine withdrawal. Repeated administration of agmatine (40-80µg/mouse, i.c.v.) before the first daily dose of nicotine from day 5 to 10 attenuated the elevated scores of somatic signs and abolished the depression and anxiety like behavior induced by nicotine withdrawal in dependent animals. However, in separate groups, its acute administration 30min before behavior analysis of nicotine withdrawal was ineffective. This result clearly shows the role of agmatine in development of nicotine dependence and its withdrawal. In extension to behavioral experiments, brain agmatine analyses, carried out at 24h time point of nicotine withdrawal demonstrated marked decrease in basal brain agmatine concentration as compared to control animals. Taken together, these data support the role of agmatine as common biological substrate for somatic signs and affective symptoms of nicotine withdrawal. This data may project therapies based on agmatine in anxiety, depression and mood changes associated with tobacco withdrawal. Copyright © 2015 Elsevier B.V. All rights reserved.

Experimental gastritis leads to anxiety- and depression-like behaviors in female but not male rats

PubMed Central

2013-01-01

Human and animals studies support the idea that there is a gender-related co-morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague–Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to-brain signaling. PMID:24345032

Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade.

PubMed

Jangra, Ashok; Sriram, Chandra Shaker; Lahkar, Mangala

2016-08-01

Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and depressive illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and depressive-like behavior in Swiss albino mice. Anxiety and depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and depressive illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.

Chronic Postnatal Stress Induces Depressive-like Behavior in Male Mice and Programs second-Hit Stress-Induced Gene Expression Patterns of OxtR and AvpR1a in Adulthood.

PubMed

Lesse, Alexandra; Rether, Kathy; Gröger, Nicole; Braun, Katharina; Bock, Jörg

2017-08-01

Chronic stress (CS) during early life represents a major risk factor for the development of mental disorders, including depression. According to the Two/Multiple-Hit hypothesis, the etiology of neuropsychiatric disorders usually involves multiple stressors experienced subsequently during different phases of life. However, the molecular and cellular mechanisms modulating neuronal and behavioral changes induced by multiple stress experiences are just poorly understood. Since the oxytocinergic and vasopressinergic systems are neuroendocrine modulators involved in environmentally driven adaptations of stress sensitivity we hypothesized that postnatal CS programs oxytocinergic and vasopressinergic receptor expression changes in response to a second stress exposure in young adulthood. First we investigated if postnatal CS (maternal separation + social isolation) induces depressive-like behavior and alters oxytocin receptor (OxtR) and arginine vasopressin receptor type 1a (AvpR1a) gene expression in the hippocampus (HC) of male mice and (2) if a second single stressor (forced swimming, FS) in young adulthood affects gene expression of OxtR and AvpR1a at adulthood dependent on CS pre-experience. We found that postnatal CS induced depressive-like behavior and enhanced AvpR1a expression in HC at young adulthood. Moreover, in line with our hypothesis, only combined stress exposure (CS + FS), but not CS or FS alone, resulted in increased gene expression of OxtR in HC at adulthood. In contrast, AvpR1a expression was decreased in both adult FS and CS + FS animals. Overall, our results provide evidence that CS programs neuroendocrine systems and thereby influences stress responses in later life periods.

Cognitive-Affective Correlates of Suicide Ideation and Attempt: Mindfulness is Negatively Associated with Suicide Attempt History but Not State Suicidality.

PubMed

Chesin, Megan; Cascardi, Michele

2018-06-11

To test whether three cognitive-affective correlates, mindfulness, emotion reactivity, and depressive symptom severity, have different associations with current suicidal ideation (SI), a history of suicide attempt (SA) and SA+SI among emerging adults. To test whether impulsive-aggression (IA) moderates associations between cognitive-affective correlates of suicidal behavior and suicidality. Survey data on current SI, SA history, mindfulness, emotion reactivity, depressive symptom severity, and IA were collected from 780 emerging adults. Results from multinomial logistic regression analysis showed greater depressive symptom severity among emerging adults with current SI, regardless of SA history. Those with a history of SA reported greater depressive symptom severity and less mindfulness than controls. IA did not moderate relationships of SI and/or SA and mindfulness, emotion reactivity, or depressive symptom severity. Mindfulness is a marker of SA, and depressive symptom severity is associated with current SI and SA history in emerging adults. IA does not moderate these associations. To the extent that a history of SA is indicative of elevated trait-like suicide risk and SI indicates state suicidality, our findings suggest that mindfulness protects against longer-term vulnerability to SA while depressive symptom severity increases with increasing suicide state-trait risk.

The co-occurrence of zinc deficiency and social isolation has the opposite effects on mood compared with either condition alone due to changes in the central norepinephrine system.

PubMed

Mitsuya, Hironori; Omata, Naoto; Kiyono, Yasushi; Mizuno, Tomoyuki; Murata, Tetsuhito; Mita, Kayo; Okazawa, Hidehiko; Wada, Yuji

2015-05-01

Nutritional and social environmental problems during the early stages of life are closely associated with the pathophysiology of mood disorders such as depression. Disruption or dysfunction of the central norepinephrine (NE) system is also considered to play a role in mood disorders. Therefore, we evaluated the effects of zinc deficiency and/or social isolation on mood and changes in the central NE system using rats. Compared with the controls, the rats subjected to zinc deficiency or social isolation alone exhibited increased anxiety-related behavior in the elevated plus maze and greater depression-like behavior in the forced swim test. However, the co-occurrence of zinc deficiency and social isolation resulted in decreased anxiety-related behavior and control levels of depression-like behavior. Social isolation alone decreased the rats' cerebral NE concentrations. The expression of the NE transporter was not affected by social isolation alone, but its expression in the locus coeruleus was markedly decreased by the co-occurrence of social isolation and zinc deficiency, and this change was accompanied by an increase in the blood concentration of 3-methoxy-4-hydroxyphenylglycol, which is a marker of central NE system activity. These findings suggest that zinc deficiency or social isolation alone induce anxious or depressive symptoms, but the presence of both conditions has anxiolytic or antidepressive effects. Furthermore, these opposing effects of mood-related behaviors were found to be associated with changes in the central NE system. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Inflammatory T helper 17 cells promote depression-like behavior in mice.

PubMed

Beurel, Eléonore; Harrington, Laurie E; Jope, Richard S

2013-04-01

Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact central nervous system functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models, Th17 cells promote susceptibility to depression-like behaviors. Behavioral characteristics were measured in male mice administered Th17 cells, CD4(+) cells, or vehicle and in retinoid-related orphan receptor-γT (RORγT)(+/GFP) mice or male mice treated with RORγT inhibitor or anti-interleukin-17A antibodies. Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the RORγT transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of RORγT as a potential intervention. Treatment with the RORγT inhibitor SR1001, or anti-interleukin-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness. These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.

PubMed

Miller, Oliver H; Bruns, Andreas; Ben Ammar, Imen; Mueggler, Thomas; Hall, Benjamin J

2017-08-22

The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Dopaminergic Lesion in the Olfactory Bulb Restores Olfaction and Induces Depressive-Like Behaviors in a 6-OHDA Model of Parkinson's Disease.

PubMed

Ilkiw, Jessica L; Kmita, Luana C; Targa, Adriano D S; Noseda, Ana Carolina D; Rodrigues, Lais S; Dorieux, Flávia W C; Fagotti, Juliane; Dos Santos, Patrícia; Lima, Marcelo M S

2018-06-05

Olfactory impairments and depressive behavior are commonly reported by individuals with Parkinson's disease (PD) being observed before motor symptoms. The mechanisms underlying these clinical manifestations are not fully elucidated. However, the imbalance in dopaminergic neurotransmission seems to play an important role in this context. In patients and animal models of PD, an increase in the dopaminergic interneurons of the glomerular layer in olfactory bulb (OB-gl) is observed, which may contribute to the olfactory impairment. In addition, neuronal imbalance in OB is related to depressive symptoms, as demonstrated by chemical olfactory bulbectomy. In view of that, we hypothesized that a reduction in the number or density of dopaminergic neurons present in OB could promote an olfactory improvement and, in contrast, would accentuate the depressive-like behaviors in the 6-hydroxydopamine (6-OHDA) model of PD. Therefore, we performed single or double injections of 6-OHDA within the substantia nigra pars compacta (SNpc) and/or in the OB-gl. We observed that, after 7 days, the group with nigral lesion exhibited olfactory impairment, as well as the group with the lesion in the OB-gl. However, the combination of the lesions prevented the occurrence of hyposmia. In relation to depressive-like behaviors, we observed that the SNpc injury promoted depressive-like behavior, being accentuated after a double injury. Our results demonstrated the importance of the dopaminergic neurons of the OB-gl in different non-motor features of PD, since the selective reduction of these periglomerular neurons was able to induce olfactory impairment and depressive-like behaviors.

Differential Regulation of MAPK Phosphorylation in the Dorsal Hippocampus in Response to Prolonged Morphine Withdrawal-Induced Depressive-Like Symptoms in Mice

PubMed Central

Shi, Jianguo; Wu, Bin; Dang, Wei; Du, Ying; Zhou, Qiong; Wang, Jianhua; Zhang, Rui

2013-01-01

Depression is one of the most frequent neuropsychiatric comorbidities associated with opiate addiction. Mitogen activated protein kinase (MAPK) and MAPK phosphatase (MKP) are involved in drug addiction and depression. However, the potential role of MAPK and MKP in depression caused by morphine withdrawal remains unclear. We utilized a mouse model of repeated morphine administration to examine the molecular mechanisms that contribute to prolonged withdrawal induced depressive-like behaviors. Depressive-like behaviors were significant at 1 week after withdrawal and worsened over time. Phospho-ERK (extracellular signal-regulated protein kinase) was decreased and MKP-1 was elevated in the hippocampus, and JNK (c-Jun N-terminal protein kinase), p38 (p38 protein kinase) and MKP-3 were unaffected. A pharmacological blockade of MKP-1 by intra-hippocampal sanguinarine (SA) infusion prevented the development of depressive-like behaviors and resulted in relatively normal levels of MKP-1 and phospho-ERK after withdrawal. Our findings support the association between hippocampal MAPK phosphorylation and prolonged morphine withdrawal-induced depression, and emphasize the MKP-1 as an negative regulator of the ERK phosphorylation that contributes to depression. PMID:23823128

Affective network and default mode network in depressive adolescents with disruptive behaviors

PubMed Central

Kim, Sun Mi; Park, Sung Yong; Kim, Young In; Son, Young Don; Chung, Un-Sun; Min, Kyung Joon; Han, Doug Hyun

2016-01-01

Aim Disruptive behaviors are thought to affect the progress of major depressive disorder (MDD) in adolescents. In resting-state functional connectivity (RSFC) studies of MDD, the affective network (limbic network) and the default mode network (DMN) have garnered a great deal of interest. We aimed to investigate RSFC in a sample of treatment-naïve adolescents with MDD and disruptive behaviors. Methods Twenty-two adolescents with MDD and disruptive behaviors (disrup-MDD) and 20 age- and sex-matched healthy control (HC) participants underwent resting-state functional magnetic resonance imaging (fMRI). We used a seed-based correlation approach concerning two brain circuits including the affective network and the DMN, with two seed regions including the bilateral amygdala for the limbic network and the bilateral posterior cingulate cortex (PCC) for the DMN. We also observed a correlation between RSFC and severity of depressive symptoms and disruptive behaviors. Results The disrup-MDD participants showed lower RSFC from the amygdala to the orbitofrontal cortex and parahippocampal gyrus compared to HC participants. Depression scores in disrup-MDD participants were negatively correlated with RSFC from the amygdala to the right orbitofrontal cortex. The disrup-MDD participants had higher PCC RSFC compared to HC participants in a cluster that included the left precentral gyrus, left insula, and left parietal lobe. Disruptive behavior scores in disrup-MDD patients were positively correlated with RSFC from the PCC to the left insular cortex. Conclusion Depressive mood might be correlated with the affective network, and disruptive behavior might be correlated with the DMN in adolescent depression. PMID:26770059

Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice.

PubMed

Liu, Ya-Min; Niu, Le; Wang, Lin-Lin; Bai, Li; Fang, Xiao-Yan; Li, Yu-Cheng; Yi, Li-Tao

2017-09-01

Berberine, the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis chinensis), has been shown to exert antidepressant-like effects in rodents. However, it is still not clear the involvement of neuro-inflammation suppression in the effects of berberine. The purpose of this study was to determine whether berberine affects the neuro-inflammation system in mice induced by chronic unpredictable mild stress (CUMS). Berberine was orally administrated in normal or CUMS mice for successive four weeks. Behavioral evaluation showed that berberine prevented the depressive deficits both in sucrose preference test and novelty-suppressed feeding test. The elevation of hippocampal pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as the activation of microglia were decreased by berberine. In addition, chronic berberine treatment inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway as the phosphorylated proteins of NF-κB, IκB kinase (IKK)α and IKKβ in the hippocampus were suppressed after berberine administration. Furthermore, inducible nitric oxide synthase (iNOS), one downstream target of NF-κB signaling pathway was also inhibited by berberine. In conclusion, these findings suggest that administration of berberine could prevent depressive-like behaviors in CUMS mice by suppressing neuro-inflammation in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

[The calming process of anger experience: time series changes of affects, cognitions, and behaviors].

PubMed

Hibino, Kei; Yukawa, Shintaro

2004-02-01

This study investigated time series changes and relationships of affects, cognitions, and behaviors immediately, a few days, and a week after anger episodes. Two hundred undergraduates (96 men, and 104 women) completed a questionnaire. The results were as follows. Anger intensely aroused immediately after anger episodes, and was rapidly calmed as time passed. Anger and depression correlated in each period, so depression was accompanied with anger experiences. The results of covariance structure analysis showed that aggressive behavior was evoked only by affects (especially anger) immediately, and was evoked only by cognitions (especially inflating) a few days after the episode. One week after the episode, aggressive behavior decreased, and was not influenced by affects and cognitions. Anger elicited all anger-expressive behaviors such as aggressive behavior, social sharing, and object-displacement, while depression accompanied with anger episodes elicited only object-displacement.

Ibuprofen Ameliorates Fatigue- and Depressive-like Behavior in Tumor-bearing Mice

PubMed Central

Norden, Diana M.; McCarthy, Donna O.; Bicer, Sabahattin; Devine, Raymond; Reiser, Peter J.; Godbout, Jonathan P.; Wold, Loren E.

2015-01-01

Aims Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines are associated with skeletal muscle wasting and depressive- and fatigue- like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. Main Methods Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. Key Findings Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. Significance Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF. PMID:26498217

Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats

PubMed Central

Gonzalez, M. M. C.; Aston-Jones, G.

2008-01-01

Light is an important environmental factor for regulation of mood. There is a high frequency of seasonal affective disorder in high latitudes where light exposure is limited, and bright light therapy is a successful antidepressant treatment. We recently showed that rats kept for 6 weeks in constant darkness (DD) have anatomical and behavioral features similar to depressed patients, including dysregulation of circadian sleep–waking rhythms and impairment of the noradrenergic (NA)-locus coeruleus (LC) system. Here, we analyzed the cell viability of neural systems related to the pathophysiology of depression after DD, including NA-LC, serotoninergic-raphe nuclei and dopaminergic-ventral tegmental area neurons, and evaluated the depressive behavioral profile of light-deprived rats. We found increased apoptosis in the three aminergic systems analyzed when compared with animals maintained for 6 weeks in 12:12 light-dark conditions. The most apoptosis was observed in NA-LC neurons, associated with a significant decrease in the number of cortical NA boutons. Behaviorally, DD induced a depression-like condition as measured by increased immobility in a forced swim test (FST). DD did not appear to be stressful (no effect on adrenal or body weights) but may have sensitized responses to subsequent stressors (increased fecal number during the FST). We also found that the antidepressant desipramine decreases these neural and behavioral effects of light deprivation. These findings indicate that DD induces neural damage in monoamine brain systems and this damage is associated with a depressive behavioral phenotype. Our results suggest a mechanism whereby prolonged limited light intensity could negatively impact mood. PMID:18347342

Restrictive emotionality, depressive symptoms, and suicidal thoughts and behaviors among high school students.

PubMed

Jacobson, Colleen M; Marrocco, Frank; Kleinman, Marjorie; Gould, Madelyn S

2011-06-01

Depression and suicidal thoughts and behaviors are prevalent among youth today. The current study sought to further our understanding of the correlates of depression and suicidality by assessing the relationship between restrictive emotionality (difficulty understanding and expressing emotions) and depressive symptoms and suicidal ideation and attempts among adolescents. A large group of high school students (n = 2189, 58.3% male; 13-18 years of age) completed a self-report survey as part of a 2-stage suicide screening project. Logistic regression analyses were used to assess the association between restrictive emotionality and depressive symptoms, suicidal ideation, and suicide attempts. Those reporting high restrictive emotionality were 11 times more likely to have elevated depressive symptom scores, 3 times more likely to report serious suicidal ideation (after controlling for depressive symptoms), and more than twice as likely to report a suicide attempt (after controlling for depressive symptoms) than those reporting low restrictive emotionality. Restrictive emotionality partially mediated the relationship between depressive symptoms and suicidal ideation and behavior. The pattern of association between restrictive emotionality and the outcome variables was similar for boys and girls. Restrictive emotionality is highly associated with elevated depressive symptoms and suicidal thoughts and behaviors among high school students, and may be a useful specific target in prevention and treatment efforts.

Evaluative communications between affectively ill and well mothers and their children.

PubMed

Inoff-Germain, G; Nottelmann, E D; Radke-Yarrow, M

1992-04-01

Earlier research suggests that the natural verbal discourse of mothers with their children can be important in clarifying, verifying, and evaluating the behavior in which a child is engaged, in attributing qualities to the child, and in influencing the child's self-perceptions. We investigated the potential influences of parental affective illness (bipolar affective disorder and unipolar depression in contrast to no history of psychiatric illness) on such "labeling" behavior in a sample of 61 mothers and their older (school-age) and younger (preschool-age) children. It was hypothesized that the dispositions characterizing affective illness (specifically, negativity and disengagement) would be reflected in the labeling statements of mothers with a diagnosis as they interacted with their children. Based on videotaped interactions during a visit to a home-like laboratory apartment, labeling statements were identified in terms of speaker and person being labeled ("addressee") and coded (positive, negative, mixed, or neutral) for judgmental and affective quality of the statement and reaction of the addressee. Data were analyzed (a) by family unit and (b) my mother to child statements. The general pattern of findings indicated, in relative terms, an excess of negativity on the part of family members in the bipolar group and a dearth of negative affect for mothers in the unipolar group. Negativity in the bipolar group appeared to be especially likely when the setting involved mothers and two male children. Additionally, findings are discussed in terms of sex differences in vulnerability to depression.

Breaking bonds in male prairie vole: Long-term effects on emotional and social behavior, physiology, and neurochemistry

PubMed Central

Sun, P; Smith, AS; Lei, K; Liu, Y; Wang, Z

2014-01-01

Social relationships are essential for many fundamental aspects of life while bond disruption can be detrimental to mental and physical health. Male prairie voles form enduring social bonds with their female partners, allowing the evaluation of partner loss on behavior, physiology, and neurochemistry. Males were evaluated for partner preference formation induced by 24 h of mating, and half were separated from their partner for 4 wk. In Experiment 1, partner loss significantly increased anxiety-like behaviors in the elevated plus maze and light-dark box tests and marginally increased depressive-like behaviors in the forced swim test. In addition, while intruder-directed aggression is common in pair bonded prairie voles, separated males were affiliative and lacked aggression toward an unfamiliar female and an intruding male conspecific. Partner loss increased the density of oxytocin-immunoreactivity (-ir), vasopressin-ir, and corticotrophin-releasing hormone-ir cells in the paraventricular nucleus of the hypothalamus and oxytocin-ir cells in the supraoptic nucleus. Tyrosine hydroxylase-ir was not affected. In Experiment 2, partner preference was observed after 2 wk of partner loss but eliminated after 4 wk partner loss. Body weight gain and plasma corticosterone concentrations were elevated throughout the 4 wk. No effects were observed for plasma oxytocin or vasopressin. Together, partner loss elicits anxiety-like and depression-like behaviors, disrupts bond-related behaviors, and alters neuropeptide systems that regulate such behaviors. Thus, partner loss in male prairie voles may provide a model to better understand the behavior, pathology, and neurobiology underlying partner loss and grief. PMID:24561258

Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress.

PubMed

Ilin, Yana; Richter-Levin, Gal

2009-01-01

Mood disorders affect the lives and functioning of millions each year. Epidemiological studies indicate that childhood trauma is predominantly associated with higher rates of both mood and anxiety disorders. Exposure of rats to stress during juvenility (JS) (27-29 days of age) has comparable effects and was suggested as a model of induced predisposition for these disorders. The importance of the environment in the regulation of brain, behavior and physiology has long been recognized in biological, social and medical sciences. Here, we studied the effects of JS on emotional and cognitive aspects of depressive-like behavior in adulthood, on Hypothalamic-Pituitary-Adrenal (HPA) axis reactivity and on the expression of cell adhesion molecule L1 (L1-CAM). Furthermore, we combined it with the examination of potential reversibility by enriched environment (EE) of JS - induced disturbances of emotional and cognitive aspects of behavior in adulthood. Three groups were tested: Juvenile Stress -subjected to Juvenile stress; Enriched Environment--subjected to Juvenile stress and then, from day 30 on to EE; and Naïves. In adulthood, coping and stress responses were examined using the elevated plus-maze, open field, novel setting exploration and two way shuttle avoidance learning. We found that, JS rats showed anxiety- and depressive-like behaviors in adulthood, altered HPA axis activity and altered L1-CAM expression. Increased expression of L1-CAM was evident among JS rats in the basolateral amygdala (BLA) and Thalamus (TL). Furthermore, we found that EE could reverse most of the effects of Juvenile stress, both at the behavioral, endocrine and at the biochemical levels. The interaction between JS and EE resulted in an increased expression of L1-CAM in dorsal cornu ammonis (CA) area 1 (dCA1).

Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine.

PubMed

McVey Neufeld, Karen-Anne; Kay, Sebastian; Bienenstock, John

2018-01-01

Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair-BALB/c and Swiss Webster-with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.

Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine

PubMed Central

McVey Neufeld, Karen-Anne; Kay, Sebastian; Bienenstock, John

2018-01-01

Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair—BALB/c and Swiss Webster—with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.

Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

PubMed

Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

2016-02-26

Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice

PubMed Central

Zheng, Jia; Goodyear, Laurie J.

2016-01-01

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression. PMID:28058270

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice.

PubMed

Mul, Joram D; Zheng, Jia; Goodyear, Laurie J

2016-01-01

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression.

Enduring effects of post-weaning rearing condition on depressive- and anxiety-like behaviors and motor activity in male rats.

PubMed

Mosaferi, Belal; Babri, Shirin; Ebrahimi, Hadi; Mohaddes, Gisou

2015-04-01

Environmental manipulation at early critical periods could have long-lasting effects. In spite of the great interest in the biological effects of the environmental condition so far, its long-lasting effects are less documented. This study looks at the enduring effects of rearing condition on tasks that measure affective responses and exploratory behavior in male Wistar rats. The animals were reared from weaning to adulthood in an enriched environment, standard laboratory condition, or isolated condition. Then, all rats were housed in standard laboratory cages to provide a common environment, and successively exposed to different tests between 0 and 11 weeks post-manipulation. The open field test indicated a more efficient exploratory behavior in the enriched group, and an enhanced spontaneous motor activity in both standard and isolated groups. In addition, rats reared in standard condition showed heightened motor activity in forced swimming test and elevated plus maze. Forced swimming test showed an antidepressive-like effect in the enriched environment group by increased climbing behavior. In respect to the anxiety behavior, environmental enrichment improved threat detection ability. It is concluded that rearing condition from weaning to adulthood has important and long-lasting effects on depressive- and anxiety-like and exploratory behaviors as well as motor activity. Copyright © 2015 Elsevier Inc. All rights reserved.

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice.

PubMed

Williams, Aislinn J; Yee, Patricia; Smith, Mitchell C; Murphy, Geoffrey G; Umemori, Hisashi

2016-07-01

Specific growth factors induce formation and differentiation of excitatory and inhibitory synapses, and are essential for brain development and function. Fibroblast growth factor 22 (FGF22) is important for specifying excitatory synapses during development, including in the hippocampus. Mice with a genetic deletion of FGF22 (FGF22KO) during development subsequently have fewer hippocampal excitatory synapses in adulthood. As a result, FGF22KO mice are resistant to epileptic seizure induction. In addition to playing a key role in learning, the hippocampus is known to mediate mood and anxiety. Here, we explored whether loss of FGF22 alters affective, anxiety or social cognitive behaviors in mice. We found that relative to control mice, FGF22KO mice display longer duration of floating and decreased latency to float in the forced swim test, increased immobility in the tail suspension test, and decreased preference for sucrose in the sucrose preference test, which are all suggestive of a depressive-like phenotype. No differences were observed between control and FGF22KO mice in other behavioral assays, including motor, anxiety, or social cognitive tests. These results suggest a novel role for FGF22 specifically in affective behaviors. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-Level Laser Irradiation Improves Depression-Like Behaviors in Mice.

PubMed

Xu, Zhiqiang; Guo, Xiaobo; Yang, Yong; Tucker, Donovan; Lu, Yujiao; Xin, Ning; Zhang, Gaocai; Yang, Lingli; Li, Jizhen; Du, Xiangdong; Zhang, Quanguang; Xu, Xingshun

2017-08-01

Major depressive disorder (MDD) is one of the leading forms of psychiatric disorders, characterized by aversion to mobility, neurotransmitter deficiency, and energy metabolic decline. Low-level laser therapy (LLLT) has been investigated in a variety of neurodegenerative disorders associated with mitochondrial dysfunction and functional impairments. The goal of this study was to examine the effect of LLLT on depression-like behaviors and to explore the potential mechanism by detecting mitochondrial function following LLLT. Depression models in space restriction mice and Abelson helper integration site-1 (Ahi1) knockout (KO) mice were employed in this work. Our results revealed that LLLT effectively improved depression-like behaviors, in the two depression mice models, by decreasing immobility duration in behavioral despair tests. In addition, ATP biosynthesis and the level of mitochondrial complex IV expression and activity were significantly elevated in prefrontal cortex (PFC) following LLLT. Intriguingly, LLLT has no effects on ATP content and mitochondrial complex I-IV levels in other tested brain regions, hippocampus and hypothalamus. As a whole, these findings shed light on a novel strategy of transcranial LLLT on depression improvement by ameliorating neurotransmitter abnormalities and promoting mitochondrial function in PFC. The present work provides concrete groundwork for further investigation of LLLT for depression treatment.

Interaction Effect of Social Isolation and High Dose Corticosteroid on Neurogenesis and Emotional Behavior.

PubMed

Chan, Jackie N-M; Lee, Jada C-D; Lee, Sylvia S P; Hui, Katy K Y; Chan, Alan H L; Fung, Timothy K-H; Sánchez-Vidaña, Dalinda I; Lau, Benson W-M; Ngai, Shirley P-C

2017-01-01

Hypercortisolemia is one of the clinical features found in depressed patients. This clinical feature has been mimicked in animal studies via application of exogenous corticosterone (CORT). Previous studies suggested that CORT can induce behavioral disturbance in anxious-depressive like behavior, which is associated with suppressed neurogenesis. Hippocampal neurogenesis plays an important role in adult cognitive and behavioral regulation. Its suppression may thus lead to neuropsychiatric disorders. Similar to the effects of CORT on the animals' depression-like behaviors and neurogenesis, social deprivation has been regarded as one factor that predicts poor prognosis in depression. Furthermore, social isolation is regarded as a stressor to social animals including experimental rodents. Hence, this study aims to examine if social isolation would induce further emotional or anxiety-like behavior disturbance and suppress neurogenesis in an experimental model that was repeatedly treated with CORT. Sprague-Dawley rats were used in this study to determine the effects of different housing conditions, either social isolated or group housing, in vehicle-treated control and CORT-treated animals. Forced swimming test (FST), open field test (OFT) and social interaction test (SIT) were used to assess depression-like, anxiety-like and social behaviors respectively. Immunohistochemistry was performed to quantify the number of proliferative cells and immature neurons in the hippocampus, while dendritic maturation of immature neurons was analyzed by Sholl analysis. Social isolation reduced latency to immobility in FST. Furthermore, social isolation could significantly reduce the ratio of doublecortin and bromodeoxyuridine (BrdU) positive cells of the neurogenesis assay under CORT-treated condition. The current findings suggested that the behavioral and neurological effect of social isolation is dependent on the condition of hypercortisolemia. Furthermore, social isolation may possibly augment the signs and symptoms of depressed patients with potential alteration in neurogenesis.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

PubMed Central

Wang, Peng; Li, Hui; Barde, Swapnali; Zhang, Ming-Dong; Sun, Jing; Wang, Tong; Zhang, Pan; Luo, Hanjiang; Wang, Yongjun; Yang, Yutao; Wang, Chuanyue; Svenningsson, Per; Theodorsson, Elvar; Hökfelt, Tomas G. M.; Xu, Zhi-Qing David

2016-01-01

The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects. PMID:27457954

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

PubMed Central

Serchov, Tsvetan; Clement, Hans-Willi; Schwarz, Martin K.; Iasevoli, Felice; Tosh, Dilip K.; Idzko, Marco; Jacobson, Kenneth A.; de Bartolomeis, Andrea; Normann, Claus; Biber, Knut; van Calker, Dietrich

2016-01-01

SUMMARY Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments. PMID:26247862

Elevation of synaptic protein is associated with the antidepressant-like effects of ferulic acid in a chronic model of depression.

PubMed

Liu, Ya-Min; Hu, Chun-Yue; Shen, Ji-Duo; Wu, Su-Hui; Li, Yu-Cheng; Yi, Li-Tao

2017-02-01

Ferulic acid is a hydroxycinnamic acid that widely presents in plant cell wall components. It has been demonstrated that ferulic acid can reverse depressive-like behaviors in both forced swimming test and tail suspension test. However, it is unclear whether chronic ferulic acid treatment can ameliorate the depressive-like behaviors in chronic unpredictable mild stress (CUMS). Because of the putative relationship between neurotrophic system and antidepressant-like activity, we also investigated the effects of chronic ferulic acid on the brain-derived neurotrophic factor (BDNF), postsynaptic protein PSD95, presynaptic protein synapsin I in both prefrontal cortex and hippocampus. The results showed that ferulic acid significantly alleviated CUMS-induced depressive-like behaviors in sucrose preference test and forced swimming test. In addition, ferulic acid significantly up-regulated the levels of BDNF, PSD95 and synapsin I in the prefrontal cortex and hippocampus. The present data indicated that ferulic acid exerted the antidepressant-like effects on behaviors by increasing neurotrophin-related synaptic protein levels in CUMS mice. Copyright © 2016. Published by Elsevier Inc.

Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice

PubMed Central

2011-01-01

Exogenous administration of insulin-like growth factor (IGF)-I has anti-depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF) while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng) was administered intracerebroventricularly (i.c.v.) to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng). Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST). Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1ß (IL-1ß), tumor necrosis factor-(TNF)α, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP). Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior. PMID:21306618

Association of the MAOA promoter uVNTR polymorphism with suicide attempts in patients with major depressive disorder

PubMed Central

2011-01-01

Background The MAOA uVNTR polymorphism has been documented to affect the MAOA gene at the transcriptional level and is associated with aggressive impulsive behaviors, depression associated with suicide (depressed suicide), and major depressive disorder (MDD). We hypothesized that the uVNTR polymorphism confers vulnerability to MDD, suicide or both. The aim of this study was to explore the association between the MAOA uVNTR and depressed suicide, using multiple controls. Methods Four different groups were included: 432 community controls, 385 patients with MDD who had not attempted suicide, 96 community subjects without mental disorders who had attempted suicide, and 109 patients with MDD who had attempted suicide. The MAOA uVNTR polymorphism was genotyped by a PCR technique. The symptom profiles and personal characteristics in each group were also compared. Results The MAOA 4R allele was more frequent in males with MDD than in male community controls (χ2 = 4.182, p = 0.041). Logistic regression analysis showed that, among the depressed subjects, those younger in age, more neurotic or who smoked had an increased risk of suicide (β = -0.04, p = 0.002; β = 0.15, p = 0.017; β = 0.79, p = 0.031, respectively). Moreover, among those who had attempted suicide, those younger in age, with more paternal overprotection, and more somatic symptoms were more likely to be in the MDD group than in the community group (β = -0.11, p < 0.001; β = 0.15, p = 0.026; β = 1.11, p < 0.001). Structural equation modeling (SEM) showed that nongenetic factors, such as age, paternal overprotection, and somatic symptoms, were associated with MDD, whereas depressed suicide were associated with severity of depression, personality traits, age, marital status, and inversely associated with anxiety symptoms. However, depression did not affect suicidal behavior in the community group. Conclusion The MAOA 4R allele is associated with enhanced vulnerability to suicide in depressed males, but not in community subjects. The MAOA 4R allele affects vulnerability to suicide through the mediating factor of depressive symptoms. Further large-scale studies are needed to verify the psychopathology of the relationships among MAOA uVNTR polymorphism, symptom profiles, and suicidal behavior. PMID:21605465

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal.

PubMed

Haj-Mirzaian, Arvin; Amiri, Shayan; Amini-Khoei, Hossein; Haj-Mirzaian, Arya; Hashemiaghdam, Arsalan; Ramezanzadeh, Kiana; Ghesmati, Maria; Afshari, Khashayar; Dehpour, Ahmad Reza

2018-05-01

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW. Copyright © 2018. Published by Elsevier Inc.

Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study.

PubMed

Sun, Peng; Wang, Furong; Wang, Li; Zhang, Yu; Yamamoto, Ryo; Sugai, Tokio; Zhang, Qing; Wang, Zhengda; Kato, Nobuo

2011-11-09

Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

Cognitive-Behavioral Treatment of Depressed Affect among Epileptics: Preliminary Findings.

ERIC Educational Resources Information Center

Davis, Gay R.; And Others

1984-01-01

Evaluated a program where cognitive-behavioral methods were utilized in a structured learning format with clinically depressed epileptics (N=13). Results indicated that cognitive behavioral interventions result in significant decreases in depression and increases in related areas of psychosocial functioning that are maintained over time. (LLL)

Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

PubMed

Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

2016-04-01

A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin receptor sensitizer, dicholine succinate, prevents both Toll-like receptor 4 (TLR4) upregulation and affective changes induced by a high-cholesterol diet in mice.

PubMed

Strekalova, Tatyana; Costa-Nunes, João P; Veniaminova, Ekaterina; Kubatiev, Aslan; Lesch, Klaus-Peter; Chekhonin, Vladimir P; Evans, Matthew C; Steinbusch, Harry W M

2016-05-15

High cholesterol intake in mice induces hepatic lipid dystrophy and inflammation, signs of non-alcoholic fatty liver disease (NAFLD), depressive- and anxiety-like behaviors, and the up-regulation of brain and liver Toll-like receptor 4 (Tlr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects. C57BL/6J mice were given a 0.2%-cholesterol diet for 3 weeks, alone or along with oral DS administration, or a control feed. Outcomes included behavioral measures of anxiety/depression, and Tlr4 and peroxisome-proliferator-activated-receptor-gamma coactivator-1b (PPARGC1b) expression. 50mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180mg/kg), either for the 3-week period of dietary intervention, or for the last two weeks. Three-week DS administration normalized behaviors in the forced swim and O-maze tests and abolished the Tlr4 up-regulation in the brain and liver. The delayed, 2-week DS treatment had similar effects on Tlr4 expression and largely rescued the above-mentioned behaviors. Suppression of PPARGC1b, a master regulator of mitochondrial biogenesis, by the high cholesterol diet, was prevented with the 3-week administration, and markedly diminished by the a 2-week administration of DS. None of treatments prevented hepatic dystrophy and triglyceride accumulation. Other conditions have to be tested to define possible limitations of reported effects of DS. DS treatment did not alter the patho-morphological substrates of NAFLD syndrome in mice, but ameliorated its molecular and behavioral consequences, likely by activating mitochondrial functions and anti-inflammatory mechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice.

PubMed

Liu, Yen-Wenn; Liu, Wei-Hsien; Wu, Chien-Chen; Juan, Yi-Chen; Wu, Yu-Chen; Tsai, Huei-Ping; Wang, Sabrina; Tsai, Ying-Chieh

2016-01-15

Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

PubMed Central

Allen, Patricia J.; D'Anci, Kristen E.; Kanarek, Robin B.; Renshaw, Perry F.

2013-01-01

The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. PMID:22429992

Maternal depressive symptoms and child care during toddlerhood relate to child behavior at age 5 years.

PubMed

Giles, Lynne C; Davies, Michael J; Whitrow, Melissa J; Warin, Megan J; Moore, Vivienne

2011-07-01

Disentangling the effects of maternal depression in toddlerhood from concurrent maternal depression on child behavior is difficult from previous research. Child care may modify any effects of maternal depression on subsequent child behavior, but this has not been widely investigated. We examined the influence of maternal depressive symptoms during toddlerhood on children's behavior at the age of 5 years and investigated if formal or informal child care during toddlerhood modified any relationship observed. Data were available from 438 mothers and their children (227 girls and 211 boys); the mothers who completed questionnaires during the children's infancy, in toddlerhood, and at the age of 5 years. Recurrent maternal depressive symptoms in toddlerhood (when study children were aged 2 and 3½ years) was a significant risk factor for internalizing, externalizing, and total behavior problems when children were aged 5 years. Intermittent maternal depressive symptoms (study child age 2 or 3½ years) did not significantly affect child behavior problems. Formal child care at the age of 2 years modified the effect of recurrent maternal depressive symptoms on total behavior problems at age 5 years. Informal child care in toddlerhood did not significantly affect child behavior problems. Recurrent, but not intermittent, maternal depressive symptoms when children were toddlers were associated with child behavior problems at age 5 years. As little as half a day in formal child care at the age of 2 years significantly modified the effect of recurrent maternal depressive symptoms on total behavior problems. Formal child care for toddlers of depressed mothers may have positive benefits for the child's subsequent behavior. Copyright © 2011 by the American Academy of Pediatrics.

Overt Social Support Behaviors: Associations With PTSD, Concurrent Depressive Symptoms and Gender

PubMed Central

Crevier, Myra G.; Marchand, André; Nachar, Nadim; Guay, Stéphane

2013-01-01

Women are twice as likely as men to develop a posttraumatic stress disorder (PTSD). Gender differences in social support after a traumatic event might partially explain this disparity. However, the portrait of the links among PTSD, depression, social support, and gender is still unclear. This study examined behaviors of individuals with PTSD and their significant other in relation to PTSD and concurrent depressive symptoms, and tested gender as a moderator of these associations. Observed overt supportive and countersupportive behaviors of 68 dyads composed of an individual with PTSD and a significant other in a trauma-oriented discussion were coded with a support coding system and analyzed according to gender. Gender was revealed to act as a moderator of the links between interactional behaviors of individuals with PTSD and their concurrent depressive symptoms. More specifically, women were less implicated and less likely to propose positive solutions compared with men. On the other hand, men were more implicated and less likely to criticize their significant other than were women. PTSD and concurrent depressive symptoms were related to poorer interpersonal communication in women. Hence, women and men with PTSD and concurrent depressive symptoms might benefit from gender-tailored interventions targeting symptoms and dyadic behaviors. PMID:26440610

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression.

PubMed

Cline, Brandon H; Costa-Nunes, Joao P; Cespuglio, Raymond; Markova, Natalyia; Santos, Ana I; Bukhman, Yury V; Kubatiev, Aslan; Steinbusch, Harry W M; Lesch, Klaus-Peter; Strekalova, Tatyana

2015-01-01

Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

PubMed Central

Cline, Brandon H.; Costa-Nunes, Joao P.; Cespuglio, Raymond; Markova, Natalyia; Santos, Ana I.; Bukhman, Yury V.; Kubatiev, Aslan; Steinbusch, Harry W. M.; Lesch, Klaus-Peter; Strekalova, Tatyana

2015-01-01

Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies. PMID:25767439

Boredom, depressive symptoms, and HIV risk behaviors among urban injection drug users.

PubMed

German, Danielle; Latkin, Carl A

2012-11-01

Boredom is closely aligned with depression, but is understood to be conceptually distinct. Little is known about boredom among active drug users and the potential association with depression and HIV risk. Current IDUs (n = 845) completed a baseline behavioral survey including socio-demographic characteristics, self-reported boredom, depressive symptoms (CESD score), and HIV risk behaviors. One-third of the sample reported high boredom in the past week. In multivariate analysis, those who reported boredom were less likely to be older, African-American, have a main partner, and to be employed at least part-time. Controlling for covariates, those with high boredom were almost five times as likely to report high depressive symptoms. Co-occurrence of boredom and depressive symptoms (28 %) was strongly and independently associated with a range of injection risk behaviors and sex exchange. This study demonstrates the need for more thorough understanding of mental health and HIV risk among urban drug users.

Subchronic perinatal asphyxia increased anxiety-and depression-like behaviors in the rat offspring.

PubMed

Sedláčková, Natália; Krajčiová, Martina; Koprdová, Romana; Ujházy, Eduard; Brucknerová, Ingrid; Mach, Mojmír

2014-01-01

Perinatal asphyxia is one of the major cause of mortality in newborns and cause of neurological disorders in adulthood. Brain damage is of the most concern due to high sensitivity of nervous system to suboptimal intrauterine oxygen condition. The aim of this study was to assess effect of subchronic prenatal asphyxia (SPA) during sensitive stages of brain maturation on behavioral changes in rats, as a method of prenatal programming of anxiety and depression-like behavior. Pregnant Wistar/DV females were exposed to environment containing lower oxygen (10.5% O2) during sensitive stages of brain maturation (day 19-20 of gestation) for 4h a day and anxiety- and depression-like behaviors in offspring were assessed using battery of behavioral tests--Open field (OF), Elevated plus maze (EPM), Light/dark test (L/D), Forced swim test (FST), and Stress induced hyperthermia (SIH). OF did not induced changes of locomotor and exploration activities. The anxiety-like behavior was induced by SPA in EPM and L/D. These results were significant in males SPA group only. The higher response to the stress stimulus in SIH was recorded in both males and females SPA group. The intensity of climbing on the walls of cylinder in FST in males SPA group was significantly decreased indicating depression-like behavior in adulthood. In conclusion, we found out that perinatal asphyxia on 19th and 20th day of gestation caused anxiety- and depression-like behaviors in the rat offspring. Our model of SPA has proved to be useful to study the conditions of asphyxia during pregnancy, and could be suitable model for studies uncovering the mechanisms of prenatal programming of psychiatric diseases.

Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents.

PubMed

Huang, Hui-Jie; Zhu, Xiao-Cang; Han, Qiu-Qin; Wang, Ya-Lin; Yue, Na; Wang, Jing; Yu, Rui; Li, Bing; Wu, Gen-Cheng; Liu, Qiong; Yu, Jin

2017-05-30

As a regulator of food intake, ghrelin also plays a key role in mood disorders. Previous studies reported that acute ghrelin administration defends against depressive symptoms of chronic stress. However, the effects of long-term ghrelin on rodents under chronic stress hasn't been revealed. In this study, we found chronic peripheral administration of ghrelin (5nmol/kg/day for 2 weeks, i.p.) could alleviate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress (CUMS). The depression-like behaviors were assessed by the forced swimming test (FST), and anxiety-like behaviors were assessed by the open field test (OFT) and the elevated plus maze test (EPM). Meanwhile, we observed that peripheral acylated ghrelin, together with gastral and hippocampal ghrelin prepropeptide mRNA level, were significantly up-regulated in CUMS mice. Besides, the increased protein level of growth hormone secretagogue receptor (GHSR) in hippocampus were also detected. These results suggested that the endogenous ghrelin/GHSR pathway activated by CUMS plays a role in homeostasis. Further results showed that central treatment of ghrelin (10μg/rat/day for 2 weeks, i.c.v.) or GHRP-6 (the agonist of GHSR, 10μg/rat/day for 2 weeks, i.c.v.) significantly alleviated the depression-like behaviors induced by CUMS in FST and sucrose preference test (SPT). Based on these results, we concluded that central GHSR is involved in the antidepressant-like effect of exogenous ghrelin treatment, and ghrelin/GHSR may have the inherent neuromodulatory properties against depressive symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

Involvement of Melatonin in Changing Depression-Like and Aggressive Behaviour in Rats Under Moderate Electromagnetic Shielding

NASA Astrophysics Data System (ADS)

Temuryants, N. A.; Tumanyants, K. N.; Khusainov, D. R.; Cheretaev, I. V.; Tumanyants, E. N.

2017-12-01

It was found that moderate electromagnetic shielding, which attenuates constant and variable components of the geomagnetic field (19 h per day for 10 days), induces in male rats the development of depression-like behavior. This behavior is diagnosed on the basis of increased passive swimming time and a decreased duration of active swimming in the Porsolt test. These behaviors reach their peak on days 3-4 of the experiment. The daily administration of 1 mg/kg exogenous melatonin reduces these depression-like behaviors as soon as day 1 of the experiment, and this effect persists throughout all stages of the experiment. Electromagnetic shielding and the administration of 1 mg/kg exogenous melatonin do not change the levels of intraspecies aggressiveness. An increase in melatonin dosage to 5 mg/kg even further reduces depression-like symptoms and stops the increase in intraspecies aggressiveness during the experiment. The conclusion is made that melatonin plays an important role in the mechanisms of physiological effects of a weakened electromagnetic geomagnetic field.

Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice.

PubMed

Heshmati, Mitra; Golden, Sam A; Pfau, Madeline L; Christoffel, Daniel J; Seeley, Elena L; Cahill, Michael E; Khibnik, Lena A; Russo, Scott J

2016-02-01

Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ingestion of dried-bonito broth (dashi) facilitates PV-parvalbumin-immunoreactive neurons in the brain, and affects emotional behaviors in mice.

PubMed

Jargalsaikhan, Undarmaa; Nishimaru, Hiroshi; Matsumoto, Jumpei; Takamura, Yusaku; Nakamura, Tomoya; Hori, Etsuro; Kondoh, Takashi; Ono, Taketoshi; Nishijo, Hisao

2017-12-01

Emerging evidence suggests that traditional diets and nutrition have a significant impact on brain development, and could contribute to the promotion of mental health and prevention of psychiatric disorders in children and adolescents. Moreover, deficits in parvalbumin (PV)-immunoreactive and/or GABAergic neurons are closely associated with various psychiatric disorders in children and adolescents. To investigate the possible neural mechanisms of diet involvement in mental health, we analyzed the effects of dried-bonito dashi (Japanese fish broth) (DBD) on PV-immunoreactive neurons and emotional behaviors in young mice. Male mice after weaning were fed DBD for 60 days, and tested with a resident-intruder test for aggressiveness and a forced swimming test for depression-like symptoms. After the behavioral testing, PV-immunoreactive neurons in the brain were immunohistochemically analyzed. The results indicated that DBD intake decreased aggressiveness and depression-like symptoms, and increased the densities of PV-immunoreactive neurons in the medial prefrontal cortex (mPFC), amygdala, hippocampus, and superior colliculus. These behavioral changes were correlated with the densities of PV-immunoreactive neurons in the mPFC, amygdala, and hippocampus. However, subdiaphragmatic vagotomy did not affect the effects of DBD on emotional behaviors, although it nonspecifically decreased the densities of PV-immunoreactive neurons. The results suggest that DBD might modulate emotional behaviors by promoting PV-immunoreactive and/or GABAergic neuronal activity through parallel routes. The present results highlight a new mechanism for diet involvement in brain functions, and suggest that DBD might have therapeutic potential for the promotion of mental health.

Highly palatable food access during adolescence increased anxiety-/depression-like behaviors in male, but not in female, rats.

PubMed

Kim, Jin Young; Kim, Doyun; Park, Kyungpyo; Lee, Jong-Ho; Jahng, Jeong Won

2017-04-11

This study was conducted to examine the sexual dimorphic effects of highly palatable food (HPF) access during adolescence on the neurochemistry and depression-/anxiety-like behaviors of rats. Male and female Sprague-Dawley pups had free access to chocolate cookie rich in fat (HPF) from postnatal day 28 in addition to ad libitum chow, and the control groups received only chow. The food conditions were continued throughout the entire experimental period, and the neurochemical and behavioral measurements were performed during young adulthood. Rats were subjected to the ambulatory activity, elevated plus maze, and forced swim tests. Corticosterone levels during 2 h of restraint stress were analyzed with radioimmunoassay, and ΔFosB and brain-derived neurotrophic factor (BDNF) expression in the nucleus accumbens (NAc) with Western blot analysis. Cookie access did not affect body weight gain and total caloric intake in both sexes; however, it increased retroperitoneal fat depot only in males. The time spent in open arms during elevated plus maze test was decreased and immobility during forced swim test was increased in cookie-fed males, but not in cookie-fed females. Main effect of food condition on the stress-induced corticosterone increase was observed in males, but not in females, and cookie access increased BDNF expression in the NAc only in males. Increased BDNF expression in the NAc and fat depot, in addition to the stress axis dysfunction, may play roles in the pathophysiology of depression- and/or anxiety-like behaviors induced by cookie access.

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

PubMed

Cattani, Daiane; Cesconetto, Patrícia Acordi; Tavares, Mauren Kruger; Parisotto, Eduardo Benedetti; De Oliveira, Paulo Alexandre; Rieg, Carla Elise Heinz; Leite, Marina Concli; Prediger, Rui Daniel Schröder; Wendt, Nestor Cubas; Razzera, Guilherme; Filho, Danilo Wilhelm; Zamoner, Ariane

2017-07-15

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[ 14 C]-glutamate uptake and increased 45 Ca 2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: Chronic lithium treats most, but not all features

PubMed Central

van Enkhuizen, Jordy; Milienne-Petiot, Morgane; Geyer, Mark A.; Young, Jared W.

2015-01-01

Rationale Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD. Objectives We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment. Methods C57BL/6J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for ‘behavioral despair’ (immobility) in the tail-suspension test (TST) and forced-swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM. Results Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml). Conclusions Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics. PMID:26141192

Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic-Pituitary-Adrenal Axis Function and Activating BDNF Signaling Pathway.

PubMed

Zu, Xianpeng; Zhang, Mingjian; Li, Wencai; Xie, Haisheng; Lin, Zhang; Yang, Niao; Liu, Xinru; Zhang, Weidong

2017-11-01

Preliminary studies conducted in our laboratory have confirmed that Bacopaside I (BS-I), a saponin compound isolated from Bacopa monnieri, displayed antidepressant-like activity in the mouse behavioral despair model. The present investigation aimed to verify the antidepressant-like action of BS-I using a mouse model of behavioral deficits induced by chronic unpredictable mild stress (CUMS) and further probe its underlying mechanism of action. Mice were exposed to CUMS for a period of 5 consecutive weeks to induce depression-like behavior. Then, oral gavage administrations with vehicle (model group), fluoxetine (12 mg/kg, positive group) or BS-I (5, 15, 45 mg/kg, treated group) once daily were started during the last two weeks of CUMS procedure. The results showed that BS-I significantly ameliorated CUMS-induced depression-like behaviors in mice, as characterized by an elevated sucrose consumption in the sucrose preference test and reduced immobility time without affecting spontaneous locomotor activity in the forced swimming test, tail suspension test and open field test. It was also found that BS-I treatment reversed the increased level of plasma corticosterone and decreased mRNA and protein expressions of glucocorticoid receptor induced by CUMS exposure, indicating that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity of CUMS-exposed mice was restored by BS-I treatment. Furthermore, chronic administration of BS-I elevated expression levels of brain-derived neurotrophic factor (BDNF) (mRNA and protein) and activated the phosphorylation of extracellular signal-regulated kinase and cAMP response element-binding protein in the hippocampus and prefrontal cortex in mice subjected to CUMS procedure. Taken together, these results indicated that BS-I exhibited an obvious antidepressant-like effect in mouse model of CUMS-induced depression that was mediated, at least in part, by modulating HPA hyperactivity and activating BDNF signaling pathway.

Fathers' Depression Related to Positive and Negative Parenting Behaviors With 1-Year-Old Children

PubMed Central

Davis, Matthew M.; Freed, Gary L.; Clark, Sarah J.

2011-01-01

OBJECTIVE: To examine the associations between depression in fathers of 1-year-old children and specific positive and negative parenting behaviors discussed by pediatric providers at well-child visits. METHODS: We performed a cross-sectional secondary analysis by using interview data from 1746 fathers of 1-year-old children in the Fragile Families and Child Wellbeing Study. Positive parenting behaviors included fathers' reports of playing games, singing songs, and reading stories to their children ≥3 days in a typical week. Negative parenting behavior included fathers' reports of spanking their 1-year-old children in the previous month. Depression was assessed by using the World Health Organization Composite International Diagnostic Interview Short Form. Weighted bivariate and multivariate analyses of parenting behaviors were performed while controlling for demographics and paternal substance abuse. RESULTS: Overall, 7% of fathers had depression. In bivariate analyses, depressed fathers were more likely than nondepressed fathers to report spanking their 1-year-old children in the previous month (41% compared with 13%; P < .01). In multivariate analyses, depressed fathers were less likely to report reading to their children ≥3 days in a typical week (adjusted odds ratio: 0.38 [95% confidence interval: 0.15–0.98]) and much more likely to report spanking (adjusted odds ratio: 3.92 [95% confidence interval: 1.23–12.5]). Seventy-seven percent of depressed fathers reported talking to their children's doctor in the previous year. CONCLUSIONS: Paternal depression is associated with parenting behaviors relevant to well-child visits. Pediatric providers should consider screening fathers for depression, discussing specific parenting behaviors (eg, reading to children and appropriate discipline), and referring for treatment if appropriate. PMID:21402627

The Mental and Emotional Well-Being of Children: A Portrait of States and the Nation 2007. The National Survey of Children's Health

ERIC Educational Resources Information Center

US Department of Health and Human Services, 2010

2010-01-01

Children, like adults, may have mental health problems, including depression and anxiety. They may also have behavioral conditions, such as conduct disorders; cognitive disorders, such as autism spectrum disorder; or neurological conditions, such as Tourette Syndrome. Children may also be affected by delays in their physical, cognitive, or…

Peony glycosides reverse the effects of corticosterone on behavior and brain BDNF expression in rats.

PubMed

Mao, Qing-Qiu; Huang, Zhen; Ip, Siu-Po; Xian, Yan-Fang; Che, Chun-Tao

2012-02-01

Repeated injections of corticosterone (CORT) induce the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depressive-like behavior. This study aimed to examine the antidepressant-like effect and the possible mechanisms of total glycosides of peony (TGP) in the CORT-induced depression model in rats. The results showed that the 3-week CORT injections induced the significant increase in serum CORT levels in rats. Repeated CORT injections also caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Moreover, it was found that brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex were significantly decreased in CORT-treated rats. Treatment of the rats with TGP significantly suppressed the depression-like behavior and increased brain BDNF levels in CORT-treated rats. The results suggest that TGP produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex. Copyright © 2011 Elsevier B.V. All rights reserved.

Relationship Functioning Moderates the Association Between Depressive Symptoms and Life Stressors

PubMed Central

Trombello, Joseph M.; Schoebi, Dominik; Bradbury, Thomas N.

2017-01-01

Data from 172 newlywed couples were collected over the first 4 years of marriage to test how behaviors demonstrated during marital interactions moderate associations between depressive symptoms and subsequent life stressors. Depressive symptoms and behaviors coded from problem-solving and social support interactions were analyzed as predictors of nonmarital stressors that were interpersonal and dependent on the participant's actions. Behavioral codes were found to moderate 3 of 16 symptom-to-life event associations for husbands. Husbands' reports of more depressive symptoms predicted greater levels of stress when husbands' positive affect and hard negative affect during problem-solving were relatively infrequent and when wives made frequent displays of positive behaviors during husbands' support topics. These effects remained after controlling for marital satisfaction. For wives, behavioral moderators did not interact with depressive symptoms to predict changes in stress, but marital satisfaction consistently interacted with depressive symptoms to predict future stressors beyond interpersonal behaviors. Specifically, for wives, stress generation was more evident when relationship satisfaction was low than when it was high. Our results, though different for men and women, suggest that relationship functioning can alter associations between depressive symptoms and life stress in the early years of marriage. PMID:21355647

Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

PubMed

Poretti, María Belén; Sawant, Rahul S; Rask-Andersen, Mathias; de Cuneo, Marta Fiol; Schiöth, Helgi B; Perez, Mariela F; Carlini, Valeria Paola

2016-03-01

In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states. The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior. In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland. The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline. The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus.

PubMed

Song, Xiaoyu; Liu, Bo; Cui, Lingyu; Zhou, Biao; Liu, Weiwei; Xu, Fanxing; Hayashi, Toshihiko; Hattori, Shunji; Ushiki-Kaku, Yuko; Tashiro, Shin-Ichi; Ikejima, Takashi

2017-10-01

Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin, a flavonoid derived from milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Aβ-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Aβ1-42-treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Aβ1-42-injected rats. Silibinin-treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Xiaoyaosan Improves Depressive-Like Behaviors in Mice through Regulating Apelin-APJ System in Hypothalamus.

PubMed

Yan, Zhiyi; Jiao, Haiyan; Ding, Xiufang; Ma, Qingyu; Li, Xiaojuan; Pan, Qiuxia; Wang, Tingye; Hou, Yajing; Jiang, Youming; Liu, Yueyun; Chen, Jiaxu

2018-05-03

Background: The apelin-APJ system has been considered to play a crucial role in HPA axis function, and how the traditional Chinese compound prescription Xiaoyaosan regulates the apelin-APJ system as a supplement to treat depressive disorders. Objective: To investigate the depression-like behaviors and expression of apelin and APJ in hypothalamus of chronic unpredictable mild stress (CUMS) mice and study whether these changes related to the regulation of Xiaoyaosan. Methods: 60 adult C57BL/6J mice were randomly divided into four groups, including control group, CUMS group, Xiaoyaosan treatment group and fluoxetine treatment group. Mice in the control group and CUMS group received 0.5 mL physiological saline once a day by intragastric administration. Mice in two treatment groups received Xiaoyaosan (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. After 21 days of modeling with CUMS, the expression of apelin and APJ in hypothalamus were measured by real-time fluorescence quantitative PCR, western blot and immunohistochemical staining. The physical condition, body weight, food intake and behavior tests such as open field test, sucrose preference test and force swimming test were measured to evaluate depressive-like behaviors. Results: In this study, significant behavioral changes were found in CUMS-induced mice, meanwhile the expressions of apelin and APJ in the hypothalamus were changed after modeling. The body weight, food-intake and depressive-like behaviors in CUMS-induced mice could be improved by Xiaoyaosan treatment which is similar with the efficacy of fluoxetine, while the expressions of apelin and APJ in hypothalamus were modified by Xiaoyaosan. Conclusions: The data suggest that apelin-APJ system changes in the hypothalamus may be a target of depressive disorders, and the beneficial effects of Chinese compound prescription Xiaoyaosan on depressive-like behaviors may be mediated by the apelin-APJ system.

Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits

PubMed Central

Beurel, E; Jope, R S

2014-01-01

Suicide is one of the leading causes of death in the United States, yet it remains difficult to understand the mechanistic provocations and to intervene therapeutically. Stress is recognized as a frequent precursor to suicide. Psychological stress is well established to cause activation of the inflammatory response, including causing neuroinflammation, an increase of inflammatory molecules in the central nervous system (CNS). Neuroinflammation is increasingly recognized as affecting many aspects of CNS functions and behaviors. In particular, much evidence demonstrates that inflammatory markers are elevated in traits that have been linked to suicidal behavior, including aggression, impulsivity and depression. Lithium is recognized as significantly reducing suicidal behavior, is anti-inflammatory and diminishes aggression, impulsivity and depression traits, each of which is associated with elevated inflammation. The anti-inflammatory effects of lithium result from its inhibition of glycogen synthase kinase-3 (GSK3). GSK3 has been demonstrated to strongly promote inflammation, aggressive behavior in rodents and depression-like behaviors in rodents, whereas regulation of impulsivity by GSK3 has not yet been investigated. Altogether, evidence is building supporting the hypothesis that stress activates GSK3, which in turn promotes inflammation, and that inflammation is linked to behaviors associated with suicide, including particularly aggression, impulsivity and depression. Further investigation of these links may provide a clearer understanding of the causes of suicidal behavior and provide leads for the development of effective preventative interventions, which may include inhibitors of GSK3. PMID:25514751

Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits.

PubMed

Beurel, E; Jope, R S

2014-12-16

Suicide is one of the leading causes of death in the United States, yet it remains difficult to understand the mechanistic provocations and to intervene therapeutically. Stress is recognized as a frequent precursor to suicide. Psychological stress is well established to cause activation of the inflammatory response, including causing neuroinflammation, an increase of inflammatory molecules in the central nervous system (CNS). Neuroinflammation is increasingly recognized as affecting many aspects of CNS functions and behaviors. In particular, much evidence demonstrates that inflammatory markers are elevated in traits that have been linked to suicidal behavior, including aggression, impulsivity and depression. Lithium is recognized as significantly reducing suicidal behavior, is anti-inflammatory and diminishes aggression, impulsivity and depression traits, each of which is associated with elevated inflammation. The anti-inflammatory effects of lithium result from its inhibition of glycogen synthase kinase-3 (GSK3). GSK3 has been demonstrated to strongly promote inflammation, aggressive behavior in rodents and depression-like behaviors in rodents, whereas regulation of impulsivity by GSK3 has not yet been investigated. Altogether, evidence is building supporting the hypothesis that stress activates GSK3, which in turn promotes inflammation, and that inflammation is linked to behaviors associated with suicide, including particularly aggression, impulsivity and depression. Further investigation of these links may provide a clearer understanding of the causes of suicidal behavior and provide leads for the development of effective preventative interventions, which may include inhibitors of GSK3.

Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats

PubMed Central

Pyter, Leah M.; Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2013-01-01

Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective-like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37–48) and were challenged with lipopolysaccharide (LPS; 250 μg/kg, i.p.) or saline 4.5 weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective-like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation. PMID:23348027

A Prospective Investigation of Affect, the Desire to Gamble, Gambling Motivations and Gambling Behavior in the Mood Disorders.

PubMed

Quilty, Lena C; Watson, Chris; Toneatto, Tony; Bagby, R Michael

2017-03-01

Time-sampling methodology was implemented to examine the prospective associations between affect, desire to gamble, and gambling behavior in individuals diagnosed with a mood disorder. Thirty (9 male, 21 female) adults with a lifetime diagnosis of a depressive or bipolar disorder diagnosis who endorsed current gambling and lifetime gambling harm participated in the present study. Participants completed electronic diary entries of their current affective state, desire to gamble, and gambling behavior for 30 consecutive days. Hierarchical linear modelling revealed that affect was not a predictor of gambling behavior. Instead, affect predicted the desire to gamble, with high levels of sadness and arousal independently predicting an increased desire to gamble. Desire to gamble predicted actual gambling behavior. There were no differences across diagnostic groups in terms of gambling motivations at baseline; however, during the 30-day period, participants with bipolar disorder endorsed gambling to cope with negative affect more often than did participants with depressive disorder, whereas those with depressive disorder more often endorsed gambling for social reasons or enhancement of positive affect. The present findings provide evidence that negative affect is not directly related to actual gambling behavior, and suggest that affective states rather impact the desire to gamble.

HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

PubMed Central

Zhong, Peng; Vickstrom, Casey R; Liu, Xiaojie; Hu, Ying; Yu, Laikang; Yu, Han-Gang

2018-01-01

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors. PMID:29256865

[Vulnerability to depression in children and adolescents: update and perspectives].

PubMed

Purper-Ouakil, D; Michel, G; Mouren-Siméoni, M-C

2002-01-01

Depression in children and adolescents is associated with poor psychosocial functioning, high psychiatric comorbidity, risk of recurrent episodes or onset of bipolar disorder. These findings emphasize the importance of early identification of children and adolescents having elevated risk for future depression and further development, evaluation and greater availability of prevention strategies. Our review aims an update about depressive vulnerability in children and adolescents in the perspective of better identification of at-risk populations and targeting of prevention programs. Psychopathology, in particular anxiety and disruptive disorders are well identified risk-factors for later depression. Subclinical depressive symptomatology, also termed "demoralization", also identifies high-risk populations, likely to become incident cases of depression. It is still unclear whether this condition is prodromal depression, a specific clinical entity or the expression of biological and/or cognitive vulnerability. Familial risk for depressive disorders involves both genetic and psychosocial factors. Marital discord, poor communication and dysfunctional parenting practices are often present in families with affective disorders and can be implicated in increased depressive vulnerability in the offspring. Research on individual vulnerability in children and adolescents has focused on temperamental and cognitive characteristics. Temperament traits describe individual differences in reactivity and behavior. High emotionality, defined as the tendency to become upset easily and intensely has been associated with an increased risk for subsequent major depression. However, as the majority of high scorers will not become depressive cases, emotionality should not be the only criterion for selection of at-risk populations. Cognitive style including poor self esteem, low social competence and negative attributions are also associated with increased likelihood of depressive symptoms, but their predictive value for the onset of clinical depressive episodes needs further investigation. Familial and individual vulnerability is likely to heighten the depressogenic impact of life events and psycho-social adversity. Prevention interventions have been developed in the United States for children and adolescents at-risk for depression. In France, clinicians witness growing demands from families with affective illness concerned with risk of parent-child transmission of depressive vulnerability, prevention and early identification of symptoms. To meet this kind of emerging needs and to prevent family dysfunction, a preventive program targets offspring of depressed parents and uses clinician-based family approaches. Family and individual sessions aim a better understanding of illness experience and encourage the parents to identify and foster resilience in their children. Another type of preventive intervention focuses on children and adolescents with subclinical depressive symptoms, eventually associated with behavioral problems ou high level of parental conflict, recruited in school settings. These school-based interventions combine cognitive and social problem-solving techniques. Both familial and school-based preventive interventions have proven applicable and promising in high-risk children and adolescents. Perspectives are more systematic identification of risk groups, including youngsters with past or current non affective symptoms who might benefit from depression prevention, long-term evaluation and cross-cultural applications of prevention programs.

Self-Esteem Reactivity Among Mothers of Children with Attention-Deficit/Hyperactivity Disorder: The Moderating Role of Depression History

PubMed Central

Gamble, Stephanie A.; Chronis-Tuscano, Andrea; Roberts, John E.; Ciesla, Jeffrey A.; Pelham, William E.

2013-01-01

This study examined self-esteem reactivity to a variety of contextual cues in a sample of women prone to depression. Participants were 49 mothers of children with attention-deficit/hyperactivity disorder. Across a 9-month time-period, participants completed weekly measures of self-esteem, perceived stress, positive and negative affect, and child disruptive behavior. Results indicated that mothers reported lower self-esteem during weeks they experienced greater stress, lower positive affect, higher negative affect, and more inattentive, overactive, and oppositional behavior in their children. Depression history moderated these relationships such that mothers with prior histories of depression reported greater self-esteem reactivity to these cues than never depressed mothers. PMID:24443616

Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks.

PubMed

Muller, J M; Morelli, E; Ansorge, M; Gingrich, J A

2011-03-01

Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5-htt+/-) and serotonin transporter deficient (5-htt-/-) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt-/->5-htt+/->5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt-/- mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt-/- displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offer the possibility for future investigation of the neural basis underlying 5-htt genotype-by-stress interaction shown here. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Voluntary exercise enhances activity rhythms and ameliorates anxiety- and depression-like behaviors in the sand rat model of circadian rhythm-related mood changes.

PubMed

Tal-Krivisky, Katy; Kronfeld-Schor, Noga; Einat, Haim

2015-11-01

Physical exercise is a non-pharmacological treatment for affective disorders. The mechanisms of its effects are unknown although some suggest a relationship to synchronization of circadian rhythms. One way to explore mechanisms is to utilize animal models. We previously demonstrated that the diurnal fat sand rat is an advantageous model for studying the interactions between photoperiods and mood. The current study was designed to evaluate the effects of voluntary exercise on activity rhythms and anxiety and depression-like behaviors in sand rats as a step towards better understanding of the underlying mechanisms. Male sand rats were housed in short photoperiod (SP; 5h light/19 h dark) or neutral light (NP; 12h light/12h dark) regimens for 3 weeks and divided into subgroups with or without running wheels. Activity was monitored for 3 additional weeks and then animals were tested in the elevated plus-maze, the forced swim test and the social interaction test. Activity rhythms were enhanced by the running wheels. As hypothesized, voluntary exercise had significant effects on SP animals' anxiety- and depression-like behaviors but not on NP animals. Results are discussed in the context of interactions between physical exercise, circadian rhythms and mood. We suggest that the sand rat model can be used to explore the underlying mechanism of the effects of physical exercise for mood disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

PubMed

Alvarez-Ricartes, Nathalie; Oliveros-Matus, Patricia; Mendoza, Cristhian; Perez-Urrutia, Nelson; Echeverria, Florencia; Iarkov, Alexandre; Barreto, George E; Echeverria, Valentina

2018-02-27

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Sex and repeated restraint stress interact to affect cat odor-induced defensive behavior in adult rats.

PubMed

Perrot-Sinal, Tara S; Gregus, Andrea; Boudreau, Daniel; Kalynchuk, Lisa E

2004-11-19

The overall objective of the present experiment was to assess sex differences in the effects of repeated restraint stress on fear-induced defensive behavior and general emotional behavior. Groups of male and female Long-Evans rats received either daily restraint stress (stressed) or daily brief handling (nonstressed) for 21 consecutive days. On days 22-25, a number of behavioral tests were administered concluding with a test of defensive behavior in response to a predatory odor. Stressed and nonstressed males and females were exposed to a piece of cat collar previously worn by a female domestic cat (cat odor) or a piece of collar never worn by a cat (control odor) in a familiar open field containing a hide barrier. Rats displayed pronounced defensive behavior (increased hiding and risk assessment) and decreased nondefensive behavior (grooming, rearing) in response to the cat odor. Nonstressed females exposed to cat odor displayed less risk assessment behavior relative to nonstressed males exposed to cat odor. Restraint stress had little effect on defensive behavior in male rats but significantly increased risk assessment behaviors in females. Behavior on the Porsolt forced swim test (a measure of depression-like behavior) and the open field test (a measure of anxiety-like behavior) was not affected by stress or sex. These findings indicate the utility of the predator odor paradigm in detecting subtle shifts in naturally occurring anxiety-like behaviors that may occur differentially in males and females.

Tumor Growth Increases Neuroinflammation, Fatigue and Depressive-like Behavior Prior to Alterations in Muscle Function

PubMed Central

Norden, Diana M.; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J.; Wold, Loren E.; Reiser, Peter J.; Godbout, Jonathan P.; McCarthy, Donna O.

2014-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. PMID:25102452

Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function.

PubMed

Norden, Diana M; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J; Wold, Loren E; Reiser, Peter J; Godbout, Jonathan P; McCarthy, Donna O

2015-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. Copyright © 2014 Elsevier Inc. All rights reserved.

NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice.

PubMed

Amiri, Shayan; Alijanpour, Sakineh; Tirgar, Fatemeh; Haj-Mirzaian, Arya; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Rastegar, Mojgan; Ghaderi, Marzieh; Ghazi-Khansari, Mahmoud; Zarrindast, Mohammad-Reza

2016-08-04

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors. Copyright © 2016. Published by Elsevier Ltd.

Sleep moderates and mediates the relationship between acculturation and depressive symptoms in pregnant Mexican-American women

PubMed Central

D’Anna-Hernandez, Kimberly L.; Garcia, Esmeralda; Coussons-Read, Mary; Laudenslager, Mark L.; Ross, Randal G.

2016-01-01

Purpose Greater acculturation is associated with adverse perinatal outcomes in Mexican-American women, but the mechanisms by which acculturation influences perinatal outcomes are unclear. Pregnant acculturated Mexican-American women are more likely to engage in unhealthy prenatal behaviors relative to those less acculturated, including poor sleep. As sleep disruptions are associated with acculturation and negative perinatal outcomes, particularly maternal depression, alterations in sleep may adversely affect pregnant Mexican-American women. Methods Sixty pregnant women of Mexican descent completed surveys about sleep, acculturation, depressive symptoms and potential protective factor of social support. Results Acculturation, but not social support, significantly predicted increased sleep disruptions as well as overall feeling less refreshed upon waking across pregnancy. Moderation analysis indicated that more acculturated women who took longer to fall asleep reported increased depressive symptoms. Feeling refreshed upon waking also mediated the relationship between increased acculturation and elevated maternal depressive symptoms. Conclusions Acculturation and altered sleep contribute to greater risk in Mexican-American women for maternal depressive symptoms in the perinatal period. These findings have implications for prevention and treatment of maternal mental health disorders, which may adversely affect perinatal outcomes in the vulnerable Mexican-American population. PMID:26728897

Sleep Moderates and Mediates the Relationship Between Acculturation and Depressive Symptoms in Pregnant Mexican-American Women.

PubMed

D'Anna-Hernandez, Kimberly L; Garcia, Esmeralda; Coussons-Read, Mary; Laudenslager, Mark L; Ross, Randal G

2016-02-01

Greater acculturation is associated with adverse perinatal outcomes in Mexican-American women, but the mechanisms by which acculturation influences perinatal outcomes are unclear. Pregnant acculturated Mexican-American women are more likely to engage in unhealthy prenatal behaviors relative to those less acculturated, including poor sleep. As sleep disruptions are associated with acculturation and negative perinatal outcomes, particularly maternal depression, alterations in sleep may adversely affect pregnant Mexican-American women. Sixty pregnant women of Mexican descent completed surveys about sleep, acculturation, depressive symptoms and potential protective factor of social support. Acculturation, but not social support, significantly predicted increased sleep disruptions as well as overall feeling less refreshed upon waking across pregnancy. Moderation analysis indicated that more acculturated women who took longer to fall asleep reported increased depressive symptoms. Feeling refreshed upon waking also mediated the relationship between increased acculturation and elevated maternal depressive symptoms. Acculturation and altered sleep contribute to greater risk in Mexican-American women for maternal depressive symptoms in the perinatal period. These findings have implications for prevention and treatment of maternal mental health disorders, which may adversely affect perinatal outcomes in the vulnerable Mexican-American population.

Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

PubMed Central

Zhang, Kuo; Pan, Xing; Wang, Fang; Ma, Jie; Su, Guangyue; Dong, Yingxu; Yang, Jingyu; Wu, Chunfu

2016-01-01

Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID:27502757

Acceptance and Commitment Therapy and Behavioral Activation for the Treatment of Depression: Description and Comparison

ERIC Educational Resources Information Center

Kanter, Jonathan W.; Baruch, David E.; Gaynor, Scott T.

2006-01-01

The field of clinical behavior analysis is growing rapidly and has the potential to affect and transform mainstream cognitive behavior therapy. To have such an impact, the field must provide a formulation of and intervention strategies for clinical depression, the "common cold" of outpatient populations. Two treatments for depression have emerged:…

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

PubMed Central

Wong, Peiyan; Sze, Ying; Gray, Laura Jane; Chang, Cecilia Chin Roei; Cai, Shiwei; Zhang, Xiaodong

2015-01-01

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7–11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7–11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7–11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive-like behaviors. PMID:25964750

Two Chronic Stress Models Based on Movement Restriction in Rats Respond Selectively to Antidepressant Drugs: Aldolase C As a Potential Biomarker.

PubMed

Ampuero, Estibaliz; Luarte, Alejandro; Santibañez, Marcos; Varas-Godoy, Manuel; Toledo, Jorge; Diaz-Veliz, Gabriela; Cavada, Gabriel; Rubio, F Javier; Wyneken, Ursula

2015-03-26

Clinically depressed individuals respond to different types of antidepressants, suggesting that different neurobiological mechanisms may be responsible for their depression. However, animal models to characterize this are not yet available. We induced depressive-like behaviors in rats using 2 different chronic stress models: restraint in small cages or immobilization in adaptable plastic cones. Both models increased anxiety responses evaluated by novelty-suppressed feeding and the elevated plus-maze; increased learned helplessness evaluated by the tail suspension and forced swimming tests; and increased anhedonia evaluated by the sucrose preference test. We assessed the ability of 2 different types of antidepressants to ameliorate depressive-like behaviors. We administered the serotonin reuptake inhibitor fluoxetine or the noradrenaline reuptake inhibitor reboxetine once daily for 28 days to rats that received either chronic restraint or immobilization stress, or no stress. Behavioral analysis revealed that fluoxetine ameliorated depressive-like behaviors when induced by chronic restraint stress, whereas reboxetine ameliorated these behaviors when induced by chronic immobilization stress. To further test biological differences between both models, we evaluated the levels of Aldolase C, an enzyme expressed by forebrain astrocytes that is regulated by antidepressant treatment, in the cerebrospinal fluid: chronic restraint stress, but not immobilization stress, increased the levels of Aldolase C. Moreover, the presence of astrocyte-derived Aldolase C-GFP in the cerebrospinal fluid indicates its central origin. Two stress paradigms induced depressive-like behaviors that were sensitive to different antidepressant treatments. Biomarkers such as Aldolase C could help determine optimal antidepressant treatments for clinically depressed patients. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Social defeat stress causes depression-like behavior with metabolite changes in the prefrontal cortex of rats.

PubMed

Liu, Yi-Yun; Zhou, Xin-Yu; Yang, Li-Ning; Wang, Hai-Yang; Zhang, Yu-Qing; Pu, Jun-Cai; Liu, Lan-Xiang; Gui, Si-Wen; Zeng, Li; Chen, Jian-Jun; Zhou, Chan-Juan; Xie, Peng

2017-01-01

Major depressive disorder is a serious mental disorder with high morbidity and mortality. The role of social stress in the development of depression remains unclear. Here, we used the social defeat stress paradigm to induce depression-like behavior in rats, then evaluated the behavior of the rats and measured metabolic changes in the prefrontal cortex using gas chromatography-mass spectrometry. Within the first week after the social defeat procedure, the sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM) and forced swim test (FST) were conducted to examine the depressive-like and anxiety-like behaviors. For our metabolite analysis, multivariate statistics were applied to observe the distribution of all samples and to differentiate the socially defeated group from the control group. Ingenuity pathway analysis was used to find the potential relationships among the differential metabolites. In the OFT and EPM, there were no significant differences between the two experimental groups. In the SPT and FST, socially defeated rats showed less sucrose intake and longer immobility time compared with control rats. Metabolic profiling identified 25 significant variables with good predictability. Ingenuity pathways analysis revealed that "Hereditary Disorder, Neurological Disease, Lipid Metabolism" was the most significantly altered network. Stress-induced alterations of low molecular weight metabolites were observed in the prefrontal cortex of rats. Particularly, lipid metabolism, amino acid metabolism, and energy metabolism were significantly perturbed. The results of this study suggest that repeated social defeat can lead to metabolic changes and depression-like behavior in rats.

Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.

PubMed

Cohen, Ami; Whitfield, Timothy W; Kreifeldt, Max; Koebel, Pascale; Kieffer, Brigitte L; Contet, Candice; George, Olivier; Koob, George F

2014-01-01

Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice.

PubMed

Otsuka, Tsuyoshi; Kawai, Misato; Togo, Yuki; Goda, Ryosei; Kawase, Takahiro; Matsuo, Haruka; Iwamoto, Ayaka; Nagasawa, Mao; Furuse, Mitsuhiro; Yasuo, Shinobu

2014-02-01

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. Copyright © 2013 Elsevier Ltd. All rights reserved.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

PubMed

Thakare, Vishnu N; Patil, Rajesh R; Oswal, Rajesh J; Dhakane, Valmik D; Aswar, Manoj K; Patel, Bhoomika M

2018-02-01

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Predicting outcomes of group cognitive behavior therapy for patients with affective and neurotic disorders.

PubMed

Hooke, Geoffrey R; Page, Andrew C

2002-10-01

An attempt was made to predict outcomes following group Cognitive Behavior Therapy (CBT) for patients with affective and neurotic disorders. A group of 348 patients at a private psychiatric clinic, treated in a group CBT program, completed the Depression, Anxiety, and Stress Scale (DASS) before and after treatment. Prior to treatment, data from the Locus of Control of Behavior (LCB), a Global Assessment of Function (GAF), the Health of the Nation Outcome Scales (HoNOS), and the Rosenberg Self Esteem Scale (RSE) were also collected. Results indicated that posttreatment stress scores of all patients were predicted by pretreatment stress and self-esteem. Among patients with neurotic disorders, posttreatment anxiety was predicted by initial anxiety and self-esteem whereas among patients with affective disorders, posttreatment anxiety scores were predicted by initial anxiety and GAF. For patients with neurotic disorders, self-esteem did not predict variance in posttreatment depression in addition to that explained by pretreatment depression. In contrast, for patients with affective disorders, pretreatment depression and Locus of Control predicted posttreatment depression.

Dendritic Spines in Depression: What We Learned from Animal Models

PubMed Central

Qiao, Hui; Li, Ming-Xing; Xu, Chang; Chen, Hui-Bin; An, Shu-Cheng; Ma, Xin-Ming

2016-01-01

Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms. PMID:26881133

Anti-depressant-like effects of Jieyu chufan capsules in a mouse model of unpredictable chronic mild stress

PubMed Central

Zhao, Hui; Liang, Bingyu; Yu, Linjie; Xu, Yun

2017-01-01

Jieyu chufan (JYCF) is a well-known Chinese traditional medicine used for depression; however, the molecular mechanism underlying its anti-depressant action has remained elusive. In the present study, the anti-depressant effects of JYCF and the potential mechanisms were investigated in a mouse model. Five groups of 12 C57BL/6 mice each were used in the study, including a normal control group (NC group), a model control group (MC group) and three groups, which received different doses of JYCF (1.25, 2.5 and 5 g/kg) orally for 21 days (JYCF groups). The MC group and the three JYCF groups were subjected to 3 weeks of unpredictable chronic mild stress (UCMS) to induce depression-like behavior. All groups were subjected to a sucrose consumption test along with a forced swimming test to confirm depression-like behavior, an open-field test and an elevated plus maze test to confirm anxiety-like behavior, and a Morris water maze test to evaluate spatial learning and memory. In addition, synaptic density in the hippocampus was evaluated and western blot and immunostaining were used to analyze hippocampal expression of postsynaptic density protein-95 (PSD95), synaptophysin (Syn), cyclic adenosine monophosphate response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), Akt and glycogen synthase kinase (GSK)-3β as well as their phosphorylated (p) versions. The results showed that JYCF (2.5 and 5 g/kg) alleviated depressive-like behaviors and increased synaptic density in UCMS mice. Moreover, JYCF upregulated the expression of PSD95, Syn and BDNF and increased phosphorylated Akt, CREB and GSK-3β in the hippocampus. These results suggested that JYCF exerts an anti-depressant-like activity in UCMS-induced mice, which is likely to be mediated by reversing the stress-induced disruption of BDNF and GSK-3β activity. PMID:28810562

Role of hypothalamic cannabinoid receptors in post-stroke depression in rats.

PubMed

Wang, Shanshan; Sun, Hong; Liu, Sainan; Wang, Ting; Guan, Jinqun; Jia, Jianjun

2016-03-01

One of the most common psychological consequences of stroke is post-stroke depression (PSD). While more than 30 percent of stroke patients eventually develop PSD, the neurobiological mechanisms underlying such a phenomenon have not been well investigated. Given the critical involvement of hypothalamic-pituitary-adrenal axis and endocannabinoid system in response to stressful stimuli, we evaluated the hypothesis that cannabinoid receptors in the hypothalamus are critical for modulation of post-stroke depression-like behaviors in rats. To this end, rats were treated with middle cerebral artery occlusion (MCAO) followed by chronic unpredictable mild stress (CUMS) treatment procedure. We then assessed the expression of CB1 and CB2 receptors in the hypothalamus, and evaluated the effects of pharmacological stimulations of CB1 or CB2 receptors on the expression and development of depression-like behaviors in PSD rats. We found that PSD rats exhibited decreased the expression of CB1 receptor, but not CB2 receptor, in the ventral medial hypothalamus (VMH). Such an effect was not observed in the dorsally adjacent brain regions. Furthermore, intra-VMH injections of CB2 receptor agonist, but not CB1 receptor agonist, attenuated the expression of depression-like behaviors in PSD rats. Finally, repeated intraperitoneal injections of CB1 or CB2 receptor agonists during CUMS treatment inhibited the development of depression-like behaviors in PSD rats. Taken together, these results suggest that decreased CB1 receptor expression is likely associated with the development of post-stroke depression, and CB2 receptor may be a potential therapeutic target for the treatment post-stroke depressive disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.

PubMed

Balázsfi, Diána; Pintér, Ottó; Klausz, Barbara; Kovács, Krisztina B; Fodor, Anna; Török, Bibiána; Engelmann, Mario; Zelena, Dóra

2015-01-01

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention. Copyright © 2014 Elsevier Ltd. All rights reserved.

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice.

PubMed

Lin, Jen-Cheng; Lee, Mei-Yi; Chan, Ming-Huan; Chen, Yi-Chyan; Chen, Hwei-Hsien

2016-09-01

Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.

Boredom, depressive symptoms, and HIV risk behaviors among urban injection drug users

PubMed Central

German, Danielle; Latkin, Carl A.

2013-01-01

Boredom is closely aligned with depression, but is understood to be conceptually distinct. Little is known about boredom among active drug users and the potential association with depression and HIV risk. Current IDUs (n=845) completed a baseline behavioral survey including socio-demographic characteristics, self-reported boredom, depressive symptoms (CESD score), and HIV risk behaviors. One-third of the sample reported high boredom in the past week. In multivariate analysis, those who reported boredom were less likely to be older, African-American, have a main partner, and to be employed at least part-time. Controlling for covariates, those with high boredom were almost five times as likely to report high depressive symptoms. Co-occurrence of boredom and depressive symptoms (28%) was strongly and independently associated with a range of injection risk behaviors and sex exchange. This study demonstrates the need for more thorough understanding of mental health and HIV risk among urban drug users. PMID:22760741

Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine.

PubMed

Manna, Shyamshree S S; Umathe, Sudhir N

2015-04-01

Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.

The relationship between somatic and cognitive-affective depression symptoms and error-related ERP’s

PubMed Central

Bridwell, David A.; Steele, Vaughn R.; Maurer, J. Michael; Kiehl, Kent A.; Calhoun, Vince D.

2014-01-01

Background The symptoms that contribute to the clinical diagnosis of depression likely emerge from, or are related to, underlying cognitive deficits. To understand this relationship further, we examined the relationship between self-reported somatic and cognitive-affective Beck’s Depression Inventory-II (BDI-II) symptoms and aspects of cognitive control reflected in error event-related potential (ERP) responses. Methods Task and assessment data were analyzed within 51 individuals. The group contained a broad distribution of depressive symptoms, as assessed by BDI-II scores. ERP’s were collected following error responses within a go/no-go task. Individual error ERP amplitudes were estimated by conducting group independent component analysis (ICA) on the electroencephalographic (EEG) time series and analyzing the individual reconstructed source epochs. Source error amplitudes were correlated with the subset of BDI-II scores representing somatic and cognitive-affective symptoms. Results We demonstrate a negative relationship between somatic depression symptoms (i.e. fatigue or loss of energy) (after regressing out cognitive-affective scores, age and IQ) and the central-parietal ERP response that peaks at 359 ms. The peak amplitudes within this ERP response were not significantly related to cognitive-affective symptom severity (after regressing out the somatic symptom scores, age, and IQ). Limitations These findings were obtained within a population of female adults from a maximum-security correctional facility. Thus, additional research is required to verify that they generalize to the broad population. Conclusions These results suggest that individuals with greater somatic depression symptoms demonstrate a reduced awareness of behavioral errors, and help clarify the relationship between clinical measures of self-reported depression symptoms and cognitive control. PMID:25451400

The relationship between somatic and cognitive-affective depression symptoms and error-related ERPs.

PubMed

Bridwell, David A; Steele, Vaughn R; Maurer, J Michael; Kiehl, Kent A; Calhoun, Vince D

2015-02-01

The symptoms that contribute to the clinical diagnosis of depression likely emerge from, or are related to, underlying cognitive deficits. To understand this relationship further, we examined the relationship between self-reported somatic and cognitive-affective Beck'sDepression Inventory-II (BDI-II) symptoms and aspects of cognitive control reflected in error event-related potential (ERP) responses. Task and assessment data were analyzed within 51 individuals. The group contained a broad distribution of depressive symptoms, as assessed by BDI-II scores. ERPs were collected following error responses within a go/no-go task. Individual error ERP amplitudes were estimated by conducting group independent component analysis (ICA) on the electroencephalographic (EEG) time series and analyzing the individual reconstructed source epochs. Source error amplitudes were correlated with the subset of BDI-II scores representing somatic and cognitive-affective symptoms. We demonstrate a negative relationship between somatic depression symptoms (i.e. fatigue or loss of energy) (after regressing out cognitive-affective scores, age and IQ) and the central-parietal ERP response that peaks at 359 ms. The peak amplitudes within this ERP response were not significantly related to cognitive-affective symptom severity (after regressing out the somatic symptom scores, age, and IQ). These findings were obtained within a population of female adults from a maximum-security correctional facility. Thus, additional research is required to verify that they generalize to the broad population. These results suggest that individuals with greater somatic depression symptoms demonstrate a reduced awareness of behavioral errors, and help clarify the relationship between clinical measures of self-reported depression symptoms and cognitive control. Copyright © 2014 Elsevier B.V. All rights reserved.

Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice.

PubMed

Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

2015-01-01

Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice.

Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1

PubMed Central

Ruby, Christina L.; Walker, Denise L.; An, Joyce; Kim, Jason; Choi, Doo-Sup

2012-01-01

Objectives Adenosine signaling has been implicated in the pathophysiology of several psychiatric disorders including alcoholism, depression, and anxiety. Adenosine levels are controlled in part by transport across the cell membrane by equilibrative nucleoside transporters (ENTs). Recent evidence showed that a polymorphism in the gene encoding ENT1 is associated with comorbid depression and alcoholism in women. We have previously shown that deletion of ENT1 reduces ethanol intoxication and elevates alcohol intake in mice. Interestingly, ENT1 null mice display decreased anxiety-like behavior compared to wild-type littermates. However, our behavioral studies were performed only in male mice. Here, we extend our research to include female mice, and test the effect of ENT1 knockout on other behavioral correlates of alcohol drinking, including depressive and compulsive behavior, in mice. Methods To assess depression-like behavior, we used a forced swim test modified for mice. We examined anxiety-like behavior and locomotor activity in open field chambers, and perseverant behavior using the marble-burying test. Finally, we investigated alcohol consumption and preference in female mice using a two-bottle choice paradigm. Results ENT1 null mice of both sexes showed reduced immobility time in the forced swim test and increased time in the center of the open field compared to wild-type littermates. ENT1 null mice of both sexes showed similar locomotor activity levels and habituation to the open field chambers. Female ENT1 null mice displayed increased marble-burying compared to female wild-types, but no genotype difference was evident in males. Female ENT1 null mice showed increased ethanol consumption and preference compared to female wild-types. Conclusions Our findings suggest that ENT1 contributes to several important behaviors involved in psychiatric disorders. Inhibition of ENT1 may be beneficial in treating depression and anxiety, while enhancement of ENT1 function may reduce compulsive behavior and drinking, particularly in females. PMID:23101030

Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats.

PubMed

Dávila-Hernández, Amalia; Zamudio, Sergio R; Martínez-Mota, Lucía; González-González, Roberto; Ramírez-San Juan, Eduardo

2018-05-14

Given the importance of depression and the adverse effects of conventional treatment, it is necessary to seek complementary therapies. In a rat model of depression, this study aimed to assess the behavioral and morphological effects of embedding absorbable thread in acupoints (acu-catgut), and compare the results to those of fluoxetine treatment and the corresponding control groups. Therefore, depressive-like behavior was evaluated with the forced swimming test, and dendritic morphology (in the CA1 hippocampal region) with the Golgi-Cox technique and Sholl analysis. After weaning, male Sprague-Dawley rats were housed in social isolation for 8 weeks to induce depressive-like behavior. They were then given a 21-day treatment by stimulating acupoints with acu-catgut (AC) or fluoxetine (FX) (2 mg/kg). Rats were divided into six groups: Control (socially housed), social isolation (SI), SI + AC, SI + Sham (sham embedding of thread), SI + FX and SI + VH (vehicle). Compared to fluoxetine, acu-catgut treatment was more effective in reversing depressive-like behavior elicited by SI. The SI-induced reduction in dendritic length and spine density in hippocampal CA1 pyramidal neurons was attenuated after prolonged treatment with acu-catgut or fluoxetine. Hence, both treatments proved capable of reversing depressive-like alterations caused by SI, likely due to dendritic remodeling in the hippocampus. Copyright © 2018 Elsevier B.V. All rights reserved.

Neuronal Nitric Oxide Synthase and NADPH Oxidase Interact to Affect Cognitive, Affective, and Social Behaviors in Mice

PubMed Central

Walton, James C.; Selvakumar, Balakrishnan; Weil, Zachary M.; Snyder, Solomon H.; Nelson, Randy J.

2013-01-01

Both nitric oxide (NO) and reactive oxygen species (ROS) generated by nNOS and NADPH oxidase (NOX), respectively, in the brain have been implicated in an array of behaviors ranging from learning and memory to social interactions. Although recent work has elucidated how these separate redox pathways regulate neural function and behavior, the interaction of these two pathways in the regulation of neural function and behavior remains unspecified. Toward this end, the p47phox subunit of NOX, and nNOS were deleted to generate double knockout mice that were used to characterize the behavioral outcomes of concurrent impairment of the NO and ROS pathways in the brain. Mice were tested in a battery of behavioral tasks to evaluate learning and memory, as well as social, affective, and cognitive behaviors. p47phox deletion did not affect depressive-like behavior, whereas nNOS deletion abolished it. Both p47phox and nNOS deletion singly reduced anxiety-like behavior, increased general locomotor activity, impaired spatial learning and memory, and impaired preference for social novelty. Deletion of both genes concurrently had synergistic effects to elevate locomotor activity, impair spatial learning and memory, and disrupt prepulse inhibition of acoustic startle. Although preference for social novelty was impaired in single knockouts, double knockout mice displayed elevated levels of preference for social novelty above that of wild type littermates. These data demonstrate that, depending upon modality, deletion of p47phox and nNOS genes have dissimilar, similar, or additive effects. The current findings provide evidence that the NOX and nNOS redox signaling cascades interact in the brain to affect both cognitive function and social behavior. PMID:23948215

Depressive symptoms in adolescence: the association with multiple health risk behaviors.

PubMed

Katon, Wayne; Richardson, Laura; Russo, Joan; McCarty, Carolyn A; Rockhill, Carol; McCauley, Elizabeth; Richards, Julie; Grossman, David C

2010-01-01

Although multiple studies of adolescents have examined the association of depression with individual health risk behaviors such as obesity or smoking, this is one of the few studies that examined the association between depression and multiple risk behaviors. A brief mail questionnaire, which screened for age, gender, weight, height, sedentary behaviors, physical activity, perception of general health, functional impairment and depressive symptoms, was completed by a sample of 2291 youth (60.7% response rate) aged 13-17 enrolled in a health care plan. A subset of youth who screened positive on the two-item depression screen and a random sample of those screening negative were approached to participate in a telephone interview with more in-depth information obtained on smoking and at-risk behaviors associated with drug and alcohol use. Youth screening positive for high levels of depressive symptoms compared to those with few or no depressive symptoms were significantly more likely to meet criteria for obesity, had a poorer perception of health, spent more time on the computer, got along less well with parents and friends, had more problems completing school work and were more likely to have experimented with smoking and a wide array of behaviors associated with drug and alcohol use. Because many adverse health behaviors that develop in adolescence continue into adulthood, the association of depressive symptoms with multiple risk behaviors and poor functioning suggest that early interventions are needed at an individual, school, community and primary care level. Copyright 2010 Elsevier Inc. All rights reserved.

Relationship functioning moderates the association between depressive symptoms and life stressors.

PubMed

Trombello, Joseph M; Schoebi, Dominik; Bradbury, Thomas N

2011-02-01

Data from 172 newlywed couples were collected over the first 4 years of marriage to test how behaviors demonstrated during marital interactions moderate associations between depressive symptoms and subsequent life stressors. Depressive symptoms and behaviors coded from problem-solving and social support interactions were analyzed as predictors of nonmarital stressors that were interpersonal and dependent on the participant's actions. Behavioral codes were found to moderate 3 of 16 symptom-to-life event associations for husbands. Husbands' reports of more depressive symptoms predicted greater levels of stress when husbands' positive affect and hard negative affect during problem-solving were relatively infrequent and when wives made frequent displays of positive behaviors during husbands' support topics. These effects remained after controlling for marital satisfaction. For wives, behavioral moderators did not interact with depressive symptoms to predict changes in stress, but marital satisfaction consistently interacted with depressive symptoms to predict future stressors beyond interpersonal behaviors. Specifically, for wives, stress generation was more evident when relationship satisfaction was low than when it was high. Our results, though different for men and women, suggest that relationship functioning can alter associations between depressive symptoms and life stress in the early years of marriage. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PsycINFO Database Record (c) 2011 APA, all rights reserved.

Individual differences in circadian locomotor parameters correlate with anxiety- and depression-like behavior.

PubMed

Anyan, Jeffrey; Verwey, Michael; Amir, Shimon

2017-01-01

Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion) affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock functioning and mood.

Cognitive-behavioral therapies for depression and substance use disorders: An overview of traditional, third-wave, and transdiagnostic approaches.

PubMed

Vujanovic, Anka A; Meyer, Thomas D; Heads, Angela M; Stotts, Angela L; Villarreal, Yolanda R; Schmitz, Joy M

2017-07-01

The co-occurrence of depression and substance use disorders (SUD) is highly prevalent and associated with poor treatment outcomes for both disorders. As compared to individuals suffering from either disorder alone, individuals with both conditions are likely to endure a more severe and chronic clinical course with worse treatment outcomes. Thus, current practice guidelines recommend treating these co-occurring disorders simultaneously. The overarching aims of this narrative are two-fold: (1) to provide an updated review of the current empirical status of integrated psychotherapy approaches for SUD and depression comorbidity, based on models of traditional cognitive-behavioral therapy (CBT) and newer third-wave CBT approaches, including acceptance- and mindfulness-based interventions and behavioral activation (BA); and (2) to propose a novel theoretical framework for transdiagnostic CBT for SUD-depression, based upon empirically grounded psychological mechanisms underlying this highly prevalent comorbidity. Traditional CBT approaches for the treatment of SUD-depression are well-studied. Despite advances in the development and evaluation of various third-wave psychotherapies, more work needs to be done to evaluate the efficacy of such approaches for SUD-depression. Informed by this summary of the evidence, we propose a transdiagnostic therapy approach that aims to integrate treatment elements found in empirically supported CBT-based interventions for SUD and depression. By targeting shared cognitive-affective processes underlying SUD-depression, transdiagnostic treatment models have the potential to offer a novel clinical approach to treating this difficult-to-treat comorbidity and relevant, co-occurring psychiatric disturbances, such as posttraumatic stress.

Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex.

PubMed

Chiba, Shuichi; Numakawa, Tadahiro; Ninomiya, Midori; Richards, Misty C; Wakabayashi, Chisato; Kunugi, Hiroshi

2012-10-01

Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiology of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6 hours × 28 days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We observed significant reductions in body weight gain, food intake and sucrose preference from 1 week after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We observed a decrease in the number of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot analysis, the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concentrations in PFC acute slice which were measured by high performance liquid chromatography were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety--and depression-like behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.

Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet.

PubMed

Strekalova, Tatyana; Evans, Matthew; Costa-Nunes, Joao; Bachurin, Sergey; Yeritsyan, Naira; Couch, Yvonne; Steinbusch, Harry M W; Eleonore Köhler, S; Lesch, Klaus-Peter; Anthony, Daniel C

2015-08-01

An association between metabolic abnormalities, hypercholesterolemia and affective disorders is now well recognized. Less well understood are the molecular mechanisms, both in brain and in the periphery, that underpin this phenomenon. In addition to hepatic lipid accumulation and inflammation, C57BL/6J mice fed a high-cholesterol diet (0.2%) to induce non-alcoholic fatty liver disease (NAFLD), exhibited behavioral despair, anxiogenic changes, and hyperlocomotion under bright light. These abnormalities were accompanied by increased expression of transcript and protein for Toll-like receptor 4, a pathogen-associated molecular pattern (PAMP) receptor, in the prefrontal cortex and the liver. The behavioral changes and Tlr4 expression were reversed ten days after discontinuation of the high-cholesterol diet. Remarkably, the dietary fat content and body mass of experimental mice were unchanged, suggesting a specific role for cholesterol in the molecular and behavioral changes. Expression of Sert and Cox1 were unaltered. Together, our study has demonstrated for the first time that high consumption of cholesterol results in depression- and anxiety-like changes in C57BL/6J mice and that these changes are unexpectedly associated with the increased expression of TLR4, which suggests that TLR4 may have a distinct role in the CNS unrelated to pathogen recognition. Copyright © 2015 Elsevier Inc. All rights reserved.

Dysregulation of the Caregiving System in the Context of Maternal Depression: The Role of Mistrust in the Development and Causation of Abusive Parenting Behavior.

PubMed

Ostler, Teresa

2015-01-01

This qualitative, case-based study drew on attachment and ethological theories to explore the role of mistrust, a severe attachment attitude, in the development and causation of abusive parenting behavior in mothers with severe, recurrent depression. The study analyzed a priori codes from redacted comprehensive assessments of eight women with depression and child protective services involvement to explore how mistrust was expressed; its links to extreme defenses and reported childhood experiences; and its consequences for relationships and help seeking. Analyses also identified specific stimuli that elicited abusive parenting behaviors and explored the context of depression in relation to women's attachment and caregiving histories and mental health care follow-through. Linked to suppressed feelings of vulnerability, mistrust was expressed in suspicions about support and in feelings of abandonment and betrayal. It was associated with an absence of support, family violence, role reversal, and parental mental illness. Mistrust affected mothers' ability to maintain supportive relationships and to get help for their depression, which was a persistent part of their lives. A child's cries, lack of support, partner abuse, and threats of abandonment triggered abusive parenting behavior, likely by tapping into core attachment pains related to unacknowledged longings for support. Unprepared to deal with these feelings, mothers became frustrated and redirected or displaced their anger onto their children. Mistrust may play a role in the dynamics of abusive parenting in mothers with severe, recurrent depression. Early identification and preventive intervention efforts that address this attitude could be beneficial for parenting.

Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery.

PubMed

Robson, Matthew J; Quinlan, Meagan A; Blakely, Randy D

2017-05-17

Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD-relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD.

Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviors

PubMed Central

Guo, Ming; Huang, Tung-Yi; Garza, Jacob C.; Chua, Streamson C.; Lu, Xin-Yun

2013-01-01

Previous studies have demonstrated that leptin and its receptors (LepRb) in the central nervous system play an important role in regulating depression- and anxiety-related behaviors. However, the physiological functions of LepRb in specific brain regions for mediating different emotional behaviors remain to be defined. In this study, we examined the behavioral effects of LepRb ablation in the adult hippocampus using a series of behavioral paradigms for assessing depression- and anxiety-related behaviors. Targeted deletion of LepRb was achieved using the Cre/loxP site-specific recombination system through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the dentate gyrus of adult mice homozygous for a floxed leptin receptor allele. AAV-Cre-mediated deletion of the floxed region of LepRb was detected 2 weeks after injection. In accordance with this, leptin-stimulated phophorylation of Akt was attenuated in the hippocampus of AAV-Cre injected mice. Mice injected with AAV-Cre displayed normal locomotor activity and anxiety-like behavior, as determined in the elevated plus maze, light dark box and open field tests, but showed increased depression-like behaviors in the tail suspension, sucrose preference and learned helplessness tests. Taken together, this data suggests that deletion of LepRb in the adult hippocampus is sufficient to induce depression-like behaviors. Our results support the view that leptin signaling in the hippocampus may be essential for maintaining positive mood states and active coping to stress. PMID:22932068

Diene Valepotriates from Valeriana glechomifolia Prevent Lipopolysaccharide-Induced Sickness and Depressive-Like Behavior in Mice

PubMed Central

Müller, Liz G.; Borsoi, Milene; Stolz, Eveline D.; Herzfeldt, Vivian; Viana, Alice F.; Ravazzolo, Ana Paula; Rates, Stela Maris K.

2015-01-01

Valeriana glechomifolia, a native species from southern Brazil, presents antidepressant-like activity and diene valepotriates (VAL) contribute to the pharmacological properties of the genus. It is known that depression can develop on an inflammation background in vulnerable patients and antidepressants present anti-inflammatory properties. We investigated the effects of VAL (10 mg/kg, p.o.) on sickness and depressive-like behaviors as well as proinflammatory cytokines (IL-1β and TNF-α) and BDNF expression in the cortex of mice exposed to a 5 min swimming session (as a stressful stimulus) 30 min before the E. coli LPS injection (600 µg/kg, i.p.). The forced swim + LPS induced sickness and depressive-like behaviors, increased the cortical expression of IL-1β and TNF-α, and decreased BDNF expression. VAL was orally administered to mice 1 h before (pretreatment) or 5 h after (posttreatment) E. coli LPS injection. The pretreatment with VAL restored the behavioral alterations and the expression of cortical proinflammatory cytokines in LPS-injected animals but had no effects on BDNF expression, while the posttreatment rescued only behavioral alterations. Our results demonstrate for the first time the positive effects of VAL in an experimental model of depression associated with inflammation, providing new data on the range of action of these molecules. PMID:26170871

Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion

PubMed Central

McKlveen, Jessica M.; Myers, Brent; Flak, Jonathan N.; Bundzikova, Jana; Solomon, Matia B.; Seroogy, Kim B.; Herman, James P.

2013-01-01

Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyper-locomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation. PMID:23683655

Effects of Sumsu (Bufonis venenum) Pharmacopuncture Treatment on Depression in Mice.

PubMed

Choi, Min-Ji; Kim, Ka-Na; Lee, Jae-Eun; Suh, Jin-Woo; Kim, Sung-Chul; Kwon, Ki Rok; Cho, Seung-Hun

2014-06-01

The main objective of this study was to evaluate the anti-depressant effects of pharmacopuncture using sumsu (Bufonis venenum). Animals were divided into three groups (control, sham, and experimental), with eight mice per group. The sham and the experimental groups were exposed to 2 hours of immobilization stress daily for 14 days. They were also injected with normal saline (sham) or subjected to pharmacopuncture with sumsu at the acupoints HT7, SP6, and GV20 (experimental). The depression or anxiety-like behaviors of the mice in each group were evaluated 1 day after treatment. There was no difference in locomotor activity between the groups during the open-field test; i.e., all groups had normal motor function. However, the open-field and the forced-swimming tests revealed that depression and anxiety-like behaviors were decreased significantly in the group treated with sumsu pharmacopuncture. Sumsu pharmacopuncture attenuated depressive or anxiety-like behavior in mice stressed with chronic immobilization. These results suggest that sumsu pharmacopuncture has therapeutic potential for treating neuropsychiatric disorders such as anxiety or depression disorder.

Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala.

PubMed

Li, Ming-Jia; Liu, Ling-Yu; Chen, Lin; Cai, Jie; Wan, You; Xing, Guo-Gang

2017-04-01

Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats. Moreover, we revealed that CFSS induces both sensitization of basolateral amygdala (BLA) neurons and augmentation of long-term potentiation (LTP) at the BLA-CeA synapse and meanwhile, exaggerates both SNI-induced sensitization of CeA neurons and LTP at the parabrachial (PB)-CeA synapse. In addition, we discovered that CFSS elevates SNI-induced functional up-regulation of GluN2B-containing NMDA (GluN2B-NMDA) receptors in the CeA, which is proved to be necessary for CFSS-induced augmentation of LTP at the PB-CeA synapse and exacerbation of pain hypersensitivity in SNI rats. Suppression of CFSS-elicited depressive-like behaviors by antidepressants imipramine or ifenprodil inhibits the CFSS-induced exacerbation of neuropathic pain. Collectively, our findings suggest that CFSS potentiates synaptic efficiency of the BLA-CeA pathway, leading to the activation of GluN2B-NMDA receptors and sensitization of CeA neurons, which subsequently facilitate pain-related synaptic plasticity of the PB-CeA pathway, thereby exacerbating SNI-induced neuropathic pain. We conclude that chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the CeA.

Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice.

PubMed

Ardayfio, Paul; Kim, Kwang-Soo

2006-04-01

Chronic hypercortisolemia is a hallmark of neuroendocrine and psychiatric disorders, such as Cushing's disease and depression. Whether cortisol directly contributes to the altered mood and anxiety symptoms seen in these diseases remains unclear. To address this, the authors have modeled hypercortisolemia by administering corticosterone in the drinking water of female Swiss Webster mice for 17 or 18 days (13 mg/kg). Light-dark emergence, startle habituation, and startle reactivity were measured. Chronic but not acute treatment with corticosterone increased the latency to emerge into the light compartment, an anxiogenic-like effect. Chronic corticosterone treatment did not affect startle habituation, but did reduce startle reactivity. This study suggests that chronic hypercortisolemia may contribute to anxiety-related behavior in patients with Cushing's disease and depression. ((c) 2006 APA, all rights reserved).

Early protein malnutrition negatively impacts physical growth and neurological reflexes and evokes anxiety and depressive-like behaviors.

PubMed

Belluscio, Laura M; Berardino, Bruno G; Ferroni, Nadina M; Ceruti, Julieta M; Cánepa, Eduardo T

2014-04-22

Malnutrition is a worldwide problem affecting millions of unborn and young children during the most vulnerable stages of their development. In humans, poor maternal nutrition is a major cause of intrauterine growth restriction which is associated with an increased risk of perinatal mortality and long-term morbidity. In addition, intrauterine growth restriction correlates with neurodevelopmental delays and alterations of brain structure and neurochemistry. While there is no doubt that maternal malnutrition is a principal cause of perturbed development of the fetal brain and that all nutrients have certain influence on brain maturation, proteins appear to be the most critical for the development of neurological functions. In the present study we assessed male and female mouse offspring, born to dams protein restricted during pregnancy and lactation, in physical growth and neurobehavioral development and also in social interaction, motivation, anxiety and depressive behaviors. Moreover, we evaluate the impact of the low protein diet on dams in relation to their maternal care and anxiety-related behavior given that these clearly affect pups development. We observed that maternal protein restriction during pregnancy and lactation delayed the physical growth and neurodevelopment of the offspring in a sex-independent manner. In addition, maternal undernutrition negatively affected offspring's juvenile social play, motivation, exploratory activity and risk assessment behaviors. These findings show that protein restriction during critical periods of development detrimentally program progeny behavior. Copyright © 2014 Elsevier Inc. All rights reserved.

Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion.

PubMed

Jesse, Cristiano R; Wilhelm, Ethel A; Nogueira, Cristina W

2010-12-01

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics. The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior. Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1-5 mg/kg), fluoxetine, amitriptyline, or bupropion (10-30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior. The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST. These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.

Interferon-γ and Tumor Necrosis Factor-α Mediate the Upregulation of Indoleamine 2,3-Dioxygenase and the Induction of Depressive-Like Behavior in Mice in Response to Bacillus Calmette-Guérin

PubMed Central

O’Connor, Jason C.; André, Caroline; Wang, Yunxia; Lawson, Marcus A.; Szegedi, Sandra S.; Lestage, Jacques; Castanon, Nathalie; Kelley, Keith W.; Dantzer, Robert

2010-01-01

Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)γ and tumor necrosis factor (TNF)α in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNγR−/− mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNγR−/− mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNγR−/− mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNγ, interleukin(IL)-1β, TNFα, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNγR−/− mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFα mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNγR−/− mice compared with WT controls. Pretreatment of mice with the TNFα antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNγ and TNFα synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNγ, with TNFα, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection. PMID:19339614

INFLAMMATION IS INCREASED WITH ANXIETY- AND DEPRESSION-LIKE SIGNS IN A RAT MODEL OF SPINAL CORD INJURY

PubMed Central

Maldonado-Bouchard, Sioui; Peters, Kelsey; Woller, Sarah A.; Madahian, Behrouz; Faghihi, Usef; Patel, Shivani; Bake, Shameena; Hook, Michelle A

2015-01-01

Spinal cord injury (SCI) leads to increased anxiety and depression in as many as 60% of patients. Yet, despite extensive clinical research focused on understanding the variables influencing psychological well-being following SCI, risk factors that decrease it remain unclear. We hypothesized that excitation of the immune system, inherent to SCI, may contribute to the decrease in psychological well-being. To test this hypothesis, we used a battery of established behavioral tests to assess depression and anxiety in spinally contused rats. The behavioral tests, and subsequent statistical analyses, revealed three cohorts of subjects that displayed behavioral characteristics of 1) depression, 2) depression and anxiety, or 3) no signs of decreased psychological well-being. Subsequent molecular analyses demonstrated that the psychological cohorts differed not only in behavioral symptoms, but also in peripheral (serum) and central (hippocampi and spinal cord) levels of pro-inflammatory cytokines. Subjects exhibiting a purely depression-like profile showed higher levels of pro-inflammatory cytokines peripherally, whereas subjects exhibiting a depression- and anxiety-like profile showed higher levels of pro-inflammatory cytokines centrally (hippocampi and spinal cord). These changes in inflammation were not associated with injury severity; suggesting that the association between inflammation and the expression of behaviors characteristic of decreased psychological well-being was not confounded by differential impairments in motor ability. These data support the hypothesis that inflammatory changes are associated with decreased psychological well-being following SCI. PMID:26296565

Facebook False Self-Presentation Behaviors and Negative Mental Health.

PubMed

Wright, Elizabeth J; White, Katherine M; Obst, Patricia L

2018-01-01

As research examining what constitutes Facebook false self-presentation is lacking, the aim of this study was to develop a preliminary inventory of Facebook false self-presentation behaviors, as well as identify predictors and possible outcomes. Participants (N = 211) completed questions regarding frequency of engagement in Facebook false self-presentation behaviors, as well as self-esteem, social influences, motivation strategies, well-being, depression, anxiety, and stress. Results indicated the presence of two distinct false self-presentation behaviors: lying (e.g., untruthful status updates, profile creation) and liking behaviors (e.g., liking posts dishonestly), each associated with different predictors and outcomes. Results indicated that moral norms significantly predicted lying behaviors; and age, self-esteem, group norms, and moral norms significantly predicted liking behaviors. Unexpectedly, liking behaviors were associated with depression, anxiety, and stress, whereas lying behaviors were related to anxiety only. Findings highlight associations between online self-presentation strategies, in particular liking behaviors, on Facebook and possible offline negative mental health.

Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice.

PubMed

Amiri, Shayan; Haj-Mirzaian, Arya; Momeny, Majid; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Poursaman, Simin; Rastegar, Mojgan; Nikoui, Vahid; Mokhtari, Tahmineh; Ghazi-Khansari, Mahmoud; Hosseini, Mir-Jamal

2017-01-06

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A 2 (cPLA 2 ) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Behavioral assays to model cognitive and affective dimensions of depression and anxiety in rats

PubMed Central

Lapiz-Bluhm, M. Danet S.; Bondi, Corina O.; Doyen, Julianne; Rodriguez, Gustavo; Bédard-Arana, Tania; Morilak, David A.

2008-01-01

Animal models have been used extensively to investigate neuropsychiatric disorders, such as depression, and their treatment. However, the etiology and pathophysiology of many such disorders are largely unknown, which makes validation of animal models particularly challenging. Further, many diagnostic symptoms are difficult to define, operationalize and quantify, especially in experimental animals such as rats. Thus, rather than attempting to model such complex human syndromes as depression in their entirety, it can be more productive instead to define and model components of the illness that may account for clusters of co-varying symptoms, and that may share common underlying neurobiological mechanisms. In our preclinical investigations of the neural regulatory mechanisms linking stress to depression and anxiety disorders, as well as the mechanisms by which chronic treatment with antidepressant drugs may exert their beneficial effects in these conditions, we have employed a number of behavioral tests in rats to model specific cognitive and anxiety-like components of depression and anxiety disorders. In this paper, we review the procedures for conducting four such behavioral assays: the attentional set-shifting test, the elevated-plus maze, the social interaction test and the shock-probe defensive burying test. The purpose is to serve as a guide to the utility and limitations of these tools, and as an aid in optimizing their use and productivity. PMID:18673411

Early life stress and later peer distress on depressive behavior in adolescent female rats: Effects of a novel intervention on GABA and D2 receptors.

PubMed

Lukkes, Jodi L; Meda, Shirisha; Thompson, Britta S; Freund, Nadja; Andersen, Susan L

2017-07-14

Early life adversity (ELA) increases the risk of depression during adolescence that may result from a decline in parvalbumin (PVB) secondary to increased neuroinflammation. In this study, we investigated depressive-like behavior following exposure to two different types of stressors that are relevant for their developmental period: 1) chronic ELA (maternal separation; MS) and 2) an acute emotional stressor during adolescence (witnessing their peers receive multiple shocks; WIT), and their interaction. We also determined whether reducing inflammation by cyclooxygenase-2 (COX-2) inhibition would prevent the onset of depressive-like behavior. Female Sprague-Dawley rat pups underwent MS for four-hours/day or received typical care (CON) between postnatal days (P) 2 and P20. A COX-2 inhibitor (COX-2I) or vehicle was administered every other day between P30 and P38. Subjects were tested for learned helplessness to assess depressive-like behavior at P40 (adolescence). MS females demonstrated increased escape latency and decreased PVB in the prefrontal cortex (PFC) and dorsal raphe that were attenuated by COX-2I intervention. Helplessness was also associated with an increase in D2 receptors in the accumbens. In contrast, WIT elevated escape latency in CON, but reduced latency in MS females. Furthermore, COX-2I intervention decreased escape latency in both CON and MS after WIT. WIT reduced PVB levels in the basolateral amygdala and increased PFC levels to CON levels. Our data suggest that decreased PVB in the PFC is important for the expression of depressive-like behavior and suggest that COX-2I intervention may provide a novel prevention for depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Reduced Vesicular Acetylcholine Transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain.

PubMed

Pádua-Reis, Marina; Aquino, Nayara S; Oliveira, Vinícius E M; Szawka, Raphael E; Prado, Marco A M; Prado, Vânia F; Pereira, Grace S

2017-07-14

Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

Group Rumination: Social Interactions Around Music in People with Depression

PubMed Central

Garrido, Sandra; Eerola, Tuomas; McFerran, Katrina

2017-01-01

One of the most important roles that music serves in human society is the promotion of social relationships and group cohesion. In general, emotional experiences tend to be amplified in group settings through processes of social feedback. However, previous research has established that listening to sad music can intensify negative emotions in people with tendencies to rumination and depression. This study therefore investigated the phenomenon of ruminating with music, and the question of whether listening to sad music in group settings provides social benefits for emotionally vulnerable listeners, or whether it further exaggerates depressive tendencies. Participants recruited via online depression groups and mental health websites were surveyed as to music listening habits. Results revealed that people with depression were more likely to engage in “group rumination” using music, and that this behavior could be partially explained by a general tendency to ruminate using music. Both affective states and coping styles were found to be related to the affective outcomes of group interactions around music. These findings go some way toward clarifying the situations in which group interactions around music are able to provide important social benefits for those involved, and situations in which negative emotions can be amplified by the group context. PMID:28421014

High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: A model of post-partum stress and possible depression.

PubMed

Brummelte, Susanne; Pawluski, Jodi L; Galea, Liisa A M

2006-09-01

Post-partum stress and depression (PPD) have a significant effect on child development and behavior. Depression is associated with hypercortisolism in humans, and the fluctuating levels of hormones, including corticosterone, during pregnancy and the post-partum, may contribute to PPD. The present study was developed to investigate the effects of high-level corticosterone (CORT) post-partum in the mother on postnatal neurogenesis and behavior in the offspring. Sprague-Dawley dams were treated with either CORT (40 mg/kg) or sesame oil injections daily for 26 days beginning the day after giving birth. Dams were tested in the forced swim test (FST) and in the open field test (OFT) on days 24-26 post-partum. Results showed that the dams exposed to CORT expressed "depressive-like" behavior compared to controls, with decreased struggling behavior and increased immobility in the FST. To investigate the effects of treatment on hippocampal postnatal cell proliferation and survival in the offspring, males and females from treated dams were injected with BrdU (50 mg/kg) on postnatal day 21 and perfused either 24 h (cell proliferation) or 21 days (cell survival) later. Furthermore, male and female offspring from each litter were tested in adulthood on various behavioral tests, including the forced swim test, open field test, resistance to capture test and elevated plus maze. Intriguingly, male, but not female, offspring of CORT-treated dams exhibited decreased postnatal cell proliferation in the dentate gyrus. Both male and female offspring of CORT-treated dams showed higher resistance to capture and greater locomotor activity as assessed in the open field test. As high levels of CORT may be a characteristic of stress and/or depression, these findings support a model of 'CORT-induced' post-partum stress and possibly depression and demonstrate that the offspring of affected dams can exhibit changes in postnatal neurogenesis and behavior in adulthood.

Pathways from childhood abuse to prospective revictimization: depression, sex to reduce negative affect, and forecasted sexual behavior.

PubMed

Miron, Lynsey R; Orcutt, Holly K

2014-11-01

Research suggests that adverse events in childhood, such as childhood physical, sexual, and emotional abuse, confer risk for later sexual assault. Psychological distress, coping strategies, and sexual behavior may help explain the path from childhood abuse to revictimization. The present study explored how the use of sex to regulate negative affect (SRNA) operates independently, and in combination with other psychosocial factors to increase college women's (N=541) risk of experiencing prospective adult sexual assault (ASA). Sequential multiple mediator models in Mplus were used to assess the effect of three different forms of childhood abuse on prospective ASA, both independently and while controlling for other forms of childhood abuse. The indirect effect of adolescent sexual assault (AdolSA), depressive symptoms, SRNA, and participants' response to a sex-related vignette was tested using bias-corrected bootstrapping. In the full path model, childhood emotional abuse and AdolSA predicted ASA, while childhood physical and sexual abuse were directly associated with AdolSA, but not ASA. Additionally, depressive symptoms and participants' estimate of their likely behavior in a sex-related vignette directly predicted prospective ASA. Results using bootstrapping revealed that a history of childhood abuse predicted prospective ASA via diverse direct and indirect paths, as well as through a similar multiple mediator path. Overall, findings suggest that a combination of affective, coping, and sexual expectancy factors contribute to risk for revictimization in adult survivors of childhood abuse. Future research directions and targets for risk-reduction programming are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pathways from Childhood Abuse to Prospective Revictimization: Depression, Sex to Reduce Negative Affect, and Forecasted Sexual Behavior

PubMed Central

Miron, Lynsey R.; Orcutt, Holly K.

2014-01-01

Research suggests that adverse events in childhood, such as childhood physical, sexual, and emotional abuse, confer risk for later sexual assault. Psychological distress, coping strategies, and sexual behavior may help explain the path from childhood abuse to revictimization. The present study explored how the use of sex to regulate negative affect (SRNA) operates independently, and in combination with other psychosocial factors to increase college women’s (N = 541) risk of experiencing prospective adult sexual assault (ASA). Sequential multiple mediator models in Mplus were used to assess the effect of three different forms of childhood abuse on prospective ASA, both independently and while controlling for other forms of childhood abuse. The indirect effect of adolescent sexual assault (AdolSA), depressive symptoms, SRNA, and participants’ response to a sex-related vignette was tested using bias-corrected bootstrapping. In the full path model, childhood emotional abuse and AdolSA predicted ASA, while childhood physical and sexual abuse were directly associated with AdolSA, but not ASA. Additionally, depressive symptoms and participants’ estimate of their likely behavior in a sex-related vignette directly predicted prospective ASA. Results using bootstrapping revealed that a history of childhood abuse predicted prospective ASA via diverse direct and indirect paths, as well as through a similar multiple mediator path. Overall, findings suggest that a combination of affective, coping, and sexual expectancy factors contribute to risk for revictimization in adult survivors of childhood abuse. Future research directions and targets for risk-reduction programming will be discussed. PMID:25455965

The effects of sleep dysfunction on cognition, affect, and quality of life in individuals with cerebellar ataxia.

PubMed

Sonni, Akshata; Kurdziel, Lauri B F; Baran, Bengi; Spencer, Rebecca M C

2014-05-15

Cerebellar ataxia comprises a group of debilitating diseases that are the result of progressive cerebellar degeneration. Recent studies suggest that, like other neurodegenerative diseases, sleep impairments are common in cerebellar ataxia. In light of the role of sleep in mood regulation and cognition, we sought to assess interactions between sleep, cognition, and affect in individuals with cerebellar ataxia. A survey of 176 individuals with cerebellar ataxia was conducted. The battery of instruments included a modified International Cooperative Ataxia Rating Scale, Pittsburgh Sleep Quality Index, Restless Leg Syndrome Questionnaire, REM Behavior Disorder Questionnaire, Beck Depression Inventory, Epworth Sleepiness Scale, and a Composite Cognitive Questionnaire. Fifty-one percent of individuals indicated significant sleep disturbances on the Pittsburgh Sleep Quality Index, 73% of participants had two or more symptoms of restless leg syndrome, and 88% had two or more symptoms of REM behavior disorder. Ataxia severity, based on the modified International Cooperative Ataxia Rating Scale, predicted scores on the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale and REM Behavior Disorder Questionnaire. Median split analyses revealed that cognitive function appeared to be reduced and depressive symptoms were greater for those individuals with poor subjective sleep quality and severe RLS. Importantly, sleep appears to play a mediatory role between disease severity and depressive symptoms. These results suggest that disturbed sleep may have detrimental effects on cognition and affect in individuals with cerebellar ataxia. While objective measures are needed, such results suggest that treating sleep deficits in these individuals may improve cognitive and mental health as well as overall quality of life.

A longitudinal population-based study exploring treatment utilization and suicidal ideation and behavior in major depressive disorder.

PubMed

Chartrand, Hayley; Robinson, Jennifer; Bolton, James M

2012-12-10

This study aimed to longitudinally examine the relationship between treatment utilization and suicidal behavior among people with major depressive disorder in a nationally representative sample. Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (Wave 1: N=43,093; Wave 2: N=34,653). Suicidal and non-suicidal individuals at Wave 1 were compared based on subsequent treatment utilization. Suicidal behavior at Wave 2 was compared between people with major depressive disorder who had sought treatment at Wave 1 versus those that had not. Individuals with past year major depressive disorder at Wave 1 who attempted suicide were more likely to be hospitalized at follow up compared to non-suicidal people with major depressive disorder [adjusted odds ratio (AOR)=4.46; 95% confidence interval [95% CI]: 2.54-7.85]; however, they were not more likely to seek other forms of treatment. Among those with past year major depressive disorder who sought treatment at baseline, visiting an emergency room (AOR=3.08; 95% CI: 1.61-5.89) and being hospitalized (AOR=2.41; 95% CI: 1.13-5.14), was associated with an increased likelihood of attempting suicide within 3 years even after adjusting for mental disorder comorbidity, depression severity, and previous suicidal behavior. Unable to draw conclusions about completed suicide or adequacy of treatment. Suicidal behavior does not lead individuals with major depressive disorder to seek treatment with professionals or use antidepressant medications; instead, they are more likely to use emergency services. These findings suggest that treatment efforts for people with major depressive disorder who are suicidal need improvement. Copyright © 2012 Elsevier B.V. All rights reserved.

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy

PubMed Central

Dossat, Amanda M.; Sanchez-Gonzalez, Marcos A.; Koutnik, Andrew P.; Leitner, Stefano; Ruiz, Edda L.; Griffin, Brittany; Rosenberg, Jens T.; Grant, Samuel C.; Fincham, Francis D.; Pinto, Jose R.; Kabbaj, Mohamed

2017-01-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3–4 mo) and aged adult (7–8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder–related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.—Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. PMID:28235781

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

PubMed

Dossat, Amanda M; Sanchez-Gonzalez, Marcos A; Koutnik, Andrew P; Leitner, Stefano; Ruiz, Edda L; Griffin, Brittany; Rosenberg, Jens T; Grant, Samuel C; Fincham, Francis D; Pinto, Jose R; Kabbaj, Mohamed

2017-06-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. © FASEB.

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway.

PubMed

Pazini, Francis L; Cunha, Mauricio P; Rosa, Julia M; Colla, André R S; Lieberknecht, Vicente; Oliveira, Ágatha; Rodrigues, Ana Lúcia S

2016-12-01

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression.

PubMed

Liu, Lanxiang; Zhou, Xinyu; Zhang, Yuqing; Liu, Yiyun; Yang, Lining; Pu, Juncai; Zhu, Dan; Zhou, Chanjuan; Xie, Peng

2016-05-15

Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression. Copyright © 2016 Elsevier B.V. All rights reserved.

The influence of personality traits on smokers' affect, withdrawal and cessation intervention outcome.

PubMed

Cui, Yong; Tang, Rui; Lam, Cho Y; Cinciripini, Paul M; Robinson, Jason D

2016-03-01

The personality traits of harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), as measured by the Tridimensional Personality Questionnaire (TPQ), have been linked to smoking behavior. The extent to which these traits are associated with smoking withdrawal and cessation outcome is unclear. We sought to address this question among 131 treatment-seeking smokers who were randomly assigned to either a smoking cessation treatment (four 30-min behavioral counseling sessions) or a control condition. We found that HA was positively associated with baseline depressive symptoms, baseline negative affect, and post-quit withdrawal, and negatively associated with positive affect at both baseline and post-quit. Additionally, we found that smokers with higher HA scores were more likely to be abstinent. NS was negatively associated with post-quit positive affect and positively associated with post-quit negative affect and withdrawal. RD was not found to be related to any outcome measures. Our findings suggest that, despite experiencing greater baseline and post-quit negative affect, smokers higher in trait harm avoidance are more likely to quit smoking. The treatment and theoretical ramifications of these findings are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Do Parenting and the Home Environment, Maternal Depression, Neighborhood, and Chronic Poverty Affect Child Behavioral Problems Differently in Different Racial-Ethnic Groups?

PubMed Central

Pachter, Lee M.; Auinger, Peggy; Palmer, Ray; Weitzman, Michael

2006-01-01

OBJECTIVE To determine whether the processes through which parenting practices, maternal depression, neighborhood, and chronic poverty affect child behavioral problems are similar or different in minority and nonminority children in the United States. METHODS Data from 884 white, 538 black, and 404 Latino families with children who were 6 to 9 years of age in the National Longitudinal Survey of Youth were analyzed. The outcome, child behavioral problems, was measured using the Behavior Problems Index externalizing and internalizing subscales. The effects of chronic poverty, neighborhood, maternal depression, and parenting on the outcome were analyzed using multigroup structural equation modeling. RESULTS Chronic poverty affected child behavioral problems indirectly through the other variables, and parenting practices had direct effects in each racial/ethnic group. The effects of maternal depression were partially mediated through parenting in the white and Latino samples but were direct and unmediated through parenting practices in the black sample. Neighborhood effects were present in the white and black samples but were not significant for the Latino sample. CONCLUSIONS Chronic poverty, neighborhood, maternal depression, and parenting practices have effects on child behavioral problems in white, black, and Latino children, but the processes and mechanisms through which they exert their effects differ among the groups. The differences may be related to social stratification mechanisms as well as sociocultural differences in family and childrearing practices. PMID:16585331

Cognitive-behavioral therapy for adolescent depression and suicidality

PubMed Central

Spirito, Anthony; Esposito-Smythers, Christianne; Wolff, Jennifer; Uhl, Kristen

2011-01-01

Synopsis CBT has emerged as a well-established treatment for depression in children and adolescents but treatment trials for adolescents with suicidality are few in number, and their efficacy to date is rather limited. Although a definitive treatment for adolescent suicide attempters has yet to be established, the limited literature suggests that suicidal thoughts and behavior should be directly addressed for optimal treatment outcome. This chapter reviews the rationale underlying the use of CBT for the treatment of depression and suicidality in adolescents, the literature supporting the efficacy of CBT for depressed adolescents, and whether CBT for depression reduces suicidal thoughts and behavior. A description of some of the core cognitive, affective, and behavioral techniques used in CBT treatments of suicidal ideation and behavior in depressed adolescents is included. PMID:21440850

Spinal Cord Injury Causes Brain Inflammation Associated with Cognitive and Affective Changes: Role of Cell Cycle Pathways

PubMed Central

Zhao, Zaorui; Sabirzhanov, Boris; Stoica, Bogdan A.; Kumar, Alok; Luo, Tao; Skovira, Jacob; Faden, Alan I.

2014-01-01

Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression. PMID:25122899

In-depth behavioral characterization of the corticosterone mouse model and the critical involvement of housing conditions.

PubMed

Demuyser, Thomas; Deneyer, Lauren; Bentea, Eduard; Albertini, Giulia; Van Liefferinge, Joeri; Merckx, Ellen; De Prins, An; De Bundel, Dimitri; Massie, Ann; Smolders, Ilse

2016-03-15

Depression and anxiety are disabling and highly prevalent psychiatric disorders. To better understand the neurobiological basis of mood and anxiety disorders, relevant animal models are needed. The corticosterone mouse model is frequently used to study depression. Chronic stress and accompanying glucocorticoid elevation causes pathological changes in the central nervous system, which are related to psychiatric symptoms. Exogenous administration of corticosterone is therefore often used to induce depressive-like behavior in mice and in some cases also features of anxiety-like behavior are shown. However, a thorough characterization of this model has never been conducted and housing conditions of the used subjects often differ between the implemented protocols. We chronically administered a subcutaneous corticosterone bolus injection to single- and group-housed mice, and we subsequently evaluated the face validity of this model by performing a battery of behavioral tests (forced swim test, mouse-tail suspension test, saccharin intake test, novelty-suppressed feeding test, elevated plus maze, light/dark paradigm and open field test). Our results show that corticosterone treatment has a substantial overall effect on depressive-like behavior. Increases in anxiety-like behavior on the other hand are mainly seen in single housed animals, independent of treatment. The current study therefore does not only show a detailed behavioral characterization of the corticosterone mouse model, but furthermore also elucidates the critical influence of housing conditions on the behavioral outcome in this model. Copyright © 2015 Elsevier Inc. All rights reserved.

Depression and HIV Risk Behaviors among Female Sex Workers in Guangdong, China: A Multicenter Cross-Sectional Study.

PubMed

Shen, Hongcheng; Zou, Huachun; Huang, Shujie; Liu, Fengying; Zhao, Peizhen; Chen, Lei; Zhang, Ye; Luo, Xiaomin; Tang, Weiming; Zheng, Heping; Yang, Bin

2016-01-01

Background. Our study aimed to assess the burden of depression and evaluate factors associated with depression and status of HIV risk behaviors among female sex workers (FSWs) in Guangdong, China. Method. We recruited FSWs from massage parlors, saunas, restaurants, hotels, hair salons, and streets in Guangdong, China, in 2014. Information on demographic characteristics, HIV testing history, and sexual behaviors was collected using a questionnaire. A blood sample was collected to test for HIV, syphilis, and HCV. A participant was defined as being depressed if she obtained 6 points or above using the 12-item General Health Questionnaire. Results. Among the 653 participants, 41.7% were 21-30 years old and 43.6% married. Overall, 52.4% were found to be depressed. FSWs who had correct syphilis related knowledge [aOR = 1.45; 95% CI: 1.04-2.03] and had primary sex partner (1.63, 1.14-2.33) were more likely to be depressed. FSWs who did not use a condom during their last sex with the primary sex partner were less likely to be depressed (0.47, 0.31-0.71). Conclusion. Our study observed high level of depression and HIV risk behaviors among Chinese FSWs. Future interventions should integrate mental health services in comprehensive interventions to prevent depression among Chinese FSWs.

Is it contagious? Affect similarity among spouses.

PubMed

Goodman, C R; Shippy, R A

2002-08-01

Theories of emotional contagion suggest that spouses mutually experience affective or emotional states. However, empirical support for this theory is limited. Using a dyadic approach, this study examines affect similarity of depressive symptoms between elders with vision impairment and their spouses. As part of an investigation on older couples dealing with disability, 123 elders dealing with a recent vision loss and their spouses were interviewed. Guided by a stress process model, predictors of spouse depressive symptoms were examined. Hierarchical regression analyses revealed that the spouse's race, health, care-giving appraisal, self-efficacy, conflict with other family members regarding their partner, and their partner's depressive symptoms significantly predicted spouse depression. Specifically, spouses who were white, in poorer health, experienced more care-giving burden, had more family conflict, and poorer self-efficacy, were more likely to be depressed. Entered in the final step, elder depression uniquely contributed to the prediction of spouse depression. This points to affect similarity among spouses, which suggests that when one spouse is depressed, the other spouse is likely to experience a similar depressive symptomatology.

Transgenerational effects of maternal depression on affect recognition in children.

PubMed

Kluczniok, Dorothea; Hindi Attar, Catherine; Fydrich, Thomas; Fuehrer, Daniel; Jaite, Charlotte; Domes, Gregor; Winter, Sibylle; Herpertz, Sabine C; Brunner, Romuald; Boedeker, Katja; Bermpohl, Felix

2016-01-01

The association between maternal depression and adverse emotional and behavioral outcomes in children is well established. One associated factor might be altered affect recognition which may be transmitted transgenerationally. Individuals with history of depression show biased recognition of sadness. Our aim was to investigate parallels in maternal and children's affect recognition with remitted depressed mothers. 60 Mother-child dyads completed an affect recognition morphing task. We examined two groups of remitted depressed mothers, with and without history of physical or sexual abuse, and a group of healthy mothers without history of physical or sexual abuse. Children were between 5 and 12 years old. Across groups, mothers identified happy faces fastest. Mothers with remitted depression showed a higher accuracy and response bias for sadness. We found corresponding results in their children. Maternal and children's bias and accuracy for sadness were positively correlated. Effects of remitted depression were found independent of maternal history of physical or sexual abuse. Our sample size was relatively small and further longitudinal research is needed to investigate how maternal and children's affect recognition are associated with behavioral and emotional outcomes in the long term. Our data suggest a negative processing bias in mothers with remitted depression which might represent both the perpetuation of and vulnerability to depression. Children of remitted depressed mothers appear to be exposed to this processing bias outside acute depressive episodes. This may promote the development of a corresponding processing bias in the children and could make children of depressed mothers more vulnerable to depressive disorders themselves. Copyright © 2015 Elsevier B.V. All rights reserved.

[Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats].

PubMed

Malyshev, A V; Razumkina, E V; Rogozinskaia, É Ia; Sarkisova, K Iu; Dybynin, V A

2014-01-01

In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother-oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months).

Deletion of Dlk2 increases the vulnerability to anxiety-like behaviors and impairs the anxiolytic action of alprazolam.

PubMed

Navarrete, Francisco; García-Gutiérrez, María S; Laborda, Jorge; Manzanares, Jorge

2017-11-01

The purpose of this study was to evaluate the role of the non-canonical DLK2 NOTCH ligand in the regulation of emotional behavior. To this aim, anxiety and depressive-like behaviors were examined in Dlk2 knock-out (Dlk2 -/- ) and its corresponding wild-type (WT) mice. Furthermore, relative gene expression analyses of corticotropin releasing hormone (Crh) in the paraventricular nucleus (PVN), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) in the hippocampus (HIPP), and the transcription factors Hes1, Hes5 and Hey1 in the PVN, HIPP and amygdala (AMY) were carried out in Dlk2 -/- and WT mice under basal conditions and after exposure to restraint stress. The anxiolytic action of alprazolam and the relative gene expression levels of the GABA-A alpha 2 and gamma 2 receptor subunits (Gabra2 and Gabrg2) were also evaluated in the HIPP and AMY of WT and Dlk2 -/- mice. The results reveal that deletion of Dlk2 increased anxiety and depressive-like behaviors and altered the vulnerability to restraint stress on Crh gene expression in the PVN, Nr3c1 and Fkbp5 gene expression in the HIPP, and Hes1, Hes5 and Hey1 gene expression in the PVN, HIPP and AMY. Interestingly, the administration of alprazolam failed to produce an anxiolytic action in Dlk2 -/- mice. Indeed, Gabra2 and Gabrg2 gene expression levels were significantly affected under basal conditions and after stress exposure in Dlk2 -/- mice compared with WT mice. In conclusion, the results suggest that DLK2 plays an important role in the regulation of emotional behaviors and relevant targets of the stress axis, NOTCH pathway and GABAergic neurotransmission. In addition, the deletion of Dlk2 blocked the anxiolytic response to alprazolam. Future studies are needed to determine the relevance of DLK2 as a potential therapeutic target for the treatment of neuropsychiatric disorders with anxiety or depressive-like behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Victimization Mediates the Longitudinal Association Between Depressive Symptoms and Violent Behaviors in Adolescence.

PubMed

Yu, Rongqin; Branje, Susan; Meeus, Wim; Koot, Hans M; van Lier, Pol; Fazel, Seena

2018-05-01

Despite evidence of a positive link between depressive symptoms and violent behaviors, the pathways underlying this longitudinal association remain unknown. Depressive symptoms might drive and reinforce victimization which in turn could increase risk of individuals becoming violent towards others. Thus, we tested whether victimization mediated the link between depressive symptoms and violent behaviors using a 6-year longitudinal study of a community sample of adolescents. The sample included 682 Dutch adolescents (54% boys) from an ongoing longitudinal study RADAR (Research on Adolescent Development and Relationships). From ages 13 to 18 years, depressive symptoms, victimization experiences, and violent behaviors were annually assessed. We conducted longitudinal mediation analyses to test pathways to violence in adolescents with depressive symptoms. Longitudinal analyses revealed that victimization mediated the association between depressive symptoms and violent behaviors from early to late adolescence. As part of this, we found that adolescents' depressive symptoms predicted victimization, and this victimization increased risk of subsequent violent behaviors. In conclusion, links between depressive symptoms and violent behaviors are potentially important to understand adolescent development. Decreasing the occurence of victimization is likely to be an important target for the prevention of violent behaviors in adolescents with depressive symptoms.

Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

PubMed Central

Crofton, Elizabeth J.; Nenov, Miroslav N.; Zhang, Yafang; Scala, Federico; Page, Sean A.; McCue, David L.; Li, Dingge; Hommel, Jonathan D.; Laezza, Fernanda; Green, Thomas A.

2017-01-01

Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types. PMID:28126496

Mice selected for high versus low stress reactivity: a new animal model for affective disorders.

PubMed

Touma, Chadi; Bunck, Mirjam; Glasl, Lisa; Nussbaumer, Markus; Palme, Rupert; Stein, Hendrik; Wolferstätter, Michael; Zeh, Ramona; Zimbelmann, Marina; Holsboer, Florian; Landgraf, Rainer

2008-07-01

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety-related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were 'hyperactive' in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.

Adolescent voluntary exercise attenuated hippocampal innate immunity responses and depressive-like behaviors following maternal separation stress in male rats.

PubMed

Sadeghi, Mahsa; Peeri, Maghsoud; Hosseini, Mir-Jamal

2016-09-01

Early life stressful events have detrimental effects on the brain and behavior, which are associated with the development of depression. Immune-inflammatory responses have been reported to contribute in the pathophysiology of depression. Many studies have reported on the beneficial effects of exercise against stress. However, underlying mechanisms through which exercise exerts its effects were poorly studied. Therefore, it applied maternal separation (MS), as a valid animal model of early-life adversity, in rats from postnatal day (PND) 2 to 14 for 180min per day. At PND 28, male Wistar albino rats were subjected to 5 experimental groups; 1) controls 2) MS rats 3) MS rats treated with fluoxetine 5mg/kg to PND 60, 4) MS rats that were subjected to voluntary running wheel (RW) exercise and 5) MS rats that were subjected to mandatory treadmill (TM) exercise until adulthood. At PND 60, depressive-like behaviors were assessed by using forced swimming test (FST), splash test, and sucrose preference test (SPT). Our results revealed that depressive-like behaviors following MS stress were associated with an increase in expression of toll-like receptor 4 (Tlr-4) and its main signaling protein, Myd88, in the hippocampal formation. Also, we found that voluntary (and not mandatory) physical exercise during adolescence is protected against depressant effects of early-life stress at least partly through mitigating the innate immune responses in the hippocampus. Copyright © 2016. Published by Elsevier Inc.

Risky Sexual Behaviors as Correlates of Depression and Suicidal Ideation Among Male HIV Test-Seekers at a Voluntary Counseling and Testing Facility in Taiwan.

PubMed

Lin, Chia-Chun; Lee, Yuan-Ti; Yang, Hao-Jan

2017-04-01

This study aims at determining the level of depression and suicidal status of adult HIV test-seekers. Of the total enrolled 850 males, almost 50% reported some risk behaviors, 38.9% experienced depression, and 7.2% had suicidal ideation. Subjects with risky sexual behaviors in terms of repeated HIV test, had a history of sexually transmitted disease, engaged in one-night stands, or did not use condoms all the time with causal sexual partners were more likely to have depression. Furthermore, subjects who were bisexual/homosexual, engaged in Internet sex, engaged in one-night stands, or used addictive drugs within the past 6 months were more likely to experience suicidal ideation. The HIV testers are at risk of experiencing depression and suicidal ideation; each is associated with different types of risky sexual behaviors. It is essential for the health authority to further provide mental health services for HIV testers and to draw up an effective strategy in reducing unprotected sexual behaviors.

The postnatal 5-HT1A receptor regulates adult anxiety and depression differently via multiple molecules.

PubMed

Ishikawa, Chihiro; Shiga, Takashi

2017-08-01

Serotonin (5-HT) and the 5-HT 1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT 1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT 1A receptor, brain-derived neurotrophic factor (BDNF), GABA A receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT 1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABA A receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT 1A receptor and BDNF in the mPFC and the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABA A receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT 1A receptor and BDNF in the mPFC and by the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT 1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

PubMed

Hayase, Tamaki

2016-01-01

Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor-induced antidepressant-like effects may reflect the characteristic involvement of histone acetylation within the NC-related neurotransmitter systems other than the ECB system.

[Anxiety, depression, health-related control beliefs, and their association with health behavior in patients with ischemic heart disease].

PubMed

Rafael, Beatrix; Konkolÿ Thege, Barna; Kovács, Péter; Balog, Piroska

2015-05-17

Psychological and lifestyle factors affect the development and outcome of heart disease considerably. The aims of the authors were to examine health control, level of anxiety and depression and to analyse their relationship with health behaviour in patients with ischemic heart disease. The present cross-sectional study involved 116 patients who took part in residential cardiac rehabilitation (56.9% men, mean age: 57.65±8.22 years). 30.9% of the patients reported elevated anxiety and 21.9% increased depressive symptomatology. Social-external control belief was the strongest among respondents. Further, anxiety and depression were negatively associated with healthy diet and the frequency of exercise. Patients with stronger social-external control beliefs were more likely to seek medical attention if they suspected a disease. It is important to assess psychological risk factors linked to cardiovascular diseases in cardiac rehabilitation departments and to initiate psychological interventions if indicated.

Suppression of Oxidative Stress and 5-Lipoxygenase Activation by Edaravone Improves Depressive-Like Behavior after Concussion

PubMed Central

Hoshijima, Michihiro; Yawata, Toshio; Nobumoto, Atsuya; Tsuda, Masayuki; Shimizu, Takahiro; Saito, Motoaki; Ueba, Tetuya

2014-01-01

Abstract Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weight-drop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1- and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of OS and 5-LOX translocation. PMID:24849726

Suppression of oxidative stress and 5-lipoxygenase activation by edaravone improves depressive-like behavior after concussion.

PubMed

Higashi, Youichirou; Hoshijima, Michihiro; Yawata, Toshio; Nobumoto, Atsuya; Tsuda, Masayuki; Shimizu, Takahiro; Saito, Motoaki; Ueba, Tetuya

2014-10-15

Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weight-drop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1- and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of OS and 5-LOX translocation.

Brain antioxidant effect of mirtazapine and reversal of sedation by its combination with alpha-lipoic acid in a model of depression induced by corticosterone.

PubMed

Oliveira, Tatiana de Queiroz; de Sousa, Caren Nádia Soares; Vasconcelos, Germana Silva; de Sousa, Luciene Costa; de Oliveira, Anneheydi Araújo; Patrocínio, Cláudio Felipe Vasconcelos; Medeiros, Ingridy da Silva; Honório Júnior, José Eduardo Ribeiro; Maes, Michael; Macedo, Danielle; Vasconcelos, Silvânia Maria Mendes

2017-09-01

Depression is accompanied by activated neuro-oxidative and neuro-nitrosative pathways, while targeting these pathways has clinical efficacy in depression. This study aimed to investigate the effects of mirtazapine (MIRT) alone and combined with alpha-lipoic acid (ALA) against corticosterone (CORT) induced behavioral and oxidative alterations. Male mice received vehicle or CORT 20mg/kg during 14 days. From the 15th to 21st days they were divided in groups administered: vehicle, MIRT 3mg/kg or the combinations MIRT+ALA100 or MIRT+ALA200. On the 21st day of treatment, the animals were subjected to behavioral tests. Twenty-four hours after the last drug administration hippocampus (HC) and striatum (ST) were dissected for the determination reduced glutathione (GSH), lipid peroxidation (LP) and nitrite levels. CORT induced anxiety- and depressive-like behaviors as observed by increased immobility time in the tail suspension test and decreased sucrose consumption. MIRT or MIRT+ALA are effective in reversing anxiety- and depressive-like behaviors induced by CORT. CORT and MIRT alone prolonged sleeping time and this effect was reversed by MIRT+ALA. CORT significantly increased LP, which was reversed by MIRT or MIRT+ALA. Nitrite levels were increased in CORT-treated animals and reversed by MIRT+ALA200 (HC), MIRT or MIRT+ALA (ST). A relative small sample size and lack of a washout period between drug administration and behavioral testing. MIRT or MIRT+ALA reverse CORT-induced anxiety- and depressive-like behaviors probably via their central antioxidant effects. Augmentation of MIRT with ALA may reverse sedation, an important side effect of MIRT. Randomized controlled studies are needed to examine the clinical efficacy of this combination in human depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Differential impact of a complex environment on positive affect in an animal model of individual differences in emotionality.

PubMed

Perez-Sepulveda, J A; Flagel, S B; Garcia-Fuster, M J; Slusky, R J; Aldridge, J W; Watson, S; Akil, H

2013-09-17

Anhedonia, or the inability to experience positive feelings is a hallmark of depression. However, few animal models have relied on decreased positive affect as an index of susceptibility to depression. Rats emit frequency-modulated ultrasonic vocalizations (USVs), designated as "positive" calls in the 50-kHz range. USVs have been associated with pharmacological activation of motivational reward circuits. Here we utilized selectively-bred rats differing in "emotionality" to ask whether there are associated differences in USVs. Rats bred based on locomotor response to novelty and classified as bred High Responders (bHRs) or bred Low Responders (bLRs) exhibit inborn differences in response to environmental cues, stress responsiveness, and depression-like behavior. These animals also exhibit differences in anxiety-like behavior, which are reversed by exposure to environmental complexity (EC). Finally, these animals exhibit unique profiles of responsiveness to rewarding stimuli accompanied with distinct patterns of dopamine regulation. We investigated whether acute and chronic environmental manipulations impacted USVs in bHRs and bLRs. We found that, relative to bLRs, bHRs emitted significantly more 50-kHz USVs. However, if a bLR is accompanied by another bLR, there is a significant increase in 50-kHZ USVs emitted by this phenotype. bHRs emitted increases in 50-kHZ UVSs upon first exposure to EC, whereas bLRs showed a similar increase only after repeated exposure. bLRs' increase in positive affect after chronic EC was coupled with significant positive correlations between corticosterone levels and c-fos mRNA in the accumbens. Conversely, a decline in the rate of positive calls in bHRs after chronic EC was associated with a negative correlation between corticosterone and accumbens c-fos mRNA. These studies demonstrate that inborn differences in emotionality interact with the environment to influence positive affect and underscore the potential interaction between glucocorticoids and the mesolimbic reward circuitry in modulating 50-kHz calls. Published by Elsevier Ltd.

Beneficial effect of etazolate on depression-like behavior and, learning, and memory impairment in a model of Parkinson's disease.

PubMed

Alzoubi, Karem H; Mokhemer, Enas; Abuirmeileh, Amjad N

2018-09-17

The aim of this study was to evaluate etazolate against depression-like behavior and, learning and memory impairment induced by 6- hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD). This aim was achieved through comparing 6-OHDA lesioned rats in the presence and absence of etazolate. The 6-OHDA was used to induce lesion as a model of PD. Etazolate was administered at a dose of 1 mg/kg/day for 14 days, starting 7 days after lesion induction. Apomorphine-induced rotation test was used to evaluate 6-OHDA-induced motor deficits, tail suspension test was used to assess depression-like symptoms, and the radial arms water maze (RAWM) was used to evaluate special learning and memory functions. Antioxidant biomarkers and BDNF protein levels were assessed in the hippocampus. Results revealed that etazolate administration significantly improved 6-OHDA-induced PD related symptoms including motor deficits, depression-like behavior and impairment of both short- and long- term memory. Moreover, etazolate significantly prevented 6-OHDA-induced reduction in oxidative stress biomarkers (GSH/GSSG ratio, GPx) and BDNF levels. In conclusion, motor dysfunction, depressive- like behavior, and learning and memory deficits in the 6-OHDA rat model of PD can be significantly prevented by etazolate. This prevention could be attributed to etazolate's ability to prevent reduction in antioxidative stress biomarkers and BDNF levels. Copyright © 2018 Elsevier B.V. All rights reserved.

Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats.

PubMed

Li, Jiali; Luo, Yixiao; Zhang, Ruoxi; Shi, Haishui; Zhu, Weili; Shi, Jie

2015-11-30

The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.

PubMed

Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Ilchibaeva, Tatyana V; Khotskin, Nikita V; Semenova, Alina A; Popova, Nina K

2014-11-01

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of repeated deep brain stimulation on depressive- and anxiety-like behavior in rats: comparing entopeduncular and subthalamic nuclei.

PubMed

Creed, Meaghan C; Hamani, Clement; Nobrega, José N

2013-07-01

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity. To compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats. DBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels. Repeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS. Together these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN. Copyright © 2013 Elsevier Inc. All rights reserved.

Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP+ cells loss induced by restraint stress in mice.

PubMed

Perez-Urrutia, Nelson; Mendoza, Cristhian; Alvarez-Ricartes, Nathalie; Oliveros-Matus, Patricia; Echeverria, Florencia; Grizzell, J Alex; Barreto, George E; Iarkov, Alexandre; Echeverria, Valentina

2017-09-01

Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

PubMed

Gupta, Deepali; Thangaraj, Devadoss; Radhakrishnan, Mahesh

2016-01-15

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions. Copyright © 2015 Elsevier B.V. All rights reserved.

Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors.

PubMed

Chu, Cuilin; Wei, Hui; Zhu, Wanwan; Shen, Yan; Xu, Qi

2017-09-01

Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors

PubMed Central

Chu, Cuilin; Wei, Hui; Zhu, Wanwan; Shen, Yan

2017-01-01

Abstract Background Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Methods Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Results Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors. PMID:28582515

A Longitudinal Study of Parental Depressive Symptoms and Coparenting in the First 18 Months.

PubMed

Tissot, Hervé; Favez, Nicolas; Ghisletta, Paolo; Frascarolo, France; Despland, Jean-Nicolas

2017-06-01

Although the negative impact of postpartum depression on parenting behaviors has been well established-albeit separately-for mothers and fathers, the respective and joint impact of both parents' mood on family-group interactive behaviors, such as coparenting support and conflict behaviors between the parents, have not yet been investigated. The aim of this study was to examine the association between parental depressive symptoms and coparenting behaviors in a low-risk sample of families with infants, exploring reciprocity between the variables, as well as gender differences between mothers and fathers regarding these links. At 3 (T1), 9 (T2), and 18 months postpartum (T3), we assessed both parents' depressive symptoms with a self-report questionnaire and observed coparenting support and conflict during triadic mother-father-child interactions. The results revealed that higher maternal depressive symptoms at T1 were associated with lower support at T1 and T2. Conflict at T3 was associated with higher maternal depressive symptoms at T3 and, more surprisingly, with less depressive symptoms in mothers at T2 and fathers at T3. Cross-lagged associations suggested that parental depressive symptoms were more likely to influence coparenting than the reverse. Moreover, maternal depressive symptoms were more likely to be linked to coparenting behaviors than were paternal depressive symptoms. These results confirm that parental-mostly maternal-depressive symptoms, even of mild intensity, may jeopardize the development of healthy family-level relations, which previous research has shown to be crucial for child development. © 2016 Family Process Institute.

Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry?

PubMed

Söderlund, Johan; Lindskog, Maria

2018-04-23

The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive-like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties.

Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

PubMed

Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza

2016-02-01

Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. Copyright © 2015 Elsevier Inc. All rights reserved.

Maternal infection during late pregnancy increases anxiety- and depression-like behaviors with increasing age in male offspring.

PubMed

Enayati, Mohsen; Solati, Jalal; Hosseini, Mohammad-Hassan; Shahi, Hamid-Reza; Saki, Golshid; Salari, Ali-Akbar

2012-02-10

Scientific reports suggest that the exposure to long-term stressors throughout or during late gestation increase anxiety- and depression-like behaviors of offspring in their later life. Moreover, several studies concluded that increasing age correlates with increased anxiety behaviors in humans and rodents. In the present study, we assessed the effects of prenatally administration of equal lipopolysaccharide (LPS) doses in various points of late gestation (days 15, 16, and 17) period, on neuroendocrine and immunological responses of pregnant mice, and subsequent long-lasting consequences of anxiety and depression with increasing age in male offspring at postnatal days (PD) 40 and 80. Four hours after the LPS injection, levels of corticosterone (COR) and pro-inflammatory cytokines (PIC) in pregnant mice, as compared to the control dams, were increased significantly. Furthermore, maternal inflammation raised the levels of COR, anxiety- and depression-like behaviors with increasing age in male offspring in comparison with saline male offspring. These data support other studies demonstrating that maternal stress increases the levels of anxiety and depression in offspring. Additionally, our data confirm other findings indicating that increasing age correlates with increased anxiety or depression behaviors in humans and rodents. Findings of this study suggest that time course of an inflammation response or stressor application during various stages of gestation and ages of offspring are important factors for assessing neuropsychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Positive parenting for positive parents: HIV/AIDS, poverty, caregiver depression, child behavior, and parenting in South Africa.

PubMed

Lachman, Jamie M; Cluver, Lucie D; Boyes, Mark E; Kuo, Caroline; Casale, Marisa

2014-01-01

Families affected by HIV/AIDS in the developing world experience higher risks of psychosocial problems than nonaffected families. Positive parenting behavior may buffer against the negative impact of child AIDS-orphanhood and caregiver AIDS-sickness on child well-being. Although there is substantial literature regarding the predictors of parenting behavior in Western populations, there is insufficient evidence on HIV/AIDS as a risk factor for poor parenting in low- and middle-income countries. This paper examines the relationship between HIV/AIDS and positive parenting by comparing HIV/AIDS-affected and nonaffected caregiver-child dyads (n=2477) from a cross-sectional survey in KwaZulu-Natal, South Africa (27.7% AIDS-ill caregivers; 7.4% child AIDS-orphanhood). Multiple mediation analyses tested an ecological model with poverty, caregiver depression, perceived social support, and child behavior problems as potential mediators of the association of HIV/AIDS with positive parenting. Results indicate that familial HIV/AIDS's association to reduced positive parenting was consistent with mediation by poverty, caregiver depression, and child behavior problems. Parenting interventions that situate positive parenting within a wider ecological framework by improving child behavior problems and caregiver depression may buffer against risks for poor child mental and physical health outcomes in families affected by HIV/AIDS and poverty.

Water spray-induced grooming is negatively correlated with depressive behavior in the forced swimming test in rats.

PubMed

Shiota, Noboru; Narikiyo, Kimiya; Masuda, Akira; Aou, Shuji

2016-05-01

Rodents show grooming, a typical self-care behavior, under stress and non-stress conditions. Previous studies revealed that grooming under stress conditions such as the open-field test (OFT) or the elevated plus-maze test (EPM) is associated with anxiety, but the roles of grooming under non-stress conditions are not well understood. Here, we examined spray-induced grooming as a model of grooming under a non-stress condition to investigate the relationship between this grooming and depression-like behavior in the forced swim test (FST) and tail suspension test, and we compared spray-induced grooming with OFT- and EPM-induced grooming. The main finding was that the duration of spray-induced grooming, but not that of OFT/EPM-induced grooming, was negatively correlated with the duration of immobility in the FST, an index of depression-like behavior. The results suggest that spray-induced grooming is functionally different from the grooming in the OFT and EPM and is related to reduction of depressive behavior.

Association of Depressive Symptoms and Substance Use With Risky Sexual Behavior and Sexually Transmitted Infections Among African American Female Adolescents Seeking Sexual Health Care.

PubMed

Jackson, Jerrold M; Seth, Puja; DiClemente, Ralph J; Lin, Anne

2015-10-01

We examined how depression and substance use interacted to predict risky sexual behavior and sexually transmitted infections (STIs) among African American female adolescents. We measured depressive symptoms, substance use, sexual behavior, and STIs in 701 African American female adolescents, aged 14 to 20 years, at baseline and at 6-month intervals for 36 months in Atlanta, Georgia (2005-2007). We used generalized estimating equation models to examine effects over the 36-month follow-up period. At baseline, more than 40% of adolescents reported significant depressive symptoms; 64% also reported substance use in the 90 days before assessment. Depression was associated with recently incarcerated partner involvement, sexual sensation seeking, unprotected sex, and prevalent STIs (all P < .001). In addition, adolescents with depressive symptoms who reported any substance use (i.e., marijuana, alcohol, Ecstasy) were more likely to report incarcerated partner involvement, sexual sensation seeking, unprotected sex, and have an incident STI over the 36-month follow-up (all P < .05). African American female adolescents who reported depressive symptoms and substance use were more likely to engage in risky behavior and acquire incident STIs. This population might benefit from future prevention efforts targeting the intersection of depression and substance use.

Association of Depressive Symptoms and Substance Use With Risky Sexual Behavior and Sexually Transmitted Infections Among African American Female Adolescents Seeking Sexual Health Care

PubMed Central

Seth, Puja; DiClemente, Ralph J.; Lin, Anne

2015-01-01

Objectives. We examined how depression and substance use interacted to predict risky sexual behavior and sexually transmitted infections (STIs) among African American female adolescents. Methods. We measured depressive symptoms, substance use, sexual behavior, and STIs in 701 African American female adolescents, aged 14 to 20 years, at baseline and at 6-month intervals for 36 months in Atlanta, Georgia (2005–2007). We used generalized estimating equation models to examine effects over the 36-month follow-up period. Results. At baseline, more than 40% of adolescents reported significant depressive symptoms; 64% also reported substance use in the 90 days before assessment. Depression was associated with recently incarcerated partner involvement, sexual sensation seeking, unprotected sex, and prevalent STIs (all P < .001). In addition, adolescents with depressive symptoms who reported any substance use (i.e., marijuana, alcohol, Ecstasy) were more likely to report incarcerated partner involvement, sexual sensation seeking, unprotected sex, and have an incident STI over the 36-month follow-up (all P < .05). Conclusions. African American female adolescents who reported depressive symptoms and substance use were more likely to engage in risky behavior and acquire incident STIs. This population might benefit from future prevention efforts targeting the intersection of depression and substance use. PMID:25905854

Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.

PubMed

Jangra, Ashok; Sriram, Chandra Shaker; Dwivedi, Shubham; Gurjar, Satendra Singh; Hussain, Md Iftikar; Borah, Probodh; Lahkar, Mangala

2017-01-01

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

Comparison of fluoxetine and 1-methyl-L-tryptophan in treatment of depression-like illness in Bacillus Calmette-Guerin-induced inflammatory model of depression in mice.

PubMed

Rana, Proteesh; Sharma, Amit K; Jain, Smita; Deshmukh, Pravin; Bhattacharya, S K; Banerjee, B D; Mediratta, Pramod K

2016-11-01

The inflammatory response system has been implicated in the pathophysiology of major depression. The pro-inflammatory cytokines like interferon-γ induce the enzyme indoleamine-2,3-dioxygenase (IDO) of the kynurenine pathway of tryptophan metabolism. The induction of IDO reduces the availability of tryptophan for serotonin synthesis. Furthermore, the metabolites of kynurenine pathway have neurotoxic property, which along with decreased serotonin may account for depression-like illness. The aim of this study was to compare the effects of treatment with fluoxetine and 1-methyl-L-tryptophan (1-MT) on Bacillus Calmette-Guerin (BCG)-induced inflammatory model of depression in mice. Behavioral tests included locomotor activity, forced swim test (FST) and tail suspension test (TST). Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in homogenized whole brain samples. Comet assays were performed to assess neurotoxicity. The results of this study demonstrate that BCG treatment resulted in an increase in duration of immobility in FST and TST as compared to the saline group. Further, it produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. The hippocampal tissue from BCG group had significantly more comet cells than the saline group. 1-MT and fluoxetine were able to reverse the BCG-induced depression-like behavior and the derangement in oxidative stress parameters. Fluoxetine and 1-MT also reversed the BCG-induced neurotoxicity in such mice. 1-Methyl-L-tryptophan exhibits antidepressant-like effect comparable to that of fluoxetine in treating BCG-induced depression-like behavior in mice.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression.

PubMed

Lim, Patrick H; Wert, Stephanie L; Tunc-Ozcan, Elif; Marr, Robert; Ferreira, Adriana; Redei, Eva E

2018-02-25

Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression-like behavior in this model. Copyright © 2018 Elsevier B.V. All rights reserved.

A gut feeling: Microbiome-brain-immune interactions modulate social and affective behaviors.

PubMed

Sylvia, Kristyn E; Demas, Gregory E

2018-03-01

The expression of a wide range of social and affective behaviors, including aggression and investigation, as well as anxiety- and depressive-like behaviors, involves interactions among many different physiological systems, including the neuroendocrine and immune systems. Recent work suggests that the gut microbiome may also play a critical role in modulating behavior and likely functions as an important integrator across physiological systems. Microbes within the gut may communicate with the brain via both neural and humoral pathways, providing numerous avenues of research in the area of the gut-brain axis. We are now just beginning to understand the intricate relationships among the brain, microbiome, and immune system and how they work in concert to influence behavior. The effects of different forms of experience (e.g., changes in diet, immune challenge, and psychological stress) on the brain, gut microbiome, and the immune system have often been studied independently. Though because these systems do not work in isolation, it is essential to shift our focus to the connections among them as we move forward in our investigations of the gut-brain axis, the shaping of behavioral phenotypes, and the possible clinical implications of these interactions. This review summarizes the recent progress the field has made in understanding the important role the gut microbiome plays in the modulation of social and affective behaviors, as well as some of the intricate mechanisms by which the microbiome may be communicating with the brain and immune system. Copyright © 2018 Elsevier Inc. All rights reserved.

On the effect of minocycline on the depressive-like behavior of mice repeatedly exposed to malathion: interaction between nitric oxide and cholinergic system.

PubMed

Saeedi Saravi, Seyed Soheil; Amirkhanloo, Roya; Arefidoust, Alireza; Yaftian, Rahele; Saeedi Saravi, Seyed Sobhan; Shokrzadeh, Mohammad; Dehpour, Ahmad Reza

2016-06-01

This study was performed to investigate the antidepressant-like effect of minocycline in mice exposed to organophosphate pesticide malathion and possible involvement of nitric oxide/cGMP pathway in this paradigm. Mice were administered specific doses of malathion once daily for 7 consecutive days. After induction of depression, different doses of minocycline were daily injected alone or combined with non-specific NOS inhibitor, L-NAME, specific inducible NOS inhibitor, AG, NO precursor, L-arginine, and PDE5I, sildenafil. After locomotion assessment in open-field test, immobility times were recorded in the FST and TST. Moreover, hippocampal nitrite concentrations and acetylcholinesterase activity were measured. The results showed that repeated exposure to malathion induces depressive-like behavior at dose of 250 mg/kg. Minocycline (160 mg/kg) significantly reduced immobility times in FST and TST (P < 0.001). Combination of sub-effective doses of minocycline (80 mg/kg) with either L-NAME (3 mg/kg) or AG (25 mg/kg) significantly exerted a robust antidepressant-like effect in FST and TST (P < 0.001). Furthermore, minocycline at the same dose which has antidepressant-like effect, significantly reduced hippocampal nitrite concentration. The investigation indicates the essential role for NO/cGMP pathway in malathion-induced depressive-like behavior and antidepressant-like effect of minocycline. Moreover, the interaction between nitrergic and cholinergic systems are suggested to be involved in malathion-induced depression.

Association of Maternal Depressive Symptoms and Offspring Physical Health in Low-Income Families.

PubMed

Thompson, Sarah M; Jiang, Lu; Hammen, Constance; Whaley, Shannon E

2018-06-01

Objectives The present study sought to examine the association between maternal depressive symptoms and characteristics of offspring physical health, including health status, health behaviors, and healthcare utilization, among low-income families. Maternal engagement was explored as a mediator of observed effects. Methods Cross-sectional survey data from a community sample of 4589 low-income women and their preschool-age children participating in the WIC program in Los Angeles County were analyzed using logistic, Poisson, and zero-inflated negative binomial regression. Mediation was tested via conditional process analyses. Results After controlling for the effects of demographic characteristics including maternal health insurance coverage, employment status, education, and preferred language, children of depressed women (N = 1025) were significantly more likely than children of non-depressed women (N = 3564) to receive a "poor" or "fair" maternal rating of general health (OR 2.34), eat fewer vegetables (IRR: 0.94) more sweets (IRR: 1.20) and sugary drinks daily (IRR: 1.32), and consume fast food more often (OR 1.21). These children were also less likely to have health insurance (OR 1.59) and more likely to receive medical care from a public medical clinic or hospital emergency room (OR 1.30). Reduced maternal engagement partially mediated associations between maternal depressive symptoms and several child health outcomes including poor diet, health insurance coverage, and use of public medical services. Conclusions for Practice Maternal depressive symptoms are associated with poor health among preschool-age children in low-income families. Prevention, screening, and treatment efforts aimed at reducing the prevalence of maternal depression may positively affect young children's health.

Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice

PubMed Central

Yun, Sanghee; Donovan, Michael H.; Ross, Michele N.; Richardson, Devon R.; Reister, Robin; Farnbauch, Laure A.; Fischer, Stephanie J.; Riethmacher, Dieter; Gershenfeld, Howard K.; Lagace, Diane C.; Eisch, Amelia J.

2016-01-01

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors. PMID:26795203

BEHAVIORAL EFFECTS OF FLUOXETINE IN AN ANIMAL MODEL OF ANXIETY/DEPRESSION ARE MEDIATED BY BOTH NEUROGENESIS-DEPENDENT AND INDEPENDENT MECHANISMS

PubMed Central

David, Denis J.; Samuels, Benjamin Adam; Rainer, Quentin; Wang, Jing-Wen; Marsteller, Douglas; Mendez, Indira; Drew, Michael; Craig, Douglas A.; Guiard, Bruno P.; Guilloux, Jean-Philippe; Artymyshyn, Roman P.; Gardier, Alain M; Gerald, Christophe; Antonijevic, Irina A.; Leonardo, E. David; Hen, René

2009-01-01

SUMMARY Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some but not all behavioral paradigms, suggesting both neurogenesis-dependent and independent mechanisms of antidepressant actions. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that β-arrestin signaling is necessary for the antidepressant effects of fluoxetine. PMID:19477151

Employed Parents' Depression: Effects of Spouse Support and Child Behavior.

ERIC Educational Resources Information Center

Tiedje, Linda Beth; Downey, Geraldine

This study was undertaken to assess the impact of children's behaviors on employed parents' adjustment and to test a specific model of how spouse support may facilitate coping with the stress of a difficult child. It was hypothesized that child behavioral difficulty and spouse support would affect maternal depression through the mediation of…

[Effects of diabetes and obesity on the higher brain functions in rodents].

PubMed

Asato, Megumi; Ikeda, Hiroko; Kamei, Junzo

2012-11-01

Metabolic disorders, such as diabetes and obesity, have been indicated to disturb the function of the central nervous system (CNS) as well as several peripheral organs. Clinically, it is well recognized that the prevalence of anxiety and depression is higher in diabetic and obesity patients than in the general population. We have recently indicated that streptozotocin-induced diabetic and diet-induced obesity mice have enhanced fear memory and higher anxiety-like behavior in several tests such as the conditioned fear, tail-suspension, hole-board and elevated open-platform tests. The changes in fear memory and anxiety-like behavior of diabetic and obese mice are due to the dysfunction of central glutamatergic and monoaminergic systems, which is mediated by the changes of intracellular signaling. These results suggest that metabolic disorders strongly affect the function of the CNS and disturb the higher brain functions. These dysfunctions of the CNS in diabetes and obesity are involved in the increased prevalence of anxiety disorders and depression. Normalization of these dysfunctions in the CNS will be a new attractive target to treat the metabolic disorders and their complications.

Cross-Cultural Examination of Depression Expression and Help-Seeking Behavior: A Comparative Study of American and Korean College Students.

ERIC Educational Resources Information Center

Yoo, Sung-Kyung; Skovholt, Thomas M.

2001-01-01

Examines cross-cultural differences in depression expression and help-seeking behavior among college students in the United States and Korea. Results indicate that the Korean students showed more somatization tendency, negative affect, and negative help-seeking behavior. Negative help-seeking behavior of Korean students was shown to relate to…

Neurobehavioral comorbidities of epilepsy: Role of inflammation.

PubMed

Mazarati, Andrey M; Lewis, Megan L; Pittman, Quentin J

2017-07-01

Epilepsy is associated with a high incidence of comorbid neurologic and psychiatric disorders. This review focuses on the association of epilepsy with autism spectrum disorder (ASD) and depression. There is high concordance of these behavioral pathologies with epilepsy. We review data that unambiguously reveal that epilepsy, ASD, and depression are associated with elevated brain inflammatory markers and that these may interact with serotoninergic pathways. Interference with inflammatory pathways or actions can reduce the severity of seizures, depression, and ASD-like behavior. Inflammation in the brain can be induced by seizure activity as well as by behavioral, environmental, and physiologic stressors. Furthermore, induction of inflammation at an early time point during gestation and in early neonatal life can precipitate both an ASD-like phenotype as well as a more excitable brain. It appears likely that priming of the brain due to early inflammation could provide a means by which subsequent inflammatory processes associated with epilepsy, ASD, and depression may lead to comorbidity. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Prenatal maternal immune activation increases anxiety- and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis.

PubMed

Majidi-Zolbanin, J; Doosti, M-H; Kosari-Nasab, M; Salari, A-A

2015-05-21

Multiple sclerosis (MS) is thought to result from a combination of genetics and environmental factors. Several lines of evidence indicate that significant prevalence of anxiety and depression-related disorders in MS patients can influence the progression of the disease. Although we and others have already reported the consequences of prenatal maternal immune activation on anxiety and depression, less is known about the interplay between maternal inflammation, MS and gender. We here investigated the effects of maternal immune activation with Poly I:C during mid-gestation on the progression of clinical symptoms of experimental autoimmune encephalomyelitis (EAE; a mouse model of MS), and then anxiety- and depressive-like behaviors in non-EAE and EAE-induced offspring were evaluated. Stress-induced corticosterone and tumor necrosis factor-alpha (TNF-α) levels in EAE-induced offspring were also measured. Maternal immune activation increased anxiety and depression in male offspring, but not in females. This immune challenge also resulted in an earlier onset of the EAE clinical signs in male offspring and enhanced the severity of the disease in both male and female offspring. Interestingly, the severity of the disease was associated with increased anxiety/depressive-like behaviors and elevated corticosterone or TNF-α levels in both sexes. Overall, these data suggest that maternal immune activation with Poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors, and the clinical symptoms of EAE in a sex-dependent manner in non-EAE or EAE-induced offspring. Finally, the progression of EAE in offspring seems to be linked to maternal immune activation-induced dysregulation in neuro-immune-endocrine system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Sensitization of Depressive-like Behavior during Repeated Maternal Separation is Associated with More-Rapid Increase in Core Body Temperature and Reduced Plasma Cortisol Levels

PubMed Central

Yusko, Brittany; Hawk, Kiel; Schiml, Patricia A.; Deak, Terrence; Hennessy, Michael B.

2011-01-01

Infant guinea pigs exhibit a 2-stage response to maternal separation: an initial active stage, characterized by vocalizing, and a second passive stage marked by depressive-like behavior (hunched posture, prolonged eye-closure, extensive piloerection) that appears to be mediated by proinflammatory activity. Recently we found that pups showed an enhanced (i.e., sensitized) depressive-like behavioral response during repeated separation. Further, core body temperature was higher during the beginning of a second separation compared to the first, suggesting a more-rapid stress-induced febrile response to separation the second day, though the possibility that temperature was already elevated prior to the second separation could not be ruled out. Therefore, the present study examined temperature prior to, and during, 2 daily separations. We also examined the temperature response to a third separation conducted 3 days after the second, and assessed the effect of repeated separation on plasma cortisol levels. Core temperature did not differ just prior to the separations, but showed a more-rapid increase and then decline during both a second and third separation than during a first. Temperature responses were not associated with changes in motor activity. Depressive-like behavior was greater during the second and third separations. Pups separated a first time showed a larger plasma cortisol response at the conclusion of separation than did animals of the same age separated a third time. In all, the results indicate that the sensitization of depressive-like behavior during repeated separations over several days is accompanied by a more-rapid febrile response that may be related to a reduction of glucocorticoid suppression. PMID:22079581

Effectiveness of memantine on depression-like behavior, memory deficits and brain mRNA levels of BDNF and TrkB in rats subjected to repeated unpredictable stress.

PubMed

Amidfar, Meysam; Kim, Yong-Ku; Wiborg, Ove

2018-06-01

Previous clinical and preclinical studies have indicated that the N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, has neuroprotective properties as well as antidepressant effects. The present study was designed to examine behavioral and molecular effects of memantine administration in rats subjected to the repeated unpredictable stress (RUS) paradigm. Rats were split into four groups at random including control+saline, control+memantine, stressed+saline and stressed+memantine. After 10days of exposure to the RUS paradigm, rats were administered memantine (20mg/kg) intraperitoneally (ip) for 14days. Depression-like behavior and memory performance were assessed by measuring immobility time in the forced swim test and passive avoidance test, respectively. The mRNA levels of BDNF and TrkB in the prefrontal cortex and hippocampus were measured by real-time quantitative PCR. Our results demonstrated that the RUS paradigm caused depression-like behavior and impairment of memory retrieval in rats. We did not find significant changes in BDNF or TrkB mRNA levels in hippocampus, but mRNA levels of TrkB in the prefrontal cortex showed a significant downregulation. Administration of memantine reversed depression-like behavior and memory impairment and significantly increased BDNF and TrkB mRNA levels in both prefrontal cortex and hippocampus of stress exposed rats. Our study supports the hypothesis that drugs with antagonistic properties on the NMDA receptor, such as memantine, might be efficient in treatment of major depression. Our results also suggest that upregulated mRNA levels of BDNF and TrkB in the brain might be essential for antidepressant-like activity of memantine in stress exposed rats. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior.

PubMed

Sarkar, Ambalika; Chachra, Parul; Kennedy, Pamela; Pena, Catherine J; Desouza, Lynette A; Nestler, Eric J; Vaidya, Vidita A

2014-08-01

Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of perturbed emotionality following fluoxetine exposure in early life.

Dietary arginine depletion reduces depressive-like responses in male, but not female, mice.

PubMed

Workman, Joanna L; Weber, Michael D; Nelson, Randy J

2011-09-30

Previous behavioral studies have manipulated nitric oxide (NO) production either by pharmacological inhibition of its synthetic enzyme, nitric oxide synthase (NOS), or by deletion of the genes that code for NOS. However manipulation of dietary intake of the NO precursor, L-arginine, has been understudied in regard to behavioral regulation. L-Arginine is a common amino acid present in many mammalian diets and is essential during development. In the brain L-arginine is converted into NO and citrulline by the enzyme, neuronal NOS (nNOS). In Experiment 1, paired mice were fed a diet comprised either of an L-arginine-depleted, L-arginine-supplemented, or standard level of L-arginine during pregnancy. Offspring were continuously fed the same diets and were tested in adulthood in elevated plus maze, forced swim, and resident-intruder aggression tests. L-Arginine depletion reduced depressive-like responses in male, but not female, mice and failed to significantly alter anxiety-like or aggressive behaviors. Arginine depletion throughout life reduced body mass overall and eliminated the sex difference in body mass. Additionally, arginine depletion significantly increased corticosterone concentrations, which negatively correlated with time spent floating. In Experiment 2, adult mice were fed arginine-defined diets two weeks prior to and during behavioral testing, and again tested in the aforementioned tests. Arginine depletion reduced depressive-like responses in the forced swim test, but did not alter behavior in the elevated plus maze or the resident intruder aggression test. Corticosterone concentrations were not altered by arginine diet manipulation in adulthood. These results indicate that arginine depletion throughout development, as well as during a discrete period during adulthood ameliorates depressive-like responses. These results may yield new insights into the etiology and sex differences of depression. Copyright © 2011 Elsevier B.V. All rights reserved.

Depression and HIV Risk Behaviors among Female Sex Workers in Guangdong, China: A Multicenter Cross-Sectional Study

PubMed Central

Huang, Shujie; Liu, Fengying; Zhao, Peizhen; Chen, Lei; Zhang, Ye; Luo, Xiaomin; Tang, Weiming

2016-01-01

Background. Our study aimed to assess the burden of depression and evaluate factors associated with depression and status of HIV risk behaviors among female sex workers (FSWs) in Guangdong, China. Method. We recruited FSWs from massage parlors, saunas, restaurants, hotels, hair salons, and streets in Guangdong, China, in 2014. Information on demographic characteristics, HIV testing history, and sexual behaviors was collected using a questionnaire. A blood sample was collected to test for HIV, syphilis, and HCV. A participant was defined as being depressed if she obtained 6 points or above using the 12-item General Health Questionnaire. Results. Among the 653 participants, 41.7% were 21–30 years old and 43.6% married. Overall, 52.4% were found to be depressed. FSWs who had correct syphilis related knowledge [aOR = 1.45; 95% CI: 1.04–2.03] and had primary sex partner (1.63, 1.14–2.33) were more likely to be depressed. FSWs who did not use a condom during their last sex with the primary sex partner were less likely to be depressed (0.47, 0.31–0.71). Conclusion. Our study observed high level of depression and HIV risk behaviors among Chinese FSWs. Future interventions should integrate mental health services in comprehensive interventions to prevent depression among Chinese FSWs. PMID:28097145

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

PubMed

Shen, Ji-Duo; Wei, Yu; Li, Yu-Jie; Qiao, Jing-Yi; Li, Yu-Cheng

2017-08-01

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

PubMed

Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

2014-03-15

A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice.

PubMed

Palotai, Miklós; Telegdy, Gyula; Tanaka, Masaru; Bagosi, Zsolt; Jászberényi, Miklós

2014-11-01

Little is known about the action of neuropeptide AF (NPAF) on anxiety and depression. Only our previous study provides evidence that NPAF induces anxiety-like behavior in rats. Therefore, the aim of the present study was to investigate the action of NPAF on depression-like behavior and the underlying neurotransmissions in mice. In order to determine whether there are species differences between rats and mice, we have investigated the action of NPAF on anxiety-like behavior in mice as well. A modified forced swimming test (mFST) and an elevated plus maze test (EPMT) were used to investigate the depression and anxiety-related behaviors, respectively. Mice were treated with NPAF 30min prior to the tests. In the mFST, the animals were pretreated with a non-selective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2/D3/D4 dopamine receptor antagonist, haloperidol, a α1/α2β-adrenergic receptor antagonist, prazosin or a non-selective β-adrenergic receptor antagonist, propranolol 30min before the NPAF administration. In the mFST, NPAF decreased the immobility time and increased the climbing and swimming times. This action was reversed completely by methysergide and partially by atropine, whereas cyproheptadine, haloperidol, prazosin and propranolol were ineffective. In the EPMT, NPAF decreased the time spent in the arms (open/open+closed). Our results demonstrate that NPAF induces anti-depressant-like behavior in mice, which is mediated, at least in part, through 5HT2-serotonergic and muscarinic cholinergic neurotransmissions. In addition, the NPAF-induced anxiety is species-independent, since it develops also in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Incoordination among Subcellular Compartments Is Associated with Depression-Like Behavior Induced by Chronic Mild Stress

PubMed Central

Xu, Aiping; Cui, Shan

2016-01-01

Background: Major depressive disorder is characterized as persistent low mood. A chronically stressful life in genetically susceptible individuals is presumably the major etiology that leads to dysfunctions of monoamine and hypothalamus-pituitary-adrenal axis. These pathogenic factors cause neuron atrophy in the limbic system for major depressive disorder. Cell-specific pathophysiology is unclear, so we investigated prelimbic cortical GABAergic neurons and their interaction with glutamatergic neurons in depression-like mice. Methods: Mice were treated with chronic unpredictable mild stress for 3 weeks until they expressed depression-like behaviors confirmed by sucrose preference, Y-maze, and forced swimming tests. The structures and functions of GABAergic and glutamatergic units in prelimbic cortices were studied by cell imaging and electrophysiology in chronic unpredictable mild stress-induced depression mice vs controls. Results: In depression-like mice, prelimbic cortical GABAergic neurons show incoordination among the subcellular compartments, such as decreased excitability and synaptic outputs as well as increased reception from excitatory inputs. GABAergic synapses on glutamatergic cells demonstrate decreased presynaptic innervation and increased postsynaptic responsiveness. Conclusions: Chronic unpredictable mild stress-induced incoordination in prelimbic cortical GABAergic and glutamatergic neurons dysregulates their target neurons, which may be the pathological basis for depressive mood. The rebalance of compatibility among subcellular compartments would be an ideal strategy to treat neural disorders. PMID:26506857

Targeting β-Catenin in GLAST-Expressing Cells: Impact on Anxiety and Depression-Related Behavior and Hippocampal Proliferation.

PubMed

Vidal, Rebeca; Garro-Martínez, Emilio; Díaz, Álvaro; Castro, Elena; Florensa-Zanuy, Eva; Taketo, Makoto M; Pazos, Ángel; Pilar-Cuéllar, Fuencisla

2018-05-08

β-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood disorders, associated to neurogenesis and neuroplasticity. Decreased β-catenin protein levels have been observed in the hippocampus and prefrontal cortex of depressed subjects. Additionally, the antidepressants exert, at least in part, their neurogenic effects by increasing β-catenin levels in the subgranular zone of the hippocampus. To further understand the role of β-catenin in depression and anxiety, we generated two conditional transgenic mice in which β-catenin was either inactivated or stabilized in cells expressing CreERT under the control of the astrocyte-specific glutamate transporter (GLAST) promoter inducible by tamoxifen, which presents high expression levels on the subgranular zone of the hippocampus. Here, we show that β-catenin inactivation in GLAST-expressing cells enhanced anxious/depressive-like responses. These behavioral changes were associated with impaired hippocampal proliferation and markers of immature neurons as doublecortin. On the other hand, β-catenin stabilization induced an anxiolytic-like effect in the novelty suppressed feeding test and tended to ameliorate depressive-related behaviors. In these mice, the control over the Wnt/β-catenin pathway seems to be tighter as evidenced by the lack of changes in some proliferation markers. Moreover, animals with stabilized β-catenin showed resilience to some anxious/depressive manifestations when subjected to the corticosterone model of depression. Our findings demonstrate that β-catenin present in GLAST-expressing cells plays a critical role in the development of anxious/depressive-like behaviors and resilience, which parallels its regulatory function on hippocampal proliferation. Further studies need to be done to clarify the importance of these changes in other brain areas also implicated in the neurobiology of anxiety and depressive disorders.

Inferential Style, School Teachers, and Depressive Symptoms in College Students

ERIC Educational Resources Information Center

Pittard, Caroline M.; Pössel, Patrick; Lau, Timothy

2017-01-01

Depressive symptoms affect around half of students at some point during college. According to the hopelessness theory of depression, making negative inferences about stressful events is a vulnerability for developing depression. Negative and socio-emotional teaching behavior can be stressors that are associated with depression in school students.…

A Multigroup, Longitudinal Study of Truant Youths, Marijuana Use, Depression, and STD-Associated Sexual Risk Behavior

ERIC Educational Resources Information Center

Dembo, Richard; M. Krupa, Julie; Wareham, Jennifer; Schmeidler, James; DiClemente, Ralph J.

2017-01-01

Truant youths are likely to engage in a number of problem behaviors, including sexual risky behaviors. Previous research involving non-truant youths has found sexual risk behaviors to be related to marijuana use and depression, with differential effects for male and female youths. Using data collected in a National Institute on Drug Abuse…

Lithium attenuated the behavioral despair induced by acute neurogenic stress through blockade of opioid receptors in mice.

PubMed

Khaloo, Pegah; Sadeghi, Banafshe; Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Haj-Mirzaian, Arya; Zolfagharie, Samira; Dehpour, Ahmad-Reza

2016-10-01

Major depressive disorder is disease with high rate of morbidity and mortality. Stressful events lead to depression and they can be used as a model of depression in rodents. In this study we aimed to investigate whether lithium modifies the stressed-induced depression through blockade of opioid receptors in mice. We used foot shock stress as stressor and forced swimming test (FST), tail suspension test (TST) and open field test (OFT) to evaluation the behavioral responses in mice. We also used naltrexone hydrochloride (as opioid receptor antagonist), and morphine (as opioid receptor agonist). Our results displayed that foot-shock stress significantly increased the immobility time in TST and FST but it could not change the locomotor behavior in OFT. When we combined the low concentrations of lithium and naltrexone a significant reduction in immobility time was seen in the FST and TST in comparison with control foot-shock stressed group administered saline only. Despite the fact that our data showed low concentrations of lithium, when administered independently did not significantly affect the immobility time. Also our data indicated that concurrent administration of lithium and naltrexone had no effect on open field test. Further we demonstrated that simultaneous administration of morphine and lithium reverses the antidepressant like effect of active doses of lithium. Our data acclaimed that we lithium can augment stressed-induced depression and opioid pathways are involved in this action. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Metabolic effects of light deprivation in the prefrontal cortex of rats with depression-like behavior: In vivo proton magnetic resonance spectroscopy at 7T.

PubMed

Yoo, Chi-Hyeon; Song, Kyu-Ho; Lim, Song-I; Woo, Dong-Cheol; Choe, Bo-Young

2018-05-15

Recent evidence suggests that the glutamate system plays an important role in the pathogenesis of major depressive disorder (MDD). The aim of this study was to investigate the effects of light deprivation (LD) in the prefrontal cortex (PFC) of animals with depression-like behavior, targeting the glutamate system, using in vivo proton magnetic resonance spectroscopy ( 1 H MRS). Male Sprague-Dawley rats were housed in constant darkness for six weeks (n = 12; LD group), while controls (n = 8) were housed under normal light cycles. The animals were assessed with forced swim tests. Point-resolved spectroscopy was used to quantify metabolite levels in the PFC. To substantiate the validity of the use of in vivo 1 H MRS in this study, the spectra obtained in the in vivo 1 H MRS, parametrically matched spectral simulation, and in vitro experiments were analyzed. The results of the spectral analyses showed that the quantification of glutamate and glutamine was not significantly affected by spectral overlaps. Thus, these results suggested that in vivo 1 H MRS can be used to reliably investigate the glutamate system. The results of the forced swim test showed LD-induced behavioral despairs in the animals. The levels of glutamate, myo-inositol, phosphocreatine, and total creatine were found significantly (p < 0.010) increased in the PFC of the LD animals compared with the controls. These results suggested that the LD-induced metabolic changes were consistent with the previous findings in patients with MDD and that short-echo-time in vivo 1 H MRS can be used to effectively measure depression-induced alterations in glutamate systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

PubMed

Fernández Macedo, Georgina Valeria; Cladouchos, María Laura; Sifonios, Laura; Cassanelli, Pablo Martín; Wikinski, Silvia

2013-02-01

Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.

A novel training approach to activate alternative behaviors for smoking in depressed smokers.

PubMed

Kopetz, Catalina; MacPherson, Laura; Mitchell, Avery D; Houston-Ludlam, Alexandra N; Wiers, Reinout W

2017-02-01

The current research developed and tested a novel training strategy to alter the implicit associations between alternative behaviors to smoking and negative affect, and explored its effects on depressive symptoms and on smoking behavior as part of a quit attempt. Using a joystick, participants identified as smokers with depressive symptoms were trained to approach alternative behaviors to smoking in the context of negative affect. Specifically, in the experimental condition, participants were trained to avoid smoking-related targets and to approach alternative activities. In the control condition, participants pushed and pulled an equal amount of smoking and alternative activity-related targets. Compared with the participants in the control condition, those in the experimental condition showed an increase in the accessibility of the alternative activity relative to smoking and a decrease in depressive symptoms. Smoking outcomes did not differ significantly across the 2 conditions. Taken together these results indicate that the value of alternative behaviors to smoking can be modified in the lab without participants' conscious intentions with implications for depressive symptomatology. Future research is required to explore the impact of such training on smoking outcomes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Depression FAQs

Cancer.gov

Depression affects about 15 million American adults every year. Women are more likely to get depression than men. In general, about one out of every four women will get depression at some point in her life.

Examining the Moderating Effect of Depressive Symptoms on the Relation Between Exercise and Self-Efficacy During the Initiation of Regular Exercise

PubMed Central

Kangas, Julie L.; Baldwin, Austin S.; Rosenfield, David; Smits, Jasper A. J.; Rethorst, Chad D.

2016-01-01

Objective People with depressive symptoms typically report lower levels of exercise self-efficacy and are more likely to discontinue regular exercise than others, but it is unclear how depressive symptoms affect people’s exercise self-efficacy. Among potential sources of self-efficacy, engaging in the relevant behavior is the strongest (Bandura, 1997). Thus, we sought to clarify how depressive symptoms affect the same-day relation between engaging in exercise and self-efficacy during the initiation of regular exercise. Methods Participants (N=116) were physically inactive adults (35% reported clinically significant depressive symptoms at baseline) who initiated regular exercise and completed daily assessments of exercise minutes and self-efficacy for four weeks. We tested whether (a) self-efficacy differed on days when exercise did and did not occur, and (b) the difference was moderated by depressive symptoms. Mixed linear models were used to examine these relations. Results An interaction between exercise occurrence and depressive symptoms (p<.001) indicated that self-efficacy was lower on days when no exercise occurred, but this difference was significantly larger for people with high depressive symptoms. People with high depressive symptoms had lower self-efficacy than those with low depressive symptoms on days when no exercise occurred (p=.03), but self-efficacy did not differ on days when exercise occurred (p=.34). Conclusions During the critical period of initiating regular exercise, daily self-efficacy for people with high depressive symptoms is more sensitive to whether they exercised than for people with low depressive symptoms. This may partially explain why people with depression tend to have difficulty maintaining regular exercise. PMID:25110850

Melatonin ameliorates anxiety and depression-like behaviors and modulates proteomic changes in triple transgenic mice of Alzheimer's disease.

PubMed

Nie, Lulin; Wei, Gang; Peng, Shengming; Qu, Zhongsen; Yang, Ying; Yang, Qian; Huang, Xinfeng; Liu, Jianjun; Zhuang, Zhixiong; Yang, Xifei

2017-07-08

Alzheimer's disease (AD) is a devastating neurodegenerative disease accompanied by neuropsychiatric symptoms, such as anxiety and depression. The levels of melatonin decrease in brains of AD patients. The potential effect of melatonin on anxiety and depression behaviors in AD and the underlying mechanisms remain unclear. In this study, we treated 10-month-old triple transgenic mice of AD (3xTg-AD) with melatonin (10 mg/kg body weight/day) for 1 month and explored the effects of melatonin on anxiety and depression-like behaviors in 3xTg-AD mice and the protein expression of hippocampal tissues. The behavioral test showed that melatonin ameliorated anxiety and depression-like behaviors of 3xTg-AD mice as measured by open field test, elevated plus maze test, forced swimming test, and tail suspension test. By carrying out two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 46 differentially expressed proteins in hippocampus between the wild-type (WT) mice and non-treated 3xTg-AD mice. A total of 21 differentially expressed proteins were revealed in hippocampus between melatonin-treated and non-treated 3xTg-AD mice. Among these differentially expressed proteins, glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) were significantly down-regulated in hippocampus of 3xTg-AD mice compared with the WT mice. The expression of these two proteins was modulated by melatonin treatment. Our study suggested that melatonin could be used as a potential candidate drug to improve the neuropsychiatric behaviors in AD via modulating the expression of the proteins (i.e. GSTP1 and CPLX1) involved in anxiety and depression behaviors. © 2017 BioFactors, 43(4):593-611, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Depressive symptoms and interpersonal needs as mediators of forgiveness and suicidal behavior among rural primary care patients.

PubMed

Nsamenang, Sheri A; Webb, Jon R; Cukrowicz, Kelly C; Hirsch, Jameson K

2013-07-01

Suicide is the 10th leading cause of death in the US, and rates of suicide are higher in rural than urban areas. As proposed by the Interpersonal-Psychological Theory of Suicide, thwarted belongingness and perceived burdensomeness are risk factors for suicidal behavior, although protective individual-level characteristics such as forgiveness, may indirectly affect suicidal behavior by decreasing the deleterious effect of thwarted interpersonal needs. A sample of uninsured adults recruited from a rural primary clinic (N=101) completed the Brief Multidimensional Measure of Religiousness and Spirituality; Suicidal Behaviors Questionnaire-Revised; Interpersonal Needs Questionnaire; and Center for Epidemiologic Studies Depression Scale. Parallel and serial multivariable mediation analyses were conducted to test for direct and indirect effects of forgiveness on suicidal behavior. In parallel mediation, covarying depressive symptoms, forgiveness of self had an indirect effect on suicidal behavior, through perceived burdensomeness. Inclusion of depressive symptoms as a mediator revealed an indirect effect of forgiveness of self and others on suicidal behavior via depression, thwarted belongingness, and perceived burdensomeness in a serial mediation model. A longitudinal study, with an equal representation of males and diverse populations is needed to replicate our findings. Our findings have implications for the role health providers can play in addressing suicide with rural patients. Promoting forgiveness, may, in turn affect interpersonal functioning and decrease risk for suicidal behavior. Copyright © 2013 Elsevier B.V. All rights reserved.

Depressive Symptoms Effect on Self Care Behavior During the First Month After Myocardial Infarction

PubMed Central

Niakan, Maryam; Paryad, Ezzat; Leili, Ehsan Kazemnezhad; Sheikholeslami, Farzane

2015-01-01

Aim: To determine the effect of severity of depression symptoms on self care behavior in 15th and 30th day after myocardial infarction (MI). Materials and Methods: Gathering data for this cross sectional study was done by Beck depression and self care behavior questionnaires in a heart especial hospital in Rasht in north of Iran. Sample size was 132 after MI patients and data collected from June 2011 to January 2012. Results: Scores of depression symptoms in 15th and 30th day after MI and score of self care behavior in these days had significant difference (P<0.0001). Spearman test showed self care behavior had significant relationship with depression symptoms (P<0.0001). GEE model also showed with control of socio demographic and illness related factors, depression symptoms can decrease self care behavior scores (P<0.001). Conclusion: Severity of depression symptoms increase in 15th to 30th day after MI. This issue can affect on self care behavior. This issue is emphasized on nurses’ notice to plan suitable self care program for these patients. PMID:25946944

Depressive symptoms effect on self care behavior during the first month after myocardial infarction.

PubMed

Niakan, Maryam; Paryad, Ezzat; Kazemnezhad Leili, Ehsan; Sheikholeslami, Farzane

2015-01-26

To determine the effect of severity of depression symptoms on self care behavior in 15th and 30th day after myocardial infarction (MI). Gathering data for this cross sectional study was done by Beck depression and self care behavior questionnaires in a heart especial hospital in Rasht in north of Iran .Sample size was 132 after MI patients and data collected from June 2011 to January 2012. Scores of depression symptoms in 15th and 30th day after MI and score of self care behavior in these days had significant difference (P<0.0001) .Spearman test showed self care behavior had significant relationship with depression symptoms (P<0.0001). GEE model also showed with control of socio demographic and illness related factors, depression symptoms can decrease self care behavior scores (P<0.001). Severity of depression symptoms increase in 15th to 30th day after MI .This issue can affect on self care behavior. This issue is emphasized on nurses' notice to plan suitable self care program for these patients.

Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels.

PubMed

Jenniches, Imke; Ternes, Svenja; Albayram, Onder; Otte, David M; Bach, Karsten; Bindila, Laura; Michel, Kerstin; Lutz, Beat; Bilkei-Gorzo, Andras; Zimmer, Andreas

2016-05-15

Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α). We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis. Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor. Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Depression and Pregnancy

MedlinePlus

... Untreated maternal depression may also negatively affect later child behavior or development. In addition, stopping your medication could lead to a return of your symptoms of depression, called a relapse. One study found that women who stopped their medications for ...

Hyperactivity and depression-like traits in Bax KO mice

PubMed Central

Krahe, Thomas E.; Medina, Alexandre E.; Lantz, Crystal L.; Filgueiras, Cláudio C.

2018-01-01

The Bax gene is a member of the Bcl-2 gene family and its pro-apoptotic Bcl-associated X (Bax) protein is believed to be crucial in regulating apoptosis during neuronal development as well as following injury. With the advent of mouse genomics, mice lacking the pro-apoptotic Bax gene (Bax KO) have been extensively used to study how cell death helps to determine synaptic circuitry formation during neurodevelopment and disease. Surprisingly, in spite of its wide use and the association of programmed neuronal death with motor dysfunctions and depression, the effects of Bax deletion on mice spontaneous locomotor activity and depression-like traits are unknown. Here we examine the behavioral characteristics of Bax KO male mice using classical paradigms to evaluate spontaneous locomotor activity and depressive-like responses. In the open field, Bax KO animals exhibited greater locomotor activity than their control littermates. In the forced swimming test, Bax KO mice displayed greater immobility times, a behavior despair state, when compared to controls. Collectively, our findings corroborate the notion that a fine balance between cell survival and death early during development is critical for normal brain function later in life. Furthermore, it points out the importance of considering depressive-like and hyperactivity behavioral phenotypes when conducting neurodevelopmental and other studies using the Bax KO strain. PMID:26363094

Relationship between after-school care of adolescents and substance use, risk taking, depressed mood, and academic achievement.

PubMed

Richardson, J L; Radziszewska, B; Dent, C W; Flay, B R

1993-07-01

To examine the relationship between parental monitoring and six negative behaviors: cigarette, alcohol, and marijuana use; depressed mood; risk taking; and lower academic grades. Survey of 3993 ninth-grade students in six school districts in southern California. The sample consisted of 1930 boys and 2063 girls, self-classified as non-Hispanic white (32%), African-American (13%), Hispanic (46%), or Asian (9%). A relationship was found between unsupervised care after school and susceptibility to cigarette, alcohol, and marijuana use; depressed mood; risk taking; and lower academic grades. Adolescents who were unsupervised at home were slightly more likely to engage in problem behavior than those who were supervised at home. Adolescents at a neighbor's house, at school, or at a job and especially those who "hang out" were most likely to engage in problem behavior. Risk was higher if the parent had an unengaged parenting style. Although girls were less likely than boys to engage in problem behavior when supervised, as supervision decreased they were significantly more likely to have each of these problems. Family structure had little impact on risk. Self-care, especially when it occurs outside of the home, is associated with substance use, risk taking, depressed mood, and lower academic grades.

Anti-P ribosomal antibodies induce defect in smell capability in a model of CNS -SLE (depression).

PubMed

Katzav, Aviva; Ben-Ziv, Tal; Chapman, Joab; Blank, Miri; Reichlin, Morris; Shoenfeld, Yehuda

2008-12-01

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with more than 100 different autoantibodies, some of which may be associated with specific neuropsychiatric (NPSLE) manifestations. Injection of anti-P ribosomal antibodies (anti-P) directly to the brain ventricles of mice induces depression manifested by increased immobility time in the forced swim test (FST). Mice were injected intracerebroventricularily (ICV) with affinity-purified human anti-P antibodies or normal commercial IgG as control. Mice were examined for depression by the forced swimming test (FST) and for olfactory function by the smell threshold test. Treatments included the antidepressant drug fluoxetine or aroma therapy by exposure to lemon or cinnamon odor. Mice injected with anti-P developed depression-like behavior, which improved significantly upon treatment with fluoxetine. Depressed mice had a significant deficit in olfactory function which was not reversed by fluoxetine. Exposure of anti-P-injected mice to lemon odor was associated with some improvement of the immobility time, a measure of depression. ICV injection of anti-P induces both depression-like behavior and impaired olfactory function in mice. Fluoxetine and possibly lemon odor exposure improve depressive behavior in these mice.

Alteration in plasma corticosterone levels following long term oral administration of lead produces depression like symptoms in rats.

PubMed

Haider, Saida; Saleem, Sadia; Tabassum, Saiqa; Khaliq, Saima; Shamim, Saima; Batool, Zehra; Parveen, Tahira; Inam, Qurat-ul-ain; Haleem, Darakhshan J

2013-03-01

Lead toxicity is known to induce a broad range of physiological, biochemical and behavioral dysfunctions that may result in adverse effects on several organs, including the central nervous system. Long-term exposure to low levels of lead (Pb(2+)) has been shown to produce behavioral deficits in rodents and humans by affecting hypothalamic-pituitary-adrenal (HPA) axis. These deficits are thought to be associated with altered brain monoamine neurotransmission and due to changes in glucocorticoids levels. This study was designed to investigate the effects of Pb(2+)exposure on growth rate, locomotor activity, anxiety, depression, plasma corticosterone and brain serotonin (5-HT) levels in rats. Rats were exposed to lead in drinking water (500 ppm; lead acetate) for 5 weeks. The assessment of depression was done using the forced swimming test (FST). Estimation of brain 5-HT was determined by high-performance liquid chromatography with electrochemical detection. Plasma corticosterone was determined by spectrofluorimetric method. The present study showed that long term exposure to Pb(2+) significantly decreased the food intake followed by the decrease in growth rate in Pb(2+)exposed rats as compared to control group. No significant changes in open field activity were observed following Pb(2+)exposure while significant increase in anxiogenic effect was observed. Increased plasma corticosterone and decreased 5-HT levels were exhibited by Pb(2+)exposed rats as compared to controls. A significant increase in depressive like symptoms was exhibited by Pb(2+)exposed rats as compared to control rats. The results are discussed in the context of Pb(2+) inducing a stress-like response in rats leading to changes in plasma corticosterone and brain 5-HT levels via altering tryptophan pyrrolase activity.

High-fructose diet during periadolescent development increases depressive-like behavior and remodels the hypothalamic transcriptome in male rats

PubMed Central

Harrell, Constance S.; Burgado, Jillybeth; Kelly, Sean D.; Johnson, Zachary P.; Neigh, Gretchen N.

2015-01-01

Fructose consumption, which promotes insulin resistance, hypertension, and dyslipidemia, has increased by over 25% since the 1970s. In addition to metabolic dysregulation, fructose ingestion stimulates the hypothalamic-pituitary-adrenal (HPA) axis leading to elevations in glucocorticoids. Adolescents are the greatest consumers of fructose, and adolescence is a critical period for maturation of the HPA axis. Repeated consumption of high levels of fructose during adolescence has the potential to promote long-term dysregulation of the stress response. Therefore, we determined the extent to which consumption of a diet high in fructose affected behavior, serum corticosterone, and hypothalamic gene expression using a whole-transcriptomics approach. In addition, we examined the potential of a high-fructose diet to interact with exposure to chronic adolescent stress. Male Wistar rats fed the periadolescent high-fructose diet showed increased anxiety-like behavior in the elevated plus maze and depressive-like behavior in the forced swim test in adulthood, irrespective of stress history. Periadolescent fructose-fed rats also exhibited elevated basal corticosterone concentrations relative to their chow-fed peers. These behavioral and hormonal responses to the high-fructose diet did not occur in rats fed fructose during adulthood only. Finally, rats fed the high-fructose diet throughout development underwent marked hypothalamic transcript expression remodeling, with 966 genes (5.6%) significantly altered and a pronounced enrichment of significantly altered transcripts in several pathways relating to regulation of the HPA axis. Collectively, the data presented herein indicate that diet, specifically one high in fructose, has the potential to alter behavior, HPA axis function, and the hypothalamic transcriptome in male rats. PMID:26356038

Memantine improves memory impairment and depressive-like behavior induced by amphetamine withdrawal in rats.

PubMed

Marszalek-Grabska, M; Gibula-Bruzda, E; Jenda, M; Gawel, K; Kotlinska, J H

2016-07-01

Amphetamine (AMPH) induces deficits in cognition, and depressive-like behavior following withdrawal. The aim of the present study was to investigate whether pre-treatment with memantine (5mg/kg, i.p.), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, attenuates memory impairment induced by withdrawal from a 1 day binge regimen of AMPH (2mg/kg, four times every 2h, i.p.), in the novel object recognition test in rats. Herein, the influence of scopolamine (0.1mg/kg), an antagonist of the muscarinic cholinergic receptors, and the impact of MK-801 (0.1mg/kg), an antagonist of the NMDA receptors, on the memantine effect, were ascertained. Furthermore, the impact of memantine (5; 10; 20mg/kg, i.p.) was measured on depression-like effects of abstinence, 14 days after the last AMPH treatment (2mg/kg×1×14 days), in the forced swim test. In this test, the efficacy of memantine was compared to that of tricyclic antidepressant imipramine (10; 20; 30mg/kg, i.p.). Our study indicated that withdrawal from a binge regimen of AMPH impaired recognition memory. This effect was attenuated by administration of memantine at both 72h and 7 days of withdrawal. Moreover, prior administration of scopolamine, but not MK-801, decreased the memantine-induced recognition memory improvement. In addition, memantine reversed the AMPH-induced depressive-like behavior in the forced swim test in rats. The antidepressant-like effects of memantine were stronger than those of imipramine. Our study indicates that memantine constitutes a useful approach towards preventing cognitive deficits induced by withdrawal from an AMPH binge regimen and by depressive-like behavior during AMPH abstinence. Copyright © 2016 Elsevier B.V. All rights reserved.

Maternal beliefs as long-term predictors of mother-child interaction and report.

PubMed

Kochanska, G

1990-12-01

2 kinds of parental beliefs: endorsed rearing philosophy (authoritative-authoritarian dimension) and affective attitude toward child (positive-negative affect dimension) were examined in 20 normal and 36 depressed mothers as long-term predictors of their rearing behaviors and interaction patterns with their children, and of their ratings of child externalizing problems (Achenbach CBCL). The beliefs were measured when the children were toddlers (Time 1), and maternal behaviors 2-3 years later (Time 2). Mothers' endorsement of the belief in authoritative parenting predicted their frequent avoidance of prohibitive interventions. It also predicted maternal autonomy-granting to the child (more compliant and liberal responses to child-initiated control interventions). Endorsed child-rearing philosophy was a relatively more important predictor of behavior for normal mothers, and affective attitude toward child for the behavior of depressed mothers. Both actual child noncompliance and parental beliefs predicted mothers' ratings of externalizing problems in their children. The former was relatively more important for normal and latter for depressed mothers.

Male rats that differ in novelty exploration demonstrate distinct patterns of sexual behavior

PubMed Central

Cummings, Jennifer A.; Clinton, Sarah M.; Perry, Adam N.; Akil, Huda; Becker, Jill B.

2014-01-01

High versus low novelty exploration predicts a variety of behavioral differences. For example, rats selectively-bred for high novelty exploration (bred High Responders, bHR) exhibit exaggerated aggression, impulsivity, and proclivity to addictive behaviors compared to low novelty-reactive rats (bred Low Responders, bLRs), which are characterized by a high anxiety/depressive-like phenotype. Since bHR/bLR rats exhibit differences in dopaminergic circuitry and differential response to rewarding stimuli (i.e., psychostimulants, food), the present study examined whether they also differ in another key hedonic behavior – sex. Thus, adult bHR/bLR males were given five 30-min opportunities to engage in sexual activity with a receptive female. Sexual behavior and motivation were examined and compared between the groups. The bHR/bLR phenotype affected both sexual motivation and behavior, with bLR males demonstrating reduced motivation for sex compared with bHR males (i.e., fewer animals copulated, longer latency to engage in sex). The bHR males required more intromissions at a faster pace per ejaculation than did bLR males. Thus, neurobiological differences that affect motivation for drugs of abuse, aggression, and impulsivity in rats also affect sexual motivation and performance. PMID:23398441

Emodin opposes chronic unpredictable mild stress induced depressive-like behavior in mice by upregulating the levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor.

PubMed

Li, Meng; Fu, Qiang; Li, Ying; Li, Shanshan; Xue, Jinsong; Ma, Shiping

2014-10-01

Emodin, the major active component of Rhubarb, has shown neuroprotective activity. This study is attempted to investigate whether emodin possesses beneficial effects on chronic unpredictable mild stress (CUMS)-induced behavioral deficits (depression-like behaviors) and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, emodin and fluoxetine (positive control drug) were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests: open field test (OFT), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST) were applied to evaluate the antidepressant effects of emodin. Then plasma corticosterone concentration, hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) levels were tested to probe the mechanisms. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with high, plasma corticosterone concentration and low hippocampal GR and BDNF expression levels. Whereas, chronic emodin (20, 40 and 80 mg/kg) treatments reversed the behavioral deficiency induced by CUMS exposure. Treatment with emodin normalized the change of plasma corticosterone level, which demonstrated that emodin could partially restore CUMS-induced HPA axis impairments. Besides, hippocampal GR (mRNA and protein) and BDNF (mRNA) expressions were also up-regulated after emodin treatments. In conclusion, emodin remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the up-regulating GR and BDNF levels in hippocampus. Copyright © 2014 Elsevier B.V. All rights reserved.

The association of depression and anxiety with glycemic control among Mexican Americans with diabetes living near the U.S.-Mexico border.

PubMed

Kendzor, Darla E; Chen, Minxing; Reininger, Belinda M; Businelle, Michael S; Stewart, Diana W; Fisher-Hoch, Susan P; Rentfro, Anne R; Wetter, David W; McCormick, Joseph B

2014-02-18

The prevalence of diabetes is alarmingly high among Mexican American adults residing near the U.S.-Mexico border. Depression is also common among Mexican Americans with diabetes, and may have a negative influence on diabetes management. Thus, the purpose of the current study was to evaluate the associations of depression and anxiety with the behavioral management of diabetes and glycemic control among Mexican American adults living near the border. The characteristics of Mexican Americans with diabetes living in Brownsville, TX (N = 492) were compared by depression/anxiety status. Linear regression models were conducted to evaluate the associations of depression and anxiety with BMI, waist circumference, physical activity, fasting glucose, and glycated hemoglobin (HbA1c). Participants with clinically significant depression and/or anxiety were of greater age, predominantly female, less educated, more likely to have been diagnosed with diabetes, and more likely to be taking diabetes medications than those without depression or anxiety. In addition, anxious participants were more likely than those without anxiety to have been born in Mexico and to prefer study assessments in Spanish rather than English. Greater depression and anxiety were associated with poorer behavioral management of diabetes (i.e., greater BMI and waist circumference; engaging in less physical activity) and poorer glycemic control (i.e., higher fasting glucose, HbA1c). Overall, depression and anxiety appear to be linked with poorer behavioral management of diabetes and glycemic control. Findings highlight the need for comprehensive interventions along the border which target depression and anxiety in conjunction with diabetes management.

Structural equation modeling of pesticide poisoning, depression, safety, and injury.

PubMed

Beseler, Cheryl L; Stallones, Lorann

2013-01-01

The role of pesticide poisoning in risk of injuries may operate through a link between pesticide-induced depressive symptoms and reduced engagement in safety behaviors. The authors conducted structural equation modeling of cross-sectional data to examine the pattern of associations between pesticide poisoning, depressive symptoms, safety knowledge, safety behaviors, and injury. Interviews of 1637 Colorado farm operators and their spouses from 964 farms were conducted during 1993-1997. Pesticide poisoning was assessed based on a history of ever having been poisoned. The Center for Epidemiologic Studies-Depression scale was used to assess depressive symptoms. Safety knowledge and safety behaviors were assessed using ten items for each latent variable. Outcomes were safety behaviors and injuries. A total of 154 injuries occurred among 1604 individuals with complete data. Pesticide poisoning, financial problems, health, and age predicted negative affect/somatic depressive symptoms with similar effect sizes; sex did not. Depression was more strongly associated with safety behavior than was safety knowledge. Two safety behaviors were significantly associated with an increased risk of injury. This study emphasizes the importance of financial problems and health on depression, and provides further evidence for the link between neurological effects of past pesticide poisoning on risk-taking behaviors and injury.

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.

PubMed

Vahid-Ansari, Faranak; Daigle, Mireille; Manzini, M Chiara; Tanaka, Kenji F; Hen, René; Geddes, Sean D; Béïque, Jean-Claude; James, Jonathan; Merali, Zul; Albert, Paul R

2017-12-06

Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the role of Freud-1 in vivo , we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons ( cF1ko ). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1A double knock-out ( cF1/1A dko ) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out of Freud-1 on the 5-HT1A autoreceptor-negative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT1A autoreceptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment. SIGNIFICANCE STATEMENT Altered regulation of the 5-HT1A autoreceptor has been implicated in human anxiety, major depression, suicide, and resistance to antidepressants. This study uniquely identifies a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression in vivo Disruption of Freud-1 in serotonin neurons in mice links upregulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to reestablish transcriptional regulation of 5-HT1A autoreceptors could provide a more robust and sustained antidepressant response. Copyright © 2017 the authors 0270-6474/17/3711967-12$15.00/0.

Getting stuck in depression: the roles of rumination and emotional inertia.

PubMed

Koval, Peter; Kuppens, Peter; Allen, Nicholas B; Sheeber, Lisa

2012-01-01

Like many other mental disorders, depression is characterised by psychological inflexibility. Two instances of such inflexibility are rumination: repetitive cognitions focusing on the causes and consequences of depressive symptoms; and emotional inertia: the tendency for affective states to be resistant to change. In two studies, we tested the predictions that: (1) rumination and emotional inertia are related; and (2) both independently contribute to depressive symptoms. We examined emotional inertia of subjective affective experiences in daily life among a sample of non-clinical undergraduates (Study 1), and of affective behaviours during a family interaction task in a sample of clinically depressed and non-depressed adolescents (Study 2), and related it to self-reported rumination and depression severity. In both studies, rumination (particularly the brooding facet) and emotional inertia (particularly of sad/dysphoric affect) were positively associated, and both independently predicted depression severity. These findings demonstrate the importance of studying both cognitive and affective inflexibility in depression.

Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.

PubMed

Zheng, P; Zeng, B; Zhou, C; Liu, M; Fang, Z; Xu, X; Zeng, L; Chen, J; Fan, S; Du, X; Zhang, X; Yang, D; Yang, Y; Meng, H; Li, W; Melgiri, N D; Licinio, J; Wei, H; Xie, P

2016-06-01

Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metabolism.

Viral vector mediated expression of mutant huntingtin in the dorsal raphe produces disease-related neuropathology but not depressive-like behaviors in wildtype mice.

PubMed

Pitzer, Mark; Lueras, Jordan; Warden, Anna; Weber, Sydney; McBride, Jodi

2015-05-22

Huntington׳s disease (HD) is a neurodegenerative disorder caused by a mutation in the HTT gene (mHTT) encoding the protein huntingtin. An expansion in the gene׳s CAG repeat length renders a misfolded, dysfunctional protein with an abnormally long glutamine (Q) stretch at the N terminus that often incorporates into inclusion bodies and leads to neurodegeneration in many regions of the brain. HD is characterized by motor and cognitive decline as well as mood disorders, with depression being particularly common. Approximately 40% of the HD population suffers from depressive symptoms. Because these symptoms often manifest a decade or more prior to the knowledge that the person is at risk for the disease, a portion of the early depression in HD appears to be a consequence of the pathology arising from expression of the mutant gene. While the depression in HD patients is often treated with serotonin agonists, there is scant experimental evidence that the depression in HD responds well to these serotonin treatments or in a similar manner to how non-HD depression tends to respond. Additionally, at very early sub-threshold depression levels, abnormal changes in several neuronal populations are already detectable in HD patients, suggesting that a variety of brain structures may be involved. Taken together, the serotonin system is a viable candidate. However, at present there is limited evidence of the precise nuclei or circuits that play a role in HD depression. With this in mind, the current study was designed to control for the widespread brain neuropathology that occurs in HD and in transgenic mouse models of HD and focuses specifically on the influence of the midbrain dorsal raphe nucleus (DRN). The DRN provides the majority of the serotonin to the forebrain and exhibits cell loss in non-HD depression. Therefore, we employed a viral vector delivery system to investigate whether the over-expression of mHTT in the DRN׳s ventral sub-nuclei alone is sufficient to produce depressive-like behaviors. Wildtype mice were injected with an adeno-associated virus (AAV2/1) encoding HTT containing either a pathogenic (N171-82Q) or control (N171-16Q) CAG repeat length into the ventral DRN and depressive-like behaviors and motor behaviors were assessed for 12 weeks post-surgery. Quantitative PCR and immunohistochemistry (IHC) verified positive transduction in the ventral aspects of the DRN, including the ventral sub-nucleus (DRv) and interfascicular sub-nucleus (DRif). IHC demonstrated microgliosis in and around the injection site and mHTT-positive inclusions in serotonin-producing neurons and a small percentage of astrocytes in animals injected with N171-82Q compared to controls. Moreover, N171-82Q injected mice showed a 75% reduction in cells that stained positive for the serotonin synthesis enzyme, tryptophan hydroxylase-2 (TPH2) compared to controls (p<0.05). Despite mHTT-mediated pathology in the DRv and DRif, no significant changes in depressive-like behavior were detected. Consequently, we conclude that 12 weeks of N171-82Q expression in the ventral sub-nuclei of the DRN of wildtype mice causes characteristic disease-related cellular neuropathology but is not sufficient to elicit depressive-like behaviors. Ongoing studies are investigating whether a larger injection volume that transfects a larger percentage of the DRN and/or a longer time course of mHTT expression might elicit depressive-like behaviors. Moreover, mHTT expression in other regions of the brain, such as the hippocampal dentate gyrus and/or the frontal cortex might be necessary to elicit HD depression. Together, these results may prove helpful in addressing which therapeutic and/or pharmacological strategies might be most efficacious when treating depressive symptomology in patients suffering from HD. Copyright © 2015 Elsevier B.V. All rights reserved.

Emotional Impairment and Persistent Upregulation of mGlu5 Receptor following Morphine Abstinence: Implications of an mGlu5-MOPr Interaction

PubMed Central

Zanos, Panos; Georgiou, Polymnia; Gonzalez, Loreto Rojo; Hourani, Susanna; Chen, Ying; Kitchen, Ian; Kieffer, Brigitte L; Winsky-Sommerer, Raphaelle

2016-01-01

Background: A difficult problem in treating opioid addicts is the maintenance of a drug-free state because of the negative emotional symptoms associated with withdrawal, which may trigger relapse. Several lines of evidence suggest a role for the metabotropic glutamate receptor 5 in opioid addiction; however, its involvement during opioid withdrawal is not clear. Methods: Mice were treated with a 7-day escalating-dose morphine administration paradigm. Following withdrawal, the development of affective behaviors was assessed using the 3-chambered box, open-field, elevated plus-maze and forced-swim tests. Metabotropic glutamate receptor 5 autoradiographic binding was performed in mouse brains undergoing chronic morphine treatment and 7 days withdrawal. Moreover, since there is evidence showing direct effects of opioid drugs on the metabotropic glutamate receptor 5 system, the presence of an metabotropic glutamate receptor 5/μ-opioid receptor interaction was assessed by performing metabotropic glutamate receptor 5 autoradiographic binding in brains of mice lacking the μ-opioid receptor gene. Results: Withdrawal from chronic morphine administration induced anxiety-like, depressive-like, and impaired sociability behaviors concomitant with a marked upregulation of metabotropic glutamate receptor 5 binding. Administration of the metabotropic glutamate receptor 5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine, reversed morphine abstinence-induced depressive-like behaviors. A brain region-specific increase in metabotropic glutamate receptor 5 binding was observed in the nucleus accumbens shell, thalamus, hypothalamus, and amygdala of μ-opioid receptor knockout mice compared with controls. Conclusions: These results suggest an association between metabotropic glutamate receptor 5 alterations and the emergence of opioid withdrawal-related affective behaviors. This study supports metabotropic glutamate receptor 5 system as a target for the development of pharmacotherapies for the treatment of opioid addiction. Moreover, our data show direct effects of μ-opioid receptor system manipulation on metabotropic glutamate receptor 5 binding in the brain. PMID:26861145

Cholinergic neurotransmission seems not to be involved in depression but possibly in personality.

PubMed Central

Fritze, J; Lanczik, M; Sofic, E; Struck, M; Riederer, P

1995-01-01

Concordant with the adrenergic-cholinergic imbalance hypothesis of affective psychosis, there is a cholinergic supersensitivity in depression. Thus, the anticholinergic properties of some antidepressants might contribute to their efficacy. However, in the present double-blind studies (n = 20) with mianserin and viloxazine, respectively, which lack anticholinergic properties, adjunctive treatment with the anticholinergic biperiden versus placebo did not enhance the antidepressive efficacy. Therefore, we hypothesized that cholinergic supersensitivity might be linked to some possibly predisposing dimension of personality. Indeed, in healthy male volunteers (n = 11) the behavioral and cardiovascular sensitivity to physostigmine correlated significantly with "irritability" and "emotional lability" as well as with habitually passive strategies in stress coping. The rise in plasma cortisol and norepinephrine correlated with "retardation"; that of epinephrine with active coping. Thus, the cholinergic supersensitivity in affective psychoses might be linked to a personality dimension like stress sensitivity rather than to the diagnostic category itself. Images Fig. 2 PMID:7865500

Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice.

PubMed

Zeni, Ana Lúcia Bertarello; Camargo, Anderson; Dalmagro, Ana Paula

2017-09-01

Corticosterone (CORT) treatment has been evidenced to develop a depression-like state in animals, that mimic hypothalamic-pituitary-adrenal (HPA)-axis dysregulation implicated in the development of depression. The present study aimed to examine the ferulic acid (FA), a natural phenolic compound, antidepressant and antioxidant activities on the CORT chronic model. Mice orally treated with 20mg/kg of CORT for 21days were connsidered control group, while mice treated with FA (1mg/kg) or fluoxetine (10mg/kg) for the last week of CORT treatment, as drug groups. Three weeks of CORT treatment resulted in depressive-like behavior, as indicated by the increase on the immobility time in the tail suspension test, grooming in the splash test and an increase in the oxidative stress markers in the brain. It was observed that FA ameliorated the behavioral and oxidative stress alterations induced by CORT, which may plausibly suggest a mode of action for the FA antidepressant effect. The involvement of FA repairing the stress caused by HPA-axis dysfunction evidenced that this phenolic acid could be further investigated as a novel potential agent to improve the management of depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Depressive Symptoms and Perceptions of Child Difficulty Are Associated with Less Responsive Feeding Behaviors in an Observational Study of Low-Income Mothers.

PubMed

Elias, Cindy V; Power, Thomas G; Beck, Ashley E; Goodell, L Suzanne; Johnson, Susan L; Papaioannou, Maria A; Hughes, Sheryl O

2016-12-01

Maternal depressive symptoms and perceptions of child difficulty are associated with negative effects on general development and cognitive functioning in children. The study examined associations between maternal depressive symptoms, perceptions of child difficulty, and maternal feeding behaviors in a population at elevated risk for childhood obesity. Participants were 138 low-income black and Hispanic mothers and their children (ages 3-5) participating in an observational study of mealtimes among Head Start families. Three dinnertime observations were conducted over 2 weeks on each family and audio/videotaped for coding. Coding included eating influence attempts and other food- and nonfood-related interactions exhibited by the mother during dinner. Mothers completed questionnaires on depressive symptoms and perceptions of child difficulty. Linear regressions were conducted, examining associations between maternal depressive symptoms, perceptions of child difficulty, and coded parent feeding behaviors. Mothers reporting higher levels of depressive symptoms used more verbal pressure to get their child to eat during meals, were more likely to discourage child independence, and less likely to enforce table manners. Mothers reporting higher perceptions of child difficulty were less likely to have nonfood-related discussions during meals and to try to get the child to eat a different food. This study is one of the first to investigate associations between maternal depression, perceptions of child difficulty, and mother's feeding behaviors during meals using observational methodology. These results may help researchers identify specific parental characteristics and feeding practices on which to intervene when developing tailored intervention programs for reducing childhood obesity.

Childhood bullying as a risk for later depression and suicidal ideation among Finnish males.

PubMed

Klomek, Anat Brunstein; Sourander, Andre; Kumpulainen, Kirsti; Piha, Jorma; Tamminen, Tuula; Moilanen, Irma; Almqvist, Fredrik; Gould, Madelyn S

2008-07-01

Little is known about the predictive association between childhood bullying behavior with depression and suicidal ideation at age 18. The sample included 2348 boys born in 1981. Information about bullying was gathered at the age of 8 from self, parent and teacher's reports. Depression and suicidal ideation were assessed during the Finnish military call-up examination. Based on regression models, boys who were bullies frequently, but not merely sometimes, were more likely to be severely depressed and to report suicidal ideation compared to boys who were not bullies. When controlling for depression at age 8 the association between frequent bullying and severe depression was maintained but the association with suicidal ideation became non-significant. Boys who were only victimized were not more likely to be depressed or to report suicidal ideation at age 18. Boys who were frequently both bullies and victims were found to be at risk for later depression. Our finding can only be generalized to boys who were involved in bullying at elementary school age. Data at age 18 was based only on self-reports and the bullying/victimization questions were very general. Childhood bullying behavior is a risk factor for later depression. Screening and intervention for bullying behavior in the early school years is recommended to avoid subsequent internalizing problem in late adolescence.

Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trabace, L., E-mail: trabace@unifg.it; Zotti, M.; Morgese, M.G.

2011-09-01

Carvacrol is the major constituent of essential oils from aromatic plants. It showed antimicrobial, anticancer and antioxidant properties. Although it was approved for food use and included in the chemical flavorings list, no indication on its safety has been estimated. Since the use of plant extracts is relatively high among women, aim of this study was to evaluate carvacrol effects on female physiology and endocrine profiles by using female rats in proestrus and diestrus phases. Serotonin and metabolite tissue content in prefrontal cortex and nucleus accumbens, after carvacrol administration (0.15 and 0.45 g/kg p.o.), was measured. Drug effects in behavioralmore » tests for alterations in motor activity, depression, anxiety-related behaviors and endocrine alterations were also investigated. While in proestrus carvacrol reduced serotonin and metabolite levels in both brain areas, no effects were observed in diestrus phase. Only in proestrus phase, carvacrol induced a depressive-like behavior in forced swimming test, without accompanying changes in ambulation. The improvement of performance in FST after subchronic treatment with fluoxetine (20 mg/kg) suggested a specific involvement of serotonergic system. No differences were found across the groups with regard to self-grooming behavior. Moreover, in proestrus phase, carvacrol reduced only estradiol levels without binding hypothalamic estradiol receptors. Our study showed an estrous-stage specific effect of carvacrol on depressive behaviors and endocrine parameters, involving serotonergic system. Given the wide carvacrol use not only as feed additive, but also as cosmetic essence and herbal remedy, our results suggest that an accurate investigation on the effects of its chronic exposure is warranted. - Highlights: > Carvacrol induced a depressive-like phenotype in rats, depending on ovarian cyclicity. > Carvacrol selectively reduced serotonin content in female rats in proestrus phase. > Carvacrol reduced serotonin levels in areas belonging to the emotional circuit. > Carvacrol reduced plasma estradiol levels only during the proestrus phase.« less

Lack of promoter IV-driven BDNF transcription results in depression-like behavior.

PubMed

Sakata, K; Jin, L; Jha, S

2010-10-01

Transcription of Bdnf is controlled by multiple promoters, in which promoter IV contributes significantly to activity-dependent Bdnf transcription. We have generated promoter IV mutant mice [brain-derived neurotrophic factor (BDNF)-KIV] in which promoter IV-driven expression of BDNF is selectively disrupted by inserting a green fluorescent protein (GFP)-STOP cassette within the Bdnf exon IV locus. BDNF-KIV animals exhibited depression-like behavior as shown by the tail suspension test (TST), sucrose preference test (SPT) and learned helplessness test (LHT). In addition, BDNF-KIV mice showed reduced activity in the open field test (OFT) and reduced food intake in the novelty-suppressed feeding test (NSFT). The mutant mice did not display anxiety-like behavior in the light and dark box test and elevated plus maze tests. Interestingly, the mutant mice showed defective response inhibition in the passive avoidance test (PAT) even though their learning ability was intact when measured with the active avoidance test (AAT). These results suggest that promoter IV-dependent BDNF expression plays a critical role in the control of mood-related behaviors. This is the first study that directly addressed the effects of endogenous promoter-driven expression of BDNF in depression-like behavior. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Testing the self-medication hypothesis of depression and aggression in cannabis-dependent subjects.

PubMed

Arendt, Mikkel; Rosenberg, Raben; Fjordback, Lone; Brandholdt, Jack; Foldager, Leslie; Sher, Leo; Munk-Jørgensen, Povl

2007-07-01

A self-medication hypothesis has been proposed to explain the association between cannabis use and psychiatric and behavioral problems. However, little is known about the reasons for use and reactions while intoxicated in cannabis users who suffer from depression or problems controlling violent behavior. We assessed 119 cannabis-dependent subjects using the Schedules of Clinical Assessment in Neuropsychiatry (SCAN), parts of the Addiction Severity Index (ASI), and questionnaires on reasons for cannabis use and reactions to cannabis use while intoxicated. Participants with lifetime depression and problems controlling violent behavior were compared to subjects without such problems. Validity of the groupings was corroborated by use of a psychiatric treatment register, previous use of psychotropic medication and convictions for violence. Subjects with lifetime depression used cannabis for the same reasons as others. While under the influence of cannabis, they more often experienced depression, sadness, anxiety and paranoia, and they were less likely to report happiness or euphoria. Participants reporting problems controlling violent behavior more often used cannabis to decrease aggression, decrease suspiciousness, and for relaxation; while intoxicated they more often reacted with aggression. Subjects with prior depression do not use cannabis as a mean of self-medication. They are more likely to experience specific increases of adverse symptoms while under the influence of cannabis, and are less likely to experience specific symptom relief. There is some evidence that cannabis is used as a means of self-medication for problems controlling aggression.

Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain

PubMed Central

Wang, Wei; Li, Caiyue; Cai, Youqing; Pan, Zhizhong Z

2017-01-01

Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability. PMID:28849714

Effect of race and sex on primary care physicians' diagnosis and treatment of late-life depression.

PubMed

Kales, Helen C; Neighbors, Harold W; Valenstein, Marcia; Blow, Frederic C; McCarthy, John F; Ignacio, Rosalinda V; Taylor, Kiran K-K; Gillon, Leah; Mellow, Alan M

2005-05-01

To examine primary care physician (PCP) contributions toward racial and sex differences in the diagnosis and treatment of late-life depression. Survey using a computerized instrument incorporating video interviews and text, with volunteer PCPs randomly assigned to one of four standardized video vignettes of an elderly patient depicting late-life depression. Vignettes differed only in the patient/actor's race (white/African-American) or sex. American Academy of Family Physicians meeting, San Diego, California, 2002. One hundred seventy-eight U.S.-practicing postresidency PCPs who were asked to participate in a clinical decision-making study. The computerized survey instrument assessed PCPs' diagnoses, first-line treatment and management recommendations, and judgment of personal characteristics/behaviors for the patients in the vignettes. Eighty-five percent of all PCPs correctly diagnosed the elderly patient(s) with major depression. There were no significant differences in the diagnosis of depression, treatment recommendations, or PCP assessment of most patient characteristics by the race or sex of the patient/actor in the vignette, but PCP characteristics, most notably the location of medical school training (U.S. vs international), affected the likelihood of a depression diagnosis and treatment recommendations. Given standardized symptom-pictures, PCPs are just as likely to diagnose and treat depression in African-American as in white older people, suggesting that bias based simply on apparent patient race is not a likely explanation for the lower rates of depression diagnosis and treatment in older African Americans. PCPs who have trained at international medical schools may benefit from targeted training initiatives on the diagnosis and treatment of late-life depression.

3,5,6,7,8,3′,4′-Heptamethoxyflavone Ameliorates Depressive-Like Behavior and Hippocampal Neurochemical Changes in Chronic Unpredictable Mild Stressed Mice by Regulating the Brain-Derived Neurotrophic Factor: Requirement for ERK Activation

PubMed Central

Sawamoto, Atsushi; Okuyama, Satoshi; Amakura, Yoshiaki; Yoshimura, Morio; Yamada, Takashi; Yokogoshi, Hidehiko; Nakajima, Mitsunari

2017-01-01

We previously reported that the subcutaneous administration of 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), a citrus polymethoxyflavone, attenuated depressive-like behavior and increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a corticosterone-induced depression-like mouse model. We herein demonstrated that (1) HMF was detectable in the brain 10 and 30 min after its oral administration, (2) orally administered HMF improved chronic unpredictable mild stress (CUMS)-induced pathological conditions, including body weight loss and depressive-like behavior, and CUMS-induced neurochemical changes, such as reduction in BDNF expression, decrease in neurogenesis, and decreased level of phosphorylated calcium-calmodulin-dependent protein kinase II in the hippocampus, and (3) these effects of HMF were inhibited by the pre-administration of U0126, a mitogen-activated protein (MAP) kinase inhibitor. These results suggest that orally administered HMF is beneficial for the upregulation of BDNF in the hippocampus via the extracellular signal-regulated kinase1/2 (ERK1/2)/MAP system, which may account for its antidepression effects. PMID:29023414

Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice.

PubMed

Gutknecht, Lise; Popp, Sandy; Waider, Jonas; Sommerlandt, Frank M J; Göppner, Corinna; Post, Antonia; Reif, Andreas; van den Hove, Daniel; Strekalova, Tatyana; Schmitt, Angelika; Colaςo, Maria B N; Sommer, Claudia; Palme, Rupert; Lesch, Klaus-Peter

2015-07-01

While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.

Decreased anxiety- and depression-like behaviors and hyperactivity in a type 3 deiodinase-deficient mouse showing brain thyrotoxicosis and peripheral hypothyroidism.

PubMed

Stohn, J Patrizia; Martinez, M Elena; Hernandez, Arturo

2016-12-01

Hypo- and hyperthyroid states, as well as functional abnormalities in the hypothalamic-pituitary-thyroid axis have been associated with psychiatric conditions like anxiety and depression. However, the nature of this relationship is poorly understood since it is difficult to ascertain the thyroid status of the brain in humans. Data from animal models indicate that the brain exhibits efficient homeostatic mechanisms that maintain local levels of the active thyroid hormone, triiodothyronine (T3) within a narrow range. To better understand the consequences of peripheral and central thyroid status for mood-related behaviors, we used a mouse model of type 3 deiodinase (DIO3) deficiency (Dio3 -/- mouse). This enzyme inactivates thyroid hormone and is highly expressed in the adult central nervous system. Adult Dio3 -/- mice exhibit elevated levels of T3-dependent gene expression in the brain, despite peripheral hypothyroidism as indicated by low circulating levels of thyroxine and T3. Dio3 -/- mice of both sexes exhibit hyperactivity and significantly decreased anxiety-like behavior, as measured by longer time spent in the open arms of the elevated plus maze and in the light area of the light/dark box. During the tail suspension, they stayed immobile for a significantly shorter time than their wild-type littermates, suggesting decreased depression-like behavior. These results indicate that increased thyroid hormone in the brain, not necessarily in peripheral tissues, correlates with hyperactivity and with decreases in anxiety and depression-like behaviors. Our results also underscore the importance of DIO3 as a determinant of behavior by locally regulating the brain levels of thyroid hormone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Decreased Anxiety- and Depression-like Behaviors and Hyperactivity in a Type 3 Deiodinase-Deficient Mouse Showing Brain Thyrotoxicosis and Peripheral Hypothyroidism

PubMed Central

Stohn, J. Patrizia; Martinez, M. Elena; Hernandez, Arturo

2016-01-01

Hypo- and hyperthyroid states, as well as functional abnormalities in the hypothalamic-pituitary-thyroid axis have been associated with psychiatric conditions like anxiety and depression. However, the nature of this relationship is poorly understood since it is difficult to ascertain the thyroid status of the brain in humans. Data from animal models indicate that the brain exhibits efficient homeostatic mechanisms that maintain local levels of the active thyroid hormone, triiodothyronine (T3) within a narrow range. To better understand the consequences of peripheral and central thyroid status for mood-related behaviors, we used a mouse model of type 3 deiodinase (DIO3) deficiency (Dio3 −/− mouse). This enzyme inactivates thyroid hormone and is highly expressed in the adult central nervous system. Adult Dio3 −/− mice exhibit elevated levels of T3-dependent gene expression in the brain, despite peripheral hypothyroidism as indicated by low circulating levels of thyroxine and T3. Dio3 −/− mice of both sexes exhibit hyperactivity and significantly decreased anxiety-like behavior, as measured by longer time spent in the open arms of the elevated plus maze and in the light area of the light/dark box. During the tail suspension, they stayed immobile for a significantly shorter time than their wild-type littermates, suggesting decreased depression-like behavior. These results indicate that increased thyroid hormone in the brain, not necessarily in peripheral tissues, correlates with hyperactivity and with decreases in anxiety and depression-like behaviors. Our results also underscore the importance of DIO3 as a determinant of behavior by locally regulating the brain levels of thyroid hormone. PMID:27580013

Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system.

PubMed

Godbout, Jonathan P; Moreau, Maïté; Lestage, Jacques; Chen, Jing; Sparkman, Nathan L; O'Connor, Jason; Castanon, Nathalie; Kelley, Keith W; Dantzer, Robert; Johnson, Rodney W

2008-09-01

Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LPS (0.33 mg/kg intraperitoneal) induced a protracted sickness response in aged mice with reductions in locomotor and feeding activities 24 and 48 h postinjection, when young adults had fully recovered. When submitted to the forced swim test 24 h post-LPS, both young adult and aged mice exhibited an increased duration of immobility. However, when submitted to either the forced swim test or the tail suspension test 72 h post-LPS, an increased duration of immobility was evident only in aged mice. This prolonged depressive-like behavior in aged LPS-treated mice was associated with a more pronounced induction of peripheral and brain indoleamine 2,3-dioxygenase and a markedly higher turnover rate of brain serotonin (as measured by the ratio of 5-hydroxy-indoleacetic acid over 5-hydroxy-tryptamine) compared to young adult mice at 24 post-LPS injection. These results provide the first evidence that age-associated reactivity of the brain cytokine system could play a pathophysiological role in the increased prevalence of depression observed in the elderly.

Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice.

PubMed

Nishijima, Takeshi; Llorens-Martín, María; Tejeda, Gonzalo Sanchez; Inoue, Koshiro; Yamamura, Yuhei; Soya, Hideaki; Trejo, José Luis; Torres-Alemán, Ignacio

2013-05-15

While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4 weeks old) were assigned to one of the following groups, and housed until 21 weeks old; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), housed in a running wheel cage; and (3) exercise-no exercise (Ex-noEx), housed in a running wheel cage for 8 weeks and subsequently in a standard cage. Behavioral evaluations suggested that Ex-noEx mice were more anxious compared to noEx control mice, but no differences were found in depression-like behavior. The number of BrdU-labeled surviving cells in the dentate gyrus was significantly higher in Ex but not in Ex-noEx compared with noEx, indicating that the facilitative effects of exercise on cell survival are reversible. Surprisingly, the ratio of differentiation of BrdU-positive cells to doublecortin-positive immature neurons was significantly lower in Ex-noEx compared to the other groups, suggesting that the cessation of wheel running impairs an important component of hippocampal neurogenesis in mice. These results indicate that hippocampal adaptation to physical inactivity is not simply a return to the conditions present in sedentary mice. As the impaired neurogenesis is predicted to increase a vulnerability to stress-induced mood disorders, the reduction of physical activity may contribute to a greater risk of these disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests.

PubMed

Kurhe, Yeshwant; Radhakrishnan, Mahesh; Gupta, Deepali

2014-09-01

The aim of the present work was to investigate the role of ondansetron on the high fat diet (HFD) induced obese mice for behavioral and biochemical alterations using chronic unpredictable mild stress (CUMS) model of depression. Animals were fed with high fat diet for 14 weeks and subjected to different stress procedures for 4 weeks. Treatment with ondansetron was started on day 15. After day 28 behavioral assays and biochemical estimations were performed. Behavioral paradigms viz. sucrose preference test, locomotor score, forced swim test (FST) and elevated plus maze (EPM), whereas biochemical parameters like plasma glucose, total cholesterol, triglycerides and total proteins were estimated. Results examines that in behavioral assays, ondansetron significantly (P < 0.05) increased sucrose consumption, reduced immobility time in FST, increased the percent entries and time in open arm in EPM. In biochemical assessments elevated plasma glucose, total cholesterol, triglycerides and total proteins were significantly (P < 0.05) reversed by ondansetron treatment in HFD obese animals subjected to CUMS. The study indicates that the obese mice subjected to CUMS exhibited severe depressive-like symptoms and ondansetron significantly reversed the behavioral and biochemical alterations. In the present study the plasma glucose level indicates that, it could be "altered glucose level" playing an important role in depression co-morbid with obesity. Ondansetron through allosteric modulation of serotonergic system elevates the serotonin level and thereby regulates the insulin secretion and hence, reversing the "altered glucose level", could be the possible antidepressive-like mechanism against depression co-morbid with obesity.

Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior.

PubMed

Ruan, Chun-Sheng; Yang, Chun-Rui; Li, Jia-Yi; Luo, Hai-Yun; Bobrovskaya, Larisa; Zhou, Xin-Fu

2016-07-01

Exposure to stressful life events plays a central role in the development of mood disorders in vulnerable individuals. However, the mechanisms that link mood disorders to stress are poorly understood. Brain-derived neurotrophic factor (BDNF) has long been implicated in positive regulation of depression and anxiety, while its precursor (proBDNF) recently showed an opposing effect on such mental illnesses. P75(NTR) and sortilin are co-receptors of proBDNF, however, the role of these receptors in mood regulation is not established. Here, we aimed to investigate the role of sortilin in regulating mood-related behaviors and its role in the proBDNF-mediated mood abnormality in mice. We found that sortilin was up-regulated in neocortex (by 78.3%) and hippocampus (by 111%) of chronically stressed mice as assessed by western blot analysis. These changes were associated with decreased mobility in the open field test and increased depression-like behavior in the forced swimming test. We also found that sortilin deficiency in mice resulted in hyperlocomotion in the open field test and increased anxiety-like behavior in both the open field and elevated plus maze tests. No depression-like behavior in the forced swimming test and no deficit in spatial cognition in the Morris water maze test were found in the Sort1-deficient mice. Moreover, the intracellular and extracellular levels of mature BDNF and proBDNF were not changed when sortilin was absent in vivo and in vitro. Finally, we found that both WT and Sort1-deficient mice injected with proBDNF in lateral ventricle displayed increased depression-like behavior in the forced swimming test but not anxiety-like behaviors in the open field and elevated plus maze tests. The present study suggests that sortilin functions as a negative regulator of mood performance and can be a therapeutic target for the treatment of mental illness. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Genetic and Environmental Influences on the Transmission of Parental Depression to Children's Depression and Conduct Disturbance: An Extended Children of Twins Study

ERIC Educational Resources Information Center

Silberg, Judy L.; Maes, Hermine; Eaves, Lindon J.

2010-01-01

Background: Despite the increased risk of depression and conduct problems in children of depressed parents, the mechanism by which parental depression affects their children's behavioral and emotional functioning is not well understood. The present study was undertaken to determine whether parental depression represents a genuine environmental…

The Efficacy of Casual Videogame Play in Reducing Clinical Depression: A Randomized Controlled Study.

PubMed

Russoniello, Carmen V; Fish, Matthew; O'Brien, Kevin

2013-12-01

Depression is a debilitating illness that is estimated to affect more than 300 million people worldwide. Although there has been some success in treatment of this illness with pharmaceuticals and behavioral techniques like cognitive behavioral therapy, these are often costly and have stigma associated with them. The purpose of this study was to test whether a prescribed regimen of casual videogame (CVG) play could reduce symptoms associated with depression. Participants were screened for depression using the Patient Health Questionnaire-9 (PHQ-9). They were then randomized into the control (n=29) or experimental (n=30) group. Experimental participants were prescribed to play CVGs three times per week (with 24 hours between each session), for 30 minutes, over a 1-month period. Control participants surfed the National Institute of Mental Health's Web page on depression. The instrument used to test the hypothesis was the PHQ-9. Repeated-measures statistical analyses revealed there was a significant interaction of group and time, supporting the hypothesis that the groups would be different after the intervention. Moreover, when data were compared using tests of within-subjects contrasts between baseline (Time 1) and the end of the 1-month study (Time 3), we found significant decreases in depression symptoms in the experimental group. When this was compared with the control group changes, the results were still significant. We found that a prescribed regimen of playing CVGs significantly reduced symptoms of clinical depression as measured by the PHQ-9. Clinicians should consider these low-cost CVGs as a possible intervention to address psychological and somatic symptoms associated with depression.

Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats.

PubMed

Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

2016-01-01

Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that metabolic risk markers arise when vulnerable individuals are exposed to social challenges later in life.

Predicting risky sexual behavior in emerging adulthood: examination of a moderated mediation model among child sexual abuse and adult sexual assault victims.

PubMed

Littleton, Heather L; Grills, Amie E; Drum, Katherine B

2014-01-01

Although having a sexual victimization history is associated with engaging in sexual risk behavior, the mechanisms whereby sexual victimization increases risk behavior are unclear. This study examined use of sex as an affect regulation strategy as a mediator of the relationship between depressive symptoms and sexual risk behavior among 1,616 sexually active college women as well as examined having a history of child sexual abuse (CSA), adolescent/adult sexual assault (ASA), or both (CSA/ASA) as moderators. Results supported the mediated model as well as moderated mediation, where depressive symptoms were more strongly associated with use of sex as an affect regulation strategy among ASA victims, and sex as an affect regulation strategy was more strongly related to sexual risk behavior for CSA/ASA victims.

Assessing local instrument reliability and validity: a field-based example from northern Uganda.

PubMed

Betancourt, Theresa S; Bass, Judith; Borisova, Ivelina; Neugebauer, Richard; Speelman, Liesbeth; Onyango, Grace; Bolton, Paul

2009-08-01

This paper presents an approach for evaluating the reliability and validity of mental health measures in non-Western field settings. We describe this approach using the example of our development of the Acholi psychosocial assessment instrument (APAI), which is designed to assess depression-like (two tam, par and kumu), anxiety-like (ma lwor) and conduct problems (kwo maraco) among war-affected adolescents in northern Uganda. To examine the criterion validity of this measure in the absence of a traditional gold standard, we derived local syndrome terms from qualitative data and used self reports of these syndromes by indigenous people as a reference point for determining caseness. Reliability was examined using standard test-retest and inter-rater methods. Each of the subscale scores for the depression-like syndromes exhibited strong internal reliability ranging from alpha = 0.84-0.87. Internal reliability was good for anxiety (0.70), conduct problems (0.83), and the pro-social attitudes and behaviors (0.70) subscales. Combined inter-rater reliability and test-retest reliability were good for most subscales except for the conduct problem scale and prosocial scales. The pattern of significant mean differences in the corresponding APAI problem scale score between self-reported cases vs. noncases on local syndrome terms was confirmed in the data for all of the three depression-like syndromes, but not for the anxiety-like syndrome ma lwor or the conduct problem kwo maraco.

Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus

PubMed Central

Gobinath, Aarthi R.; Mahmoud, Rand; Galea, Liisa A.M.

2015-01-01

Sex differences exist in vulnerability, symptoms, and treatment of many neuropsychiatric disorders. In this review, we discuss both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan. Chronic exposure to stress is a risk factor for depression and we discuss how stress during the prenatal, postnatal, and adolescent periods differentially affects males and females depending on the method of stress and metric examined. Given that the integrity of the hippocampus is compromised in depression, we specifically focus on sex differences in how hippocampal plasticity is affected by stress and depression across the lifespan. In addition, we examine how female physiology predisposes depression in adulthood, specifically in postpartum and perimenopausal periods. Finally, we discuss the underrepresentation of women in both preclinical and clinical research and how this limits our understanding of sex differences in vulnerability, presentation, and treatment of depression. PMID:25610363

Sex differences in the outcome of juvenile social isolation on HPA axis function in rats.

PubMed

Pisu, M G; Garau, A; Boero, G; Biggio, F; Pibiri, V; Dore, R; Locci, V; Paci, E; Porcu, P; Serra, M

2016-04-21

Women are more likely than men to suffer from anxiety disorders and major depression. These disorders share hyperresponsiveness to stress as an etiological factor. Thus, sex differences in brain arousal systems and their regulation by chronic stress may account for the increased vulnerability to these disorders in women. Social isolation is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like and depressive-like behaviors. Here we investigated the sex difference in the effects of post-weaning social isolation on acute stress sensitivity and behavior in rats. In both sexes, social isolation at weaning reduced basal levels of the neuroactive steroid allopregnanolone in the brain and of corticosterone in plasma. Moreover, acute stress increased plasma corticosterone levels in both group-housed and socially isolated male and female rats; however this effect was greater in male than female rats subjected to social isolation. Intriguingly, group-housed female rats showed no change in plasma and brain levels of allopregnanolone after acute foot-shock stress. The absence of stress-induced effects on allopregnanolone synthesis might be due to the physiologically higher levels of this hormone in females vs. males. Accordingly, increasing allopregnanolone levels in male rats blunted the response to foot-shock stress in these animals. Socially isolated male, but not female, rats also display depressive-like behavior and increased hippocampal brain-derived neurotrophic factor (BDNF). The ovarian steroids could "buffer" the effect of this adverse experience in females on these parameters. Finally, the dexamethasone (DEX) suppression test indicated that the chronic stress associated with social isolation impairs feedback inhibition in both sexes in which an increase in the abundance of glucocorticoid receptors (GRs) in the hippocampus was found. Altogether, these results demonstrate that social isolation affects neuroendocrine reactivity to stress, plasticity and emotionality in a sexually dimorphic manner. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

The Effect of Congenital and Postnatal Hypothyroidism on Depression-Like Behaviors in Juvenile Rats.

PubMed

Özgür, Erdoğan; Gürbüz Özgür, Börte; Aksu, Hatice; Cesur, Gökhan

2016-12-01

The aim of this study was to investigate depression-like behaviors of juvenile rats with congenital and postnatal hypothyroidism. Twenty-seven newborn rat pups were used. First, 6-month-old Wistar Albino female rats were impregnated. Methimazole (0.025% wt/vol) was given to dam rats from the first day of pregnancy until postnatal 21 days (P21) to generate pups with congenital hypothyroidism (n=8), whereas in the postnatal hypothyroidism group (n=10), methimazole was given from P0 to P21. In the control group (n=9), dam rats were fed ad libitum and normal tap water. Offspring were fed with breast milk from their mothers. The behavioral parameters were measured with the juvenile forced swimming test (JFST). The procedure of JFST consisted of two sessions in two consecutive days: the 15-minute pre-test on day 1 and the 5-minute test on day 2. Increased immobility and decreased climbing duration were observed in both congenital and postnatal hypothyroidism groups. Decreased swimming duration was detected in the postnatal hypothyroidism group. Both hypothyroidism groups had a lower body weight gain compared with the control group, while the congenital hypothyroidism group had the lowest body weight. Our results showed that hypothyroidism had negative effects on depression-like behavior as well as on growth and development. Both congenital and postnatal hypothyroidism caused an increase in immobility time in JFST. New studies are required to understand the differing results on depression-like behavior between congenital and postnatal hypothyroidism.

Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice.

PubMed

Tao, Weiwei; Wang, Hanqing; Su, Qiang; Chen, Yanyan; Xue, Wenda; Xia, Baomei; Duan, Jinao; Chen, Gang

2016-04-30

The present study was designed to detect the anti-depressant effects of paeonol and the possible mechanisms in the lipopolysaccharide-induced depressive-like behavior. Open-field test(OFT), tail suspension test(TST) and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that LPS significantly decreased the levels of 5-HT and NE in the hippocampus. LPS also reduced open-field activity, as well as increased immobility duration in FST and TST. Paeonol administration could effectively reverse the alterations in the concentrations of 5-HT, NE and reduce the IL-6 and TNF-α levels. Moreover, paeonol effectively downregulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal. In conclusion, paeonol administration exhibited significant antidepressant-like effects in mice with LPS-induced depression. Copyright © 2016. Published by Elsevier Ireland Ltd.

Use of zinc as a treatment for traumatic brain injury in the rat: effects on cognitive and behavioral outcomes.

PubMed

Cope, Elise C; Morris, Deborah R; Scrimgeour, Angus G; Levenson, Cathy W

2012-09-01

While treatments for the behavioral deficits associated with traumatic brain injury (TBI) are currently limited, animal models suggest that zinc supplementation may increase resilience to TBI. This work tests the hypothesis that zinc supplementation after TBI can be used as treatment to improve behavioral outcomes such as anxiety, depression, and learning and memory. TBI was induced by controlled cortical impact to the medial frontal cortex. After TBI, rats were fed either a zinc adequate (ZA, 30 ppm) or zinc supplemented (ZS, 180 ppm) diet. Additional rats in each dietary group (ZA or ZS) were given a single intraperitoneal (ip) injection of zinc (30 mg/kg) 1 hour following injury. Brain injury resulted in significant increases in anxiety-like and depression-like behaviors as well as impairments in learning and memory. None of the zinc treatments (dietary or ip zinc) improved TBI-induced anxiety. The 2-bottle saccharin preference test for anhedonia revealed that dietary ZS also did not improve depression-like behaviors. However, dietary ZS combined with an early ip zinc injection significantly reduced anhedonia (P < .001). Dietary supplementation after injury, but not zinc injection, significantly improved (P < .05) cognitive behavior as measured by the time spent finding the hidden platform in the Morris water maze test compared with injured rats fed a ZA diet. These data suggest that zinc supplementation may be an effective treatment option for improving behavioral deficits such as cognitive impairment and depression following TBI.

Anhedonia but not passive floating is an indicator of depressive-like behavior in two chronic stress paradigms.

PubMed

Stepanichev, Mikhail Yu; Tishkina, Anna O; Novikova, Margarita R; Levshina, Irina P; Freiman, Sofiya V; Onufriev, Mikhail V; Levchenko, Olga A; Lazareva, Natalia A; Gulyaeva, Natalia V

2016-01-01

Depression is the most common form of mental disability in the world. Depressive episodes may be precipitated by severe acute stressful events or by mild chronic stressors. Studies on the mechanisms of depression require both appropriate experimental models (most of them based on the exposure of animals to chronic stressors), and appropriate tests for assessment of depressive states. In this study male Wistar rats were exposed to two different chronic stress paradigms: an eight-week chronic unpredictable mild stress or a two-week combined chronic stress. The behavioral effects of stress were evaluated using sucrose preference, forced swim and open field tests. After the exposure to chronic unpredictable mild stress, anhedonia was developed, activity in the open field increased, while no changes in the duration of passive floating could be detected. After chronic combined stress, anhedonia was also evident, whereas behavior in the open field and forced swim test did not change. The levels of corticosterone in the blood and brain structures involved in stress-response did not differ from control in both experiments. The absence of significant changes in corticosterone levels and passive floating may be indicative of the adaptation of animals to chronic stress. Anhedonia appears to be a more sensitive indicator of depressive-like behavioral effects of chronic stress as compared to behavior in the forced swim or open field tests.

Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression.

PubMed

Haenisch, Britta; Bilkei-Gorzo, Andras; Caron, Marc G; Bönisch, Heinz

2009-10-01

Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, nerve growth factor, and neurotrophin-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NET knock out (NETKO) mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants.

Consequences of continuous social defeat stress on anxiety- and depressive-like behaviors and ethanol reward in mice.

PubMed

Macedo, Giovana Camila; Morita, Gleice Midori; Domingues, Liz Paola; Favoretto, Cristiane Aparecida; Suchecki, Deborah; Quadros, Isabel Marian Hartmann

2018-01-01

This study employed the intruder-resident paradigm to evaluate the effects of continuous social defeat on depressive- and anxiety-like behaviors and the reinforcing and motivational actions of ethanol in male Swiss mice. Male Swiss mice were exposed to a 10-day social defeat protocol, while control mice cohabitated with a non-aggressive animal. Continuous defeat stress consisted of episodes of defeat, followed by 24h or 48h cohabitation with the aggressor until the following defeat. Mice were assessed for sucrose drinking (anhedonia), social investigation test, elevated plus-maze, conditioned place preference to ethanol, and locomotor response to ethanol. Plasma corticosterone was measured prior to, after the first and the final defeat, and 10days after the end of defeat. Defeated mice exhibited a depressive-like phenotype as indicated by social inhibition and reduced sucrose preference, relative to non-defeated controls. Defeated mice also displayed anxiety-like behavior when tested in the elevated plus-maze. Stressed animals failed to present ethanol-induced locomotor stimulation, but showed increased sensitivity for ethanol-induced conditioned place preference. Corticosterone response to defeat was the highest after the first defeat, but was still elevated after the last defeat (day 10) when compared to non-stressed controls. Baseline corticosterone levels were unchanged 10days after the final defeat. These data suggest that social defeat stress increased depressive- and anxiety-like behavior as well increased vulnerability to ethanol reward in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Early life stress paradigms in rodents: potential animal models of depression?

PubMed

Schmidt, Mathias V; Wang, Xiao-Dong; Meijer, Onno C

2011-03-01

While human depressive illness is indeed uniquely human, many of its symptoms may be modeled in rodents. Based on human etiology, the assumption has been made that depression-like behavior in rats and mice can be modulated by some of the powerful early life programming effects that are known to occur after manipulations in the first weeks of life. Here we review the evidence that is available in literature for early life manipulation as risk factors for the development of depression-like symptoms such as anhedonia, passive coping strategies, and neuroendocrine changes. Early life paradigms that were evaluated include early handling, separation, and deprivation protocols, as well as enriched and impoverished environments. We have also included a small number of stress-related pharmacological models. We find that for most early life paradigms per se, the actual validity for depression is limited. A number of models have not been tested with respect to classical depression-like behaviors, while in many cases, the outcome of such experiments is variable and depends on strain and additional factors. Because programming effects confer vulnerability rather than disease, a number of paradigms hold promise for usefulness in depression research, in combination with the proper genetic background and adult life challenges.

Social stress induces neurovascular pathology promoting depression

PubMed Central

Menard, Caroline; Pfau, Madeline L.; Hodes, Georgia E.; Kana, Veronika; Wang, Victoria X.; Bouchard, Sylvain; Takahashi, Aki; Flanigan, Meghan E.; Aleyasin, Hossein; LeClair, Katherine B.; Janssen, William G.; Labonté, Benoit; Parise, Eric M.; Lorsch, Zachary S.; Golden, Sam A.; Heshmati, Mitra; Tamminga, Carol; Turecki, Gustavo; Campbell, Matthew; Fayad, Zahi; Tang, Cheuk Ying; Merad, Miriam; Russo, Scott J.

2017-01-01

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of endothelial cell tight junction protein claudin-5 (cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 down-regulation was sufficient to induce depression-like behaviors following subthreshold social stress while chronic antidepressant treatment rescued cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or AAV-shRNA-cldn5-injected mice caused infiltration of peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein cldn5, promoting peripheral IL-6 passage across the BBB and depression. PMID:29184215

The effects of fisetin on lipopolysaccharide-induced depressive-like behavior in mice.

PubMed

Yu, Xuefeng; Jiang, Xi; Zhang, Xiangming; Chen, Ziwei; Xu, Lexing; Chen, Lei; Wang, Guokang; Pan, Jianchun

2016-10-01

Major depressive disorder (MDD) involves a series of pathological changes including the inflammation and increased cytokine levels. Fisetin, a natural flavonoid, has anti-inflammatory and antioxidant, and also has been shown in our previous studies to exert anti-depressant-like properties. The present study aimed to investigate the effect of fisetin on lipopolysaccharide (LPS)-induced depressive-like behavior and inflammation in mice. The results suggested that the immobility time in the forced swimming test (FST) and tail suspension test (TST) were increased at 6 h, 12 h and 24 h after LPS injection (0.83 mg/kg). However, only the group of 24 h treatment did not show any effect on locomotion counts. Pretreatment with fisetin at doses of 20, 40 and 80 mg/kg (p.o.) for 7 days reversed LPS-induced alterations of the immobility time in both of these two tests. Further neurochemical assays suggested that pretreatment with fisetin reversed LPS-induced overexpression of pro-inflammatory cytokine (IL-1β, IL-6 and TNF-α) in the hippocampus and the prefrontal cortex (PFC). Moreover, higher dose of fisetin effectively antagonized iNOS mRNA expression and nitrite levels via the modulation of NF-κB in the hippocampus and PFC. Taken together, fisetin may be an effective therapeutic agent for LPS-induced depressive-like behaviors, which is due to its anti-inflammatory property.

Anhedonia and anxiety underlying depressive symptomatology have distinct effects on reward-based decision-making.

PubMed

Harlé, Katia M; Guo, Dalin; Zhang, Shunan; Paulus, Martin P; Yu, Angela J

2017-01-01

Depressive pathology, which includes both heightened negative affect (e.g., anxiety) and reduced positive affect (e.g., anhedonia), is known to be associated with sub-optimal decision-making, particularly in uncertain environments. Here, we use a computational approach to quantify and disambiguate how individual differences in these affective measures specifically relate to different aspects of learning and decision-making in reward-based choice behavior. Fifty-three individuals with a range of depressed mood completed a two-armed bandit task, in which they choose between two arms with fixed but unknown reward rates. The decision-making component, which chooses among options based on current expectations about reward rates, is modeled by two different decision policies: a learning-independent Win-stay/Lose-shift (WSLS) policy that ignores all previous experiences except the last trial, and Softmax, which prefers the arm with the higher expected reward. To model the learning component for the Softmax choice policy, we use a Bayesian inference model, which updates estimated reward rates based on the observed history of trial outcomes. Softmax with Bayesian learning better fits the behavior of 55% of the participants, while the others are better fit by a learning-independent WSLS strategy. Among Softmax "users", those with higher anhedonia are less likely to choose the option estimated to be most rewarding. Moreover, the Softmax parameter mediates the inverse relationship between anhedonia and overall monetary gains. On the other hand, among WSLS "users", higher state anxiety correlates with increasingly better ability of WSLS, relative to Softmax, to explain subjects' trial-by-trial choices. In summary, there is significant variability among individuals in their reward-based, exploratory decision-making, and this variability is at least partly mediated in a very specific manner by affective attributes, such as hedonic tone and state anxiety.

Adolescent Trajectories of Depressive Symptoms: Codevelopment of Behavioral and Academic Problems.

PubMed

Brière, Frédéric N; Janosz, Michel; Fallu, Jean-Sébastien; Morizot, Julien

2015-09-01

Increasing evidence suggests the existence of heterogeneity in the development of depressive symptoms during adolescence, but little remains known regarding the implications of this heterogeneity for the development of commonly co-occurring problems. In this study, we derived trajectories of depressive symptoms in adolescents and examined the codevelopment of multiple behavioral and academic problems in these trajectories. Participants were 6,910 students from secondary schools primarily located in disadvantaged areas of Quebec (Canada) who were assessed annually from the age 12 to 16 years. Trajectories were identified using growth mixture modeling. The course of behavioral (delinquency, substance use) and academic adjustment (school liking, academic achievement) in trajectories was examined by deriving latent growth curves for each covariate conditional on trajectory membership. We identified five trajectories of stable-low (68.1%), increasing (12.1%), decreasing (8.7%), transient (8.7%), and stable-high (2.4%) depressive symptoms. Examination of conditional latent growth curves revealed that the course of behavioral and academic problems closely mirrored the course of depressive symptoms in each trajectory. This pattern of results suggests that the course of depressive symptoms and other adjustment problems over time is likely to involve an important contribution of shared underlying developmental process(es). Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Role of cortical alpha-2 adrenoceptors in alcohol withdrawal-induced depression and tricyclic antidepressants

PubMed Central

Getachew, Bruk; Hauser, Sheketha R.; Csoka, Antonei B.; Taylor, Robert E.; Tizabi, Yousef

2017-01-01

Introduction Although a role for alpha-2 adrenoceptors (alpha-2 ARs) in alcohol use disorder (AUD) and depression is suggested, very little information on a direct interaction between alcohol and these receptors is available. Methods In this study adult female Wistar and Wistar-Kyoto (WKY) rats, a putative animal model of depression, were exposed to alcohol vapor 3 h daily for 10 days (blood alcohol concentration ~150 mg%) followed by daily injection of 10 mg/kg of imipramine (IMP, a selective norepinephrine NE/serotonin reuptake inhibitor) or nomifensine (NOMI, a selective NE/dopamine reuptake inhibitor). On day 11 animals were tested for open field locomotor activity (OFLA) and forced swim test (FST) and were sacrificed 2 h later for measurement of alpha-2 ARs densities in the frontal cortex and hippocampus using [3H]RX 821002 as the specific ligand. Results Chronic alcohol treatment increased the immobility in the FST, without affecting OFLA in both Wistar and WKY rats, suggesting induction of depressive-like behavior in Wistar rats and an exacerbation of this behavior in WKY rats. Alcohol treatment also resulted in an increase in cortical but not hippocampal alpha-2 ARs densities in both Wistar and WKY rats. The behavioral effects of alcohol were completely blocked by IMP and NOMI and the neurochemical effects (increases in alpha-2 ARs) were significantly attenuated by both drugs in both strains. Conclusions The results suggest a role for cortical alpha-2 ARs in alcohol withdrawal-induced depression and that selective subtype antagonists of these receptors may be of adjunct therapeutic potential in AUD-depression co-morbidity. PMID:28414989

Emotional Stress-reactivity and Positive Affect among College Students: The Role of Depression History

PubMed Central

O’Hara, Ross E.; Armeli, Stephen; Boynton, Marcella H.; Tennen, Howard

2014-01-01

Multiple theories posit that people with a history of depression are at higher risk for a depressive episode than people who have never experienced depression, which may be partly due to differences in stress-reactivity. Additionally, both the dynamic model of affect and the broaden-and-build theory suggest that stress and positive affect interact to predict negative affect, but this moderation has never been tested in the context of depression history. The current study used multilevel modeling to examine these issues among 1549 college students with or without a history of depression. Students completed a 30-day online diary study in which they reported daily their perceived stress, positive affect, and negative affect (including depression, anxiety, and hostility). On days characterized by higher than usual stress, students with a history of depression reported greater decreases in positive affect and greater increases in depressed affect than students with no history. Furthermore, the relations between daily stress and both depressed and anxious affect were moderated by daily positive affect among students with remitted depression. These results indicate that students with a history of depression show greater stress-reactivity even when in remission, which may place them at greater risk for recurrence. These individuals may also benefit more from positive affect on higher stress days despite being less likely to experience positive affect on such days. The current findings have various implications both clinically and for research on stress, mood, and depression. PMID:24274764

Gender differences in cardiac patients: a longitudinal investigation of exercise, autonomic anxiety, negative affect and depression.

PubMed

Hunt-Shanks, Tiffany; Blanchard, Christopher; Reid, Robert D

2009-05-01

Female cardiac patients frequently experience greater anxiety and depression and engage in less exercise when compared with their male counterparts. This study considered whether exercise had similar effects on male and female cardiac patients' autonomic anxiety, negative affect and depression, and whether exercise behavior explained the gender difference in their affective functioning (e.g. autonomic anxiety, negative affect and depression). Eight hundred one participants completed the Hospital and Anxiety Depression Scale (HADS) and the leisure score index (LSI) of the Godin Leisure-Time Exercise Questionnaire at baseline, 6 months, 12 months, and 24 months. Female cardiac patients had greater autonomic anxiety, negative affect and depression and reduced exercise when compared with male cardiac patients at all time points. Although exercise was significantly related to affective outcomes at various time points for both men and women, gender did not moderate any of the exercise/affective relationships, and exercise did not mediate any of the gender/affective relationships. Further research is needed to clarify the complex relationships between gender, exercise, and the affective functioning of cardiac patients.

Depression and Behavioral Problems Among Adolescent Girls and Young Women Employees of the Textile Industry in India.

PubMed

Gnanaselvam, Nancy Angeline; Joseph, Bobby

2018-01-01

Stress and depression are common in textile industry employees due to inadequate working conditions and challenging socioeconomic conditions. The objective of the study was to assess depression and mental health among adolescent and young females currently employed in a textile factory located in Tamil Nadu compared with past employees and women who have never been employed. This cross-sectional study included a total of 107 participants in each study group who were interviewed. The Patient Health Questionnaire-9 and Strengths and Difficulties Questionnaire were administered to screen participants for depression and mental health. More current employees (16.82%) and past employees (15.88%) suffered from depression severe enough to require treatment compared with never employed girls and young women (2.8%). Of the study participants, 59.8% of current employees, 63.6% of past employees, and 32.7% of never employed women had mental health or behavior problems. In the regression model, history of abuse was significantly associated with depression. Participants who were current employees and reported family debt and a history of abuse were significantly more likely to have mental health or behavior problems. Mental health issues such as depression and behavior problems were more likely among adolescent girls currently employed in textile industries. Further studies into the causes of this phenomenon are needed.

Ethanol extract of Rehmannia glutinosa exerts antidepressant-like effects on a rat chronic unpredictable mild stress model by involving monoamines and BDNF.

PubMed

Wang, Jun-Ming; Pei, Li-Xin; Zhang, Yue-Yue; Cheng, Yong-Xian; Niu, Chun-Ling; Cui, Ying; Feng, Wei-Sheng; Wang, Gui-Fang

2018-06-01

The dried roots of Rehmannia glutinosa Libosch. (Scrophulariaceae) are of both medicinal and nutritional importance. Our previous study has found that the 80% ethanol extract of R. glutinosa (RGEE) produced antidepressant-like activities in mouse behavioral despair depression models. However, its mechanisms are still unclear. The present study aimed to observe the antidepressant-like mechanisms of RGEE on a rat chronic unpredictable mild stress (CUMS) model by involving monoaminergic neurotransmitters and brain-derived neurotrophic factor (BDNF). CUMS-stressed rats were orally given RGEE daily (150, 300, and 600 mg/kg) or fluoxetine hydrochloride (FH) for 3 weeks after starting the CUMS procedure. Sucrose preference test was carried out to observe depression-like behavior, and serum and brain tissues were used for neurochemical and fluorescent quantitative reverse transcription PCR analysis. Results demonstrated that CUMS induced depression-like behavior, whereas RGEE and FH administration inhibited this symptom. Furthermore, CUMS caused excessively elevated levels of serum corticosterone (CORT), an index of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, in a manner attenuated by RGEE and FH administration. RGEE administration also further elevated monoamine neurotransmitters and BDNF levels, up-regulated the mRNA expression of BDNF and tropomyosin-related kinase B (TrkB) in hippocampus of rats suffering CUMS. Together, our findings suggest that RGEE can improve CUMS-evoked depression-like behavior, and indicate its mechanisms may partially be associated with restoring HPA axis dysfunctions, enhancing monoamineergic nervous systems, and up-regulating BDNF and TrkB expression.

Depressive-like effect of prenatal exposure to DDT involves global DNA hypomethylation and impairment of GPER1/ESR1 protein levels but not ESR2 and AHR/ARNT signaling.

PubMed

Kajta, Malgorzata; Wnuk, Agnieszka; Rzemieniec, Joanna; Litwa, Ewa; Lason, Wladyslaw; Zelek-Molik, Agnieszka; Nalepa, Irena; Rogóż, Zofia; Grochowalski, Adam; Wojtowicz, Anna K

2017-07-01

Several lines of evidence suggest that exposures to Endocrine Disrupting Chemicals (EDCs) such as pesticides increase the risks of neuropsychiatric disorders. Despite extended residual persistence of dichlorodiphenyltrichloroethane (DDT) in the environment, the mechanisms of perinatal actions of DDT that could account for adult-onset of depression are largely unknown. This study demonstrated the isomer-specific induction of depressive-like behavior and impairment of Htr1a/serotonin signaling in one-month-old mice that were prenatally exposed to DDT. The effects were reversed by the antidepressant citalopram as evidenced in the forced swimming (FST) and tail suspension (TST) tests in the male and female mice. Prenatally administered DDT accumulated in mouse brain as determined with gas chromatography and tandem mass spectrometry, led to global DNA hypomethylation, and altered the levels of methylated DNA in specific genes. The induction of depressive-like behavior and impairment of Htr1a/serotonin signaling were accompanied by p,p'-DDT-specific decrease in the levels of estrogen receptors i.e. ESR1 and/or GPER1 depending on sex. In contrast, o,p'-DDT did not induce depressive-like effects and exhibited quite distinct pattern of biochemical alterations that was related to aryl hydrocarbon receptor (AHR), its nuclear translocator ARNT, and ESR2. Exposure to o,p'-DDT increased AHR expression in male and female brains, and reduced expression levels of ARNT and ESR2 in the female brains. The evolution of p,p'-DDT-induced depressive-like behavior was preceded by attenuation of Htr1a and Gper1/GPER1 expression as observed in the 7-day-old mouse pups. Because p,p'-DDT caused sex- and age-independent attenuation of GPER1, we suggest that impairment of GPER1 signaling plays a key role in the propagation of DDT-induced depressive-like symptoms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice.

PubMed

Islam, M R; Moriguchi, S; Tagashira, H; Fukunaga, K

2014-07-11

Rivastigmine is a non-competitive inhibitor of both acetylcholinesterase (AChE) and butylcholinesterase (BuChE) used to treat mild to moderate dementia in Alzheimer's disease (AD) patients. Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients, its ability to improve Behavioral and Psychological Symptoms of Dementia (BPSD) remains unclear. To determine whether rivastigmine treatment antagonizes depression-like behaviors, we chronically administered rivastigmine (0.1-1.0mg/kg) to olfactory bulbectomized (OBX) mice once a day for 2weeks, starting 2weeks after bulbectomy. Chronic treatment at 0.3 or 1.0mg/kg dose dependently and significantly improved depression-like behaviors, as assessed by tail suspension (TST), forced swim (FST), locomotion and novelty-suppressed feeding (NSFT) tests. Importantly, co-administration with WAY-100635 (1.0mg/kg), a 5-HT1A receptor antagonist, but not ketanserin (1.0mg/kg,), a 5-HT2A receptor antagonist, completely blocked rivastigmine-induced anti-depressive effects, suggesting that 5-HT1A receptor stimulation mediates this activity. Consistent with this observation, rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a 5-HT1A receptor-dependent manner. Furthermore, enhanced protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis. These effects were blocked by WAY-100635 but not ketanserin treatment. Finally, we confirmed that 5-HT1A but not 5-HT2A receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis. We conclude that, in addition to enhancing the cholinergic system, rivastigmine treatment restores normal function of the hippocampal serotonergic system, an activity that likely ameliorates depressive behaviors in AD patients. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments.

PubMed

Barra de la Tremblaye, P; Plamondon, H

2016-07-01

Although it is well accepted that changes in the regulation of the hypothalamic-pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress-related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus.

PubMed

Temel, Yasin; Boothman, Laura J; Blokland, Arjan; Magill, Peter J; Steinbusch, Harry W M; Visser-Vandewalle, Veerle; Sharp, Trevor

2007-10-23

Bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the surgical therapy of choice for movement disability in advanced Parkinson's disease (PD), but this procedure evokes debilitating psychiatric effects, including depressed mood, of unknown neural origin. Here, we report the unexpected finding that HFS of the STN inhibits midbrain 5-hydroxytryptamine (5-HT) neurons to evoke depression-related behavioral changes. We found that bilateral HFS of the STN consistently inhibited (40-50%) the firing rate of 5-HT neurons in the dorsal raphe nucleus of the rat, but not neighboring non-5-HT neurons. This effect was apparent at clinically relevant stimulation parameters (> or =100 Hz, > or =30 microA), was not elicited by HFS of either neighboring or remote structures to the STN, and was still present in rat models of PD. We also found that bilateral HFS of the STN evoked clear-cut, depressive-like behavior in a widely used experimental paradigm of depression (forced swim test), and this effect was also observed in a PD model. Importantly, the depressive-like behavior elicited by HFS of the STN was reversed by a selective 5-HT-enhancing antidepressant, thereby linking the behavioral change to decreased 5-HT neuronal activity. Overall, these findings link reduced 5-HT function to the psychiatric effects of HFS of the STN observed in PD patients and provide a rational basis for their clinical management. More generally, the powerful interaction between the STN and 5-HT system uncovered here offers insights into the high level of comorbidity of basal ganglia disease and mood disorder.

Role of affective self-regulatory efficacy in diverse spheres of psychosocial functioning.

PubMed

Bandura, Albert; Caprara, Gian Vittorio; Barbaranelli, Claudio; Gerbino, Maria; Pastorelli, Concetta

2003-01-01

This prospective study with 464 older adolescents (14 to 19 years at Time 1; 16 to 21 years at Time 2) tested the structural paths of influence through which perceived self-efficacy for affect regulation operates in concert with perceived behavioral efficacy in governing diverse spheres of psychosocial functioning. Self-efficacy to regulate positive and negative affect is accompanied by high efficacy to manage one's academic development, to resist social pressures for antisocial activities, and to engage oneself with empathy in others' emotional experiences. Perceived self-efficacy for affect regulation essentially operated mediationally through the latter behavioral forms of self-efficacy rather than directly on prosocial behavior, delinquent conduct, and depression. Perceived empathic self-efficacy functioned as a generalized contributor to psychosocial functioning. It was accompanied by prosocial behavior and low involvement in delinquency but increased vulnerability to depression in adolescent females.

Reproductive Steroid Regulation of Mood and Behavior.

PubMed

Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C; Schmidt, Peter J; Rubinow, David R

2016-06-13

In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e. Copyright © 2016 John Wiley & Sons, Inc.

Depression, women, and the workplace.

PubMed

Wollersheim, J P

1993-01-01

Depression is a highly prevalent disorder that causes much personal distress and difficulties in functioning at home and in the workplace. In the workplace, as elsewhere, depression can manifest as a variation in normal mood, as a symptom, as a disorder, or as a disease. Occupational health professionals are more concerned with clinical depression, a term used to signify any type of depression that causes significant personal distress and/or problems in functioning. Clinical depression is manifest in the workplace and adversely affects the employee's work satisfaction and performance. For most types of depression, women are at a higher risk than men. A number of events and variables related to women and depression were reviewed. Although the effects of some of these events, such as menopause, can be manifest in the workplace, they are not associated with an increased incidence of clinical depression. Other events, such as victimization (e.g., childhood sexual abuse or battering by an intimate partner), are associated with higher risks of depression in women. Women derive substantial satisfaction from interpersonal relationships but also are at greater risk for depression when strains and conflicts in these relationships occur. In the workplace women who have no difficulty in arranging for child care and whose spouses share in the care of children show lower rates of depression. When marriages are unhappy, women are three times as likely as men to be depressed. These findings speak to the importance of relationships to women. In the workplace, when women are depressed, problems with relationships are likely to be involved. Clinically depressed women are not difficult to identify in work settings. Dejected mood and loss of interest in usual activities are noticeable, along with numerous other symptoms that accompany depression. The effective treatment of depression depends on careful diagnosis and assessment. Both drug therapy and the more structured psychotherapies, such as cognitive-behavioral and interpersonal therapy, have demonstrated effectiveness in treating depression. For mild depression, pharmacotherapy is likely to be the treatment of choice. In cases in which the depressive symptomatology is moderate to severe, a combination of drug therapy and psychotherapy is likely to be the most effective treatment and to provide the best prophylaxis. Drug therapy seems particularly effective in promoting rapid reduction of vegetative and physical symptoms. Psychotherapy enhances coping skills at home and at work and also focuses on problem-solving, relationship difficulties, and dealing with stressors. In the area of prevention, occupational health practitioners currently can have the greatest impact in secondary prevention.(ABSTRACT TRUNCATED AT 400 WORDS)

Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice.

PubMed

Mahbod, Parinaz; Smith, Eric P; Fitzgerald, Maureen E; Morano, Rachel L; Packard, Benjamin A; Ghosal, Sriparna; Scheimann, Jessie R; Perez-Tilve, Diego; Herman, James P; Tong, Jenny

2018-01-01

Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop-floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal-regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety-related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent. Copyright © 2018 Endocrine Society.

Facial affect processing and depression susceptibility: cognitive biases and cognitive neuroscience.

PubMed

Bistricky, Steven L; Ingram, Rick E; Atchley, Ruth Ann

2011-11-01

Facial affect processing is essential to social development and functioning and is particularly relevant to models of depression. Although cognitive and interpersonal theories have long described different pathways to depression, cognitive-interpersonal and evolutionary social risk models of depression focus on the interrelation of interpersonal experience, cognition, and social behavior. We therefore review the burgeoning depressive facial affect processing literature and examine its potential for integrating disciplines, theories, and research. In particular, we evaluate studies in which information processing or cognitive neuroscience paradigms were used to assess facial affect processing in depressed and depression-susceptible populations. Most studies have assessed and supported cognitive models. This research suggests that depressed and depression-vulnerable groups show abnormal facial affect interpretation, attention, and memory, although findings vary based on depression severity, comorbid anxiety, or length of time faces are viewed. Facial affect processing biases appear to correspond with distinct neural activity patterns and increased depressive emotion and thought. Biases typically emerge in depressed moods but are occasionally found in the absence of such moods. Indirect evidence suggests that childhood neglect might cultivate abnormal facial affect processing, which can impede social functioning in ways consistent with cognitive-interpersonal and interpersonal models. However, reviewed studies provide mixed support for the social risk model prediction that depressive states prompt cognitive hypervigilance to social threat information. We recommend prospective interdisciplinary research examining whether facial affect processing abnormalities promote-or are promoted by-depressogenic attachment experiences, negative thinking, and social dysfunction.

Antidepressant-like effect of Butea superba in mice exposed to chronic mild stress and its possible mechanism of action.

PubMed

Mizuki, Daishu; Matsumoto, Kinzo; Tanaka, Ken; Thi Le, Xoan; Fujiwara, Hironori; Ishikawa, Tsutomu; Higuchi, Yoshihiro

2014-10-28

Butea superba (BS) is a Thai medicinal plant that has been used as a folk medicine to improve physical and mental conditions and to prevent impaired sexual performance in middle-aged or elderly males. We have previously reported that this plant extract could improve cognitive deficits and depression-like behavior in olfactory bulbectomized mice, an animal model of dementia and depression. In this study we examined the effect of BS on depression-like behavior in mice subjected to unpredictable chronic mild stress (UCMS) to clarify the antidepressant-like activity of BS and the molecular mechanism underlying this effect. UCMS mice were administered BS daily (300 mg of dried herb weight/kg, p.o.) or a reference drug, imipramine (IMP, 10 mg/kg, i.p.), 1 week after starting the UCMS procedure. We employed the sucrose preference test and the tail suspension test to analyze anhedonia and depression-like behavior of mice, respectively. Serum and brain tissues of mice were used for neurochemical and immunohistochemical studies. The UCMS procedure induced anhedonia and depression-like behavior, and BS treatment, as well as IMP treatment, attenuated these symptoms. UCMS caused an elevation of serum corticosterone level, an index of hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis, in a manner attenuated by BS and IMP treatment. BS treatment also attenuated UCMS-induced decrease in the expression levels of brain-derived neurotrophic factor (BDNF) mRNA, cyclic AMP-responsive element binding protein (CREB) and a phosphorylated form of N-methyl-d-aspartate receptor subunit NR1, synaptic plasticity-related signaling proteins. Moreover, the UCMS procedure reduced doublecortin-positive cells in the dentate gyrus region of the hippocampus. BS administration reversed these UCMS-induced neurochemical and histological abnormalities. These results suggest that BS can ameliorate chronic stress-induced depression-like symptoms and that the effects of BS are mediated by restoring dysfunctions of the HPA axis and synaptic plasticity-related signaling systems and neurogenesis in the hippocampus. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chronic corticosterone administration effects on behavioral emotionality in female c57bl6 mice.

PubMed

Mekiri, Maryam; Gardier, Alain M; David, Denis J; Guilloux, Jean-Philippe

2017-04-01

Understanding the pathophysiology of affective disorders and their treatment relies on the availability of experimental models that mimic aspects of the disease. Most of the studies on depressive disorders are conducted with male rodents, mostly because including females in protocols is more difficult. Indeed, there is a complex series of changes in the brain of females due to the estrous cycle, adding an important variability factor to the disease. However, twice as many women as men have a lifetime diagnosis of major depressive disorder (MDD), so we need to develop reliable female models of depression to improve our understanding of this disease. Here, we describe the effects of chronic corticosterone administration (CORT) on female mice, a procedure known to enhance behavioral emotionality in male mice. A dose-response study showed that 4 weeks of CORT exposure at 35 μg/ml in the drinking water enhanced the emotionality score of female mice, but with a very small size effect. Tests of longer treatment duration failed to potentiate the behavioral effects of CORT. As some steps of adult hippocampal neurogenesis are known to be sensitive to chronic CORT exposure, cell proliferation and survival, as well as neuronal maturation in the dentate gyrus of the hippocampus, analyses revealed no effect of chronic CORT exposure in female mice. Overall, this study showed that female C57BL6 mice are insensitive to chronic CORT as a way to model anxio-depressive-like behavior. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Liver X receptor β in the hippocampus: A potential novel target for the treatment of major depressive disorder?

PubMed

Peng, Zhengwu; Deng, Bin; Jia, Ji; Hou, Wugang; Hu, Sheng; Deng, Jiao; Lin, Wei; Hou, Lichao; Sang, Hanfei

2018-06-01

Liver X receptors (LXRs), including LXRα and LXRβ isoforms, have been implicated in multiple physiological functions including promoting neurogenesis, improving synaptic plasticity, preventing neurodegeneration, inhibiting inflammation as well as regulating cholesterol metabolism. However, a potential role of LXRs in the treatment of major depressive disorder (MDD) has never been investigated previously. Our present results demonstrated that levels of hippocampal LXRβ but not LXRα were down-regulated in rats exposed to chronic unpredictable stress (CUS) and were negatively correlated with the severity of CUS-induced depressive-like behaviors. Furthermore, rats with LXRβ knockdown by short hairpin RNA (shRNA) in hippocampus displayed depressive-like behaviors and impaired hippocampal neurogenesis similar to those observed after CUS exposure. Conversely, LXRs activation by GW3965 (GW), a synthetic dual agonist for both LXRα and LXRβ isoforms, could improve depression-like behaviors and reverse the impaired hippocampal neurogenesis in rats exposed to CUS. LXRβ knockdown by shRNA completely abrogated the antidepressant and hippocampal neurogenesis-promoting effects of GW, suggesting that LXRβ isoform mediated the antidepressant and hippocampal neurogenesis-promoting effects of the LXRα/β dual agonist. However, ablation of hippocampal neurogenesis with x-irradiation only partly but not completely abolished the antidepressant effects of GW in the behavioral tests, implying that the antidepressant effects mediated by LXRβ isoform are likely through both neurogenesis-dependent and -independent pathways. Thus, our findings suggest that LXRβ activation may represent a potential novel target for the treatment of MDD and also provide a novel insight into the underlying mechanisms of MDD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions.

PubMed

Tashiro, Tomoyuki; Murakami, Yuki; Mouri, Akihiro; Imamura, Yukio; Nabeshima, Toshitaka; Yamamoto, Yasuko; Saito, Kuniaki

2017-01-15

l-Tryptophan (TRP) is metabolized via serotonin and kynurenine pathways (KP). Several studies have demonstrated that abnormality of both pathways is involved in the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the KP, has been suggested to play major roles in physiological and pathological events mediated by bioactive kynurenine metabolites. In this study, we investigated the role of KMO in the emotional and cognitive functions by using KMO knockout (KO) mice. We measured contents of TRP and monoamines and their metabolites in the serum and hippocampus of KMO KO mice. Further, we investigated whether antidepressants improved the depressive-like behaviors in KMO KO mice. KMO KO mice showed depressive-like behaviors such as decreased sucrose preference and increased immobility in the forced swimming test and high anxiety by decreased time spent in the center area of open field. But, there was no difference in spontaneous alternation in Y-maze test, counts of rearing or locomotor activity. Higher contents of TRP metabolites such as kynurenine (KYN), kynurenic acid (KA), anthranilic acid (AA), and 3-hydroxykynurenine (3-HK) in the serum and hippocampus and decreased serotonin turnover and higher content of normetanephrine (NM) in the hippocampus were observed in the KMO KO mice. Although both antidepressant attenuated increase of immobility, sertraline but not imipramine improved decrease of sucrose preference in the KMO KO mice. These findings suggested that KMO KO mice show antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions via abnormality of kynurenine metabolism with good validities as MDD model. Copyright © 2016 Elsevier B.V. All rights reserved.

Alterations in affective behavior during the time course of alcohol hangover.

PubMed

Karadayian, Analía G; Busso, María J; Feleder, Carlos; Cutrera, Rodolfo A

2013-09-15

Alcohol hangover is a temporary state described as the unpleasant next-day effects after binge-like drinking. Hangover begins when ethanol is absent in plasma and is characterized by physical and psychological symptoms. Affective behavior is impaired during the acute phase of alcohol intoxication; however, no reports indicate if similar effects are observed during withdrawal. The aim of this work was to study the time-extension and possible fluctuations in affective behavior during a hangover episode. Male Swiss mice were injected i.p. either with saline (control group) or with ethanol (3.8g/kg BW) (hangover group). Anxiety, fear-related behavior and despair phenotype were evaluated at a basal point (ZT0) and every 2h up to 20h after blood alcohol levels were close to zero (hangover onset). Also, anhedonia signs and pain perception disabilities were studied. Mice exhibited an increase in anxiety-like behavior during 4h and 14h after hangover onset when evaluated by the elevated-plus maze and open field test respectively (p<0.05). Fear-related behavior was detected in hangover animals by the increase of freezing and decrease of line crossings and rearing frequency during 16h after hangover onset (p<0.001). Depression signs were found in hangover mice during 14h (p<0.05). Hangover mice showed a significant decrease in pain perception when tested by tail immersion test at the beginning of hangover (p<0.05). Our findings demonstrate a time-extension between 14 and 16h for hangover affective impairments. This study shows the long lasting effects of hangover over the phase of ethanol intoxication. Copyright © 2013 Elsevier B.V. All rights reserved.

Primary Care Providers’ Initial Treatment Decisions and Antidepressant Prescribing for Adolescent Depression

PubMed Central

Radovic, Ana; Farris, Coreen; Reynolds, Kerry; Reis, Evelyn C.; Miller, Elizabeth; Stein, Bradley D.

2014-01-01

OBJECTIVE Adolescent depression is a serious and undertreated public health problem. Nonetheless, pediatric primary care providers (PCPs) may have low rates of antidepressant prescribing due to structural and training barriers. We examined the impact of symptom severity and provider characteristics on initial depression treatment decisions in a setting with fewer structural barriers, an integrated behavioral health network. METHOD We administered a cross sectional survey to 58 PCPs within a large pediatric practice network. We compared PCP reports of initial treatment decisions in response to two vignettes describing depressed adolescents with either moderate or severe symptoms. We measured PCP depression knowledge, attitudes toward addressing psychosocial concerns, demographics, and practice characteristics. RESULTS Few PCPs (25% for moderate, 32% for severe) recommended an antidepressant. Compared with treatment recommendations for moderate depression, severe depression was associated with a greater likelihood of child psychiatry referral (OR 5.50[95% CI 2.47-12.2] p<.001). Depression severity did not affect the likelihood of antidepressant recommendation (OR 1.58[95% CI 0.80-3.11] p=.19). Antidepressants were more likely to be recommended by PCPs with greater depression knowledge (OR 1.72[95% CI 1.14-2.59] p=.009) and access to an on-site mental health provider (OR 5.13[95% CI 1.24-21.2] p=.02) and less likely to be recommended by PCPs who reported higher provider burden when addressing psychosocial concerns (OR 0.85[95% CI 0.75-0.98] p=.02). CONCLUSION PCPs infrequently recommended antidepressants for adolescents, regardless of depression severity. Continued PCP support through experiential training, accounting for provider burden when addressing psychosocial concerns, and co-management with mental health providers may increase PCPs’ antidepressant prescribing. PMID:24336091

Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and "depressed" mice exposed to chronic mild stress.

PubMed

Franceschelli, A; Sens, J; Herchick, S; Thelen, C; Pitychoutis, P M

2015-04-02

During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3mg/kg at 30 min and 5mg/kg at 24h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

A medicinal herb, Melissa officinalis L. ameliorates depressive-like behavior of rats in the forced swimming test via regulating the serotonergic neurotransmitter.

PubMed

Lin, Shih-Hang; Chou, Mei-Ling; Chen, Wei-Cheng; Lai, Yi-Syuan; Lu, Kuan-Hung; Hao, Cherng-Wei; Sheen, Lee-Yan

2015-12-04

Depression is a serious psychological disorder that causes extreme economic loss and social problems. However, the conventional medications typically cause side effects that result in patients opting to out of therapy. Lemon balm (Melissa officinalis L., MO) is an old and particularly reliable medicinal herb for relieving feelings of melancholy, depression and anxiety. The present study aims to investigate the antidepressant-like activity of water extract of MO (WMO) by evaluating its influence on the behaviors and the relevant neurotransmitters of rats performed to forced swimming test. Two phases of the experiment were conducted. In the acute model, rats were administered ultrapure water (control), fluoxetine, WMO, or the indicated active compound (rosmarinic acid, RA) three times in one day. In the sub-acute model, rats were respectively administered ultrapure water (control), fluoxetine, or three dosages of WMO once a day for 10 days. Locomotor activity and depression-like behavior were examined using the open field test and the forced swimming test, respectively. The levels of relevant neurotransmitters and their metabolites in the frontal cortex, amygdala, hippocampus, and striatum were analyzed by high performance liquid chromatography. In the acute model, WMO and RA significantly reduced depressive-like behavior but the type of related neurotransmitter could not be determined. The results indicated that the effect of WMO administration on the reduction of immobility time was associated with an increase in swimming time of the rats, indicative of serotonergic neurotransmission modulation. Chromatography data validated that the activity of WMO was associated with a reduction in the serotonin turnover rate. The present study shows the serotonergic antidepressant-like activity of WMO. Hence, WMO may offer a serotonergic antidepressant activity to prevent depression and to assist in conventional therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.

The relationship between self-report of depression and media usage

PubMed Central

Block, Martin; Stern, Daniel B.; Raman, Kalyan; Lee, Sang; Carey, Jim; Humphreys, Ashlee A.; Mulhern, Frank; Calder, Bobby; Schultz, Don; Rudick, Charles N.; Blood, Anne J.; Breiter, Hans C.

2014-01-01

Depression is a debilitating condition that adversely affects many aspects of a person's life and general health. Earlier work has supported the idea that there may be a relationship between the use of certain media and depression. In this study, we tested if self-report of depression (SRD), which is not a clinically based diagnosis, was associated with increased internet, television, and social media usage by using data collected in the Media Behavior and Influence Study (MBIS) database (N = 19,776 subjects). We further assessed the relationship of demographic variables to this association. These analyses found that SRD rates were in the range of published rates of clinically diagnosed major depression. It found that those who tended to use more media also tended to be more depressed, and that segmentation of SRD subjects was weighted toward internet and television usage, which was not the case with non-SRD subjects, who were segmented along social media use. This study found that those who have suffered either economic or physical life setbacks are orders of magnitude more likely to be depressed, even without disproportionately high levels of media use. However, among those that have suffered major life setbacks, high media users—particularly television watchers—were even more likely to report experiencing depression, which suggests that these effects were not just due to individuals having more time for media consumption. These findings provide an example of how Big Data can be used for medical and mental health research, helping to elucidate issues not traditionally tested in the fields of psychiatry or experimental psychology. PMID:25309388

The relationship between self-report of depression and media usage.

PubMed

Block, Martin; Stern, Daniel B; Raman, Kalyan; Lee, Sang; Carey, Jim; Humphreys, Ashlee A; Mulhern, Frank; Calder, Bobby; Schultz, Don; Rudick, Charles N; Blood, Anne J; Breiter, Hans C

2014-01-01

Depression is a debilitating condition that adversely affects many aspects of a person's life and general health. Earlier work has supported the idea that there may be a relationship between the use of certain media and depression. In this study, we tested if self-report of depression (SRD), which is not a clinically based diagnosis, was associated with increased internet, television, and social media usage by using data collected in the Media Behavior and Influence Study (MBIS) database (N = 19,776 subjects). We further assessed the relationship of demographic variables to this association. These analyses found that SRD rates were in the range of published rates of clinically diagnosed major depression. It found that those who tended to use more media also tended to be more depressed, and that segmentation of SRD subjects was weighted toward internet and television usage, which was not the case with non-SRD subjects, who were segmented along social media use. This study found that those who have suffered either economic or physical life setbacks are orders of magnitude more likely to be depressed, even without disproportionately high levels of media use. However, among those that have suffered major life setbacks, high media users-particularly television watchers-were even more likely to report experiencing depression, which suggests that these effects were not just due to individuals having more time for media consumption. These findings provide an example of how Big Data can be used for medical and mental health research, helping to elucidate issues not traditionally tested in the fields of psychiatry or experimental psychology.

IL-17A causes depression-like symptoms via NFκB and p38MAPK signaling pathways in mice: Implications for psoriasis associated depression.

PubMed

Nadeem, Ahmed; Ahmad, Sheikh F; Al-Harbi, Naif O; Fardan, Ali S; El-Sherbeeny, Ahmed M; Ibrahim, Khalid E; Attia, Sabry M

2017-09-01

Psoriasis has been shown to be associated with an increased prevalence of comorbid major depression. IL-17A plays an important role in both depression and psoriasis. IL-17A has been shown to be elevated in systemic circulation of psoriatic patients. IL-17A released from different immune cells during psoriasis may be responsible for the development of neuropsychiatric symptoms associated with depression. Therefore, this study explored the association of systemic IL-17A with depression. The present study utilized imiquimod model of psoriatic inflammation as well as IL-17A administration in mice to investigate the effect of IL-17A on depression-like behavior. Psoriatic inflammation led to enhanced IL-17A expression in peripheral immune cells of both innate and adaptive origin. This was associated with increased NFκB/p38MAPK signaling and inflammatory mediators in different brain regions, and depression-like symptoms (as reflected by sucrose preference and tail suspension tests). The role of IL-17A was further confirmed by administering it alone for ten days, followed by assessment of the same parameters. IL-17A administration produced effects similar to psoriasis-like inflammation on neurobehavior and NFκB/p38MAPK pathways. Moreover, both NFκB and p38MAPK inhibitors led to attenuation in IL-17A associated with depression-like behavior via reduction in inflammatory mediators, such as MCP-1, iNOS, IL-6, and CXCL-2. Furthermore, anti-IL17A antibody also led to a reduction in imiquimod-induced depression-like symptoms, as well as NFκB/p38MAPK signaling. The present study shows that IL-17A plays an important role in comorbid depression associated with psoriatic inflammation, where both NFκB and p38MAPK pathways play significant roles via upregulation of inflammatory mediators in the brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Opposing Effects of Acute versus Chronic Blockade of Frontal Cortex Somatostatin-Positive Inhibitory Neurons on Behavioral Emotionality in Mice

PubMed Central

Soumier, Amelie; Sibille, Etienne

2014-01-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons. PMID:24690741

Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice.

PubMed

Soumier, Amelie; Sibille, Etienne

2014-08-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons.

Cellular and molecular basis for stress-induced depression.

PubMed

Seo, J-S; Wei, J; Qin, L; Kim, Y; Yan, Z; Greengard, P

2017-10-01

Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2 + ) glutamatergic neurons. Viral expression of p11 in D2 + PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2 + neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2 + PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.

An Ω-3 fatty acid-deficient diet during gestation induces depressive-like behavior in rats: the role of the hypothalamo-pituitary-adrenal (HPA) system.

PubMed

Tang, Mimi; Liu, Yiping; Wang, Lu; Li, Huande; Cai, Hualin; Zhang, Min; Dang, Ruili; Xue, Ying; Wu, Yanqin

2018-06-08

Low intake of omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) especially docosahexaenoic acid (DHA) is associated with postpartum depression. DHA deficiency is accompanied by impaired attention and cognition, and will precipitate psychiatric symptoms. However, the effects of dietary DHA on postpartum depression remain unclear. We established a normal pregnancy model to evaluate whether an Ω-3 PUFA-deficient diet during gestation could induce depressive-like behavior and aggravate dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in rats. A between-group design was used to assess the effects of Ω-3 PUFA content (deficiency, control and supplementary) and reproductive status (virgin or parous). We assessed depressive-like behavior and measured the fatty acid composition in the liver. The protein expressions of glucocorticoid receptor (GR) and mineralocorticoid receptor (MCR) were also measured to evaluate the HPA activity. Exposure to the Ω-3 PUFA-deficient diet resulted in an increased immobility time in a forced swimming test (FST). Additionally, our results firstly showed the decreased expression of GR in the hippocampus of parous rats that were exposed to Ω-3 PUFA-deficient diets, which may partly facilitate the hyperactivity of the HPA axis and exert detrimental effects. Moreover, the reduction of GR was ameliorated by Ω-3 PUFA supplementation, providing new evidence for Ω-3 PUFAs in the progression of postpartum depression.

Unpredictable chronic mild stress induces anxiety and depression-like behaviors and inactivates AMP-activated protein kinase in mice.

PubMed

Zhu, Shenghua; Wang, Junhui; Zhang, Yanbo; Li, Victor; Kong, Jiming; He, Jue; Li, Xin-Min

2014-08-12

The unpredictable chronic mild stress (UCMS) model was developed based upon the stress-diathesis hypothesis of depression. Most effects of UCMS can be reversed by antidepressants, demonstrating a strong predictive validity of this model for depression. However, the mechanisms underlying the effects induced by UCMS remain incompletely understood. Increasing evidence has shown that AMP-activated protein kinase (AMPK) regulates intracellular energy metabolism and is especially important for neurons because neurons are known to have small energy reserves. Abnormalities in the AMPK pathway disturb normal brain functions and synaptic integrity. In the present study, we first investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in female C57BL/6N mice after 4 weeks of UCMS exposure. Stressed mice showed suppressed body weight gain, heightened anxiety, and increased immobility in the forced swim and tail suspension tests. These results are representative of some of the core symptoms of depression. Simultaneously, we observed decrease of synaptic proteins in the cortex of mice subjected to UCMS, which is associated with decreased levels of phosphorylated AMP-activated protein kinase α (AMPKα) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). Our findings suggest that AMPKα inactivation might be a mechanism by which UCMS causes anxiety/depression-like behaviors in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Alterations on the morphology, nitric oxide synthesis and activity of platelets reproduced in rats as possible biomarkers for depression are reversed by fluoxetine.

PubMed

González-Trujano, María Eva; Alvarado-Vásquez, Noé; Mendoza-Sotelo, José; López, Guadalupe; Estrada-Camarena, Erika; Martínez-Mota, Lucia; Moreno, Julia

2012-08-01

Biochemical markers associated with the prognosis of depression in humans are being described in the literature, whereas experimental studies in animal models in search for antidepressant strategies are lacking. The aim of this study was to evaluate platelet morphology, platelet activity and nitric oxide (NO) synthesis as possible biomarkers of depressive-like behavior by using FST alone and in the presence of fluoxetine. Naïve rats were compared to those receiving vehicle or fluoxetine at 10mg/kg i.p. in acute, subchronic and chronic administration in the FST. After behavioral assessment, platelets were isolated from blood samples and analyzed by flow cytometry to determine the platelet mitochondrial membrane potential and NO synthesis. In addition, HPLC and electron microscopy were used to examine 5-HT and tryptophan levels and morphology of platelets, respectively. Rats receiving vehicle and exposed to FST showed depressive-like behavior at all the times tested; after chronic FST rats showed a similar pattern of alteration in platelet morphology and in the studied as possible biochemical markers as those previously recognized in depressive humans. Depressive-like behavior in rats exposed to FST was prevented in the presence of fluoxetine administration at all the times tested and associated with the prevention of alterations in platelet morphology, platelet activity and NO synthesis, and/or in 5-HT concentrations. The results of the present study suggest that platelet function and morphology might be relevant markers for the prognosis of depression and the search for functional treatments. Besides, the relevance of FST as model to study this psychiatric illness is reinforced. Copyright © 2012 Elsevier Inc. All rights reserved.

S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression.

PubMed

du Jardin, Kristian G; Liebenberg, Nico; Cajina, Manuel; Müller, Heidi K; Elfving, Betina; Sanchez, Connie; Wegener, Gregers

2017-01-01

Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT 1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT 1B heteroreceptors in the antidepressant-like activity of S -ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S -ketamine (15 mg/kg) and the selective 5-HT 1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S -ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S -ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S -ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S -ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S -ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT 1B receptor activation during testing appears to be critical for S -ketamine's antidepressant-like potentials in this model.

Long-term effects of early adolescent methamphetamine exposure on depression-like behavior and the hypothalamic vasopressin system in mice.

PubMed

Joca, Lauren; Zuloaga, Damian G; Raber, Jacob; Siegel, Jessica A

2014-01-01

Methamphetamine (MA) has neurotoxic effects on the adult human brain that can lead to deficits in behavior and cognition. However, relatively little research has examined the behavioral or neurotoxic effects of MA in adolescents. The rising rates of adolescent MA use make it imperative that we understand the long-term effects of MA exposure on the adolescent brain and how these effects may differ from those seen in adults. In this study, the long-term effects of MA exposure during early adolescence on behavior and the vasopressin system in the paraventricular nucleus of the hypothalamus in late adolescent and adult male and female C57BL/6J mice were examined. MA exposure increased depression-like behavior in the Porsolt forced swim test in both late adolescent and adult male and female mice. Late adolescent male mice exposed to MA also showed a decrease in the number of vasopressin-immunoreactive neurons in the paraventricular nucleus compared to sex-matched saline-treated controls. Thus, similar to humans exposed to MA during adolescence, mice exposed to MA during adolescence show increased depression-like behavior later in life. These changes in behavior may be related to MA-induced alterations in vasopressin and the hypothalamic-pituitary-adrenal axis, especially in males. 2014 S. Karger AG, Basel

Psychological Distress and Emotional Expression on Facebook.

PubMed

Bazarova, Natalya N; Choi, Yoon Hyung; Whitlock, Janis; Cosley, Dan; Sosik, Victoria

2017-03-01

Social network sites (SNS) are a novel social environment for college students with psychological distress to connect with their peers, but the nature and effects of these interactions are not well understood. This study reports findings from a Facebook study among 238 college students reporting nonspecific psychological distress using the K-6 scale. Behavioral data included Facebook status updates containing affect words written by participants within the past 60 days and the number of responses (comments and likes) each update received. The updates were also coded for depression symptoms. Self-report data included participants' self-presentational concerns, the affective valence of each post, effects of responses on mood, and satisfaction with the responses to and outcome of each status update. Higher psychological distress was associated with displaying depression language on Facebook, with higher self-presentational concerns, and with less satisfaction with audiences' responses and less overall satisfaction with the outcome of the interaction. These results offer a unique glimpse into the social world of college students with psychological distress through their everyday use of Facebook, and how the interplay of this novel environment and students' mental health impacts their social behaviors and interaction meaning-making on Facebook.

Sedentary Behavior and the Risk of Depression in Patients With Acute Coronary Syndromes.

PubMed

Zhu, Yidan; Blumenthal, James A; Shi, Chuan; Jiang, Ronghuan; Patel, Anushka; Zhang, Aihua; Yu, Xin; Gao, Runlin; Wu, Yangfeng

2018-06-15

Although there is good evidence that sedentary behavior is associated with poor health outcomes in healthy persons and patients with cardiovascular disease, the mental health consequences of sedentary behavior have not been widely studied. In this report, we conducted a cross-sectional analysis to examine the relation of self-reported sedentary behavior and depression in a sample of 4,043 hospitalized men and women with acute coronary syndrome enrolled in a randomized clinical trial in rural China. Sedentary behavior was assessed by self-report, and depression was assessed with the Patient Health Questionnaire-9 (PHQ-9); a subset of 1,209 patients also completed the Beck Depression Inventory-II. Results revealed that greater sedentary behavior was associated with higher levels of depressive symptoms measured by both the PHQ-9 (p <0.001) and the Beck Depression Inventory-II (p <0.001). Compared with patients who reported that they were seldom sedentary, patients reporting that they were frequently sedentary were 4.7 times (odds ratio 4.73, 95% confidence interval 2.71 to 8.24) more likely to be clinically depressed defined as PHQ-9 scores ≥10 after adjusting for demographic factors, lifestyle behaviors, clinical characteristics, and in-hospital treatments. In conclusion, greater sedentary behavior is significantly related to greater depression in Chinese patients with acute coronary syndrome, independent of physical activity. These findings suggest that strategies to reduce sedentary behavior may improve medical outcomes and reduce risk for depression. Copyright © 2018 Elsevier Inc. All rights reserved.

The Role of Neurotrophins in Major Depressive Disorder.

PubMed

Jiang, Cheng; Salton, Stephen R

2013-03-01

Neurotrophins and other growth factors have been advanced as critical modulators of depressive behavior. Support for this model is based on analyses of knockout and transgenic mouse models, human genetic studies, and screens for gene products that are regulated by depressive behavior and/or antidepressants. Even subtle alteration in the regulated secretion of brain-derived neurotrophic factor (BDNF), for example, due to a single nucleotide polymorphism (SNP)-encoded Val-Met substitution in proBDNF that affects processing and sorting, impacts behavior and cognition. Alterations in growth factor expression result in changes in neurogenesis as well as structural changes in neuronal cytoarchitecture, including effects on dendritic length and spine density, in the hippocampus, nucleus accumbens, and prefrontal cortex. These changes have the potential to impact the plasticity and stability of synapses in the CNS, and the complex brain circuitry that regulates behavior. Here we review the role that neurotrophins play in the modulation of depressive behavior, and the downstream signaling targets they regulate that potentially mediate these behavioral pro-depressant and antidepressant effects.

The Role of Neurotrophins in Major Depressive Disorder

PubMed Central

Jiang, Cheng; Salton, Stephen R.

2013-01-01

Neurotrophins and other growth factors have been advanced as critical modulators of depressive behavior. Support for this model is based on analyses of knockout and transgenic mouse models, human genetic studies, and screens for gene products that are regulated by depressive behavior and/or antidepressants. Even subtle alteration in the regulated secretion of brain-derived neurotrophic factor (BDNF), for example, due to a single nucleotide polymorphism (SNP)-encoded Val-Met substitution in proBDNF that affects processing and sorting, impacts behavior and cognition. Alterations in growth factor expression result in changes in neurogenesis as well as structural changes in neuronal cytoarchitecture, including effects on dendritic length and spine density, in the hippocampus, nucleus accumbens, and prefrontal cortex. These changes have the potential to impact the plasticity and stability of synapses in the CNS, and the complex brain circuitry that regulates behavior. Here we review the role that neurotrophins play in the modulation of depressive behavior, and the downstream signaling targets they regulate that potentially mediate these behavioral pro-depressant and antidepressant effects. PMID:23691270

Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like behaviors.

PubMed

Ramirez, Karol; Sheridan, John F

2016-10-01

In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced social avoidance behavior, and down-regulated microglial activation 24days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive-like behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like behaviors

PubMed Central

Ramirez, Karol; Sheridan, John F.

2016-01-01

In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced social avoidance behavior, and down-regulated microglial activation 24 days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive-like behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress. PMID:27223094

Tobacco exposure and maternal psychopathology: Impact on toddler problem behavior.

PubMed

Godleski, Stephanie A; Eiden, Rina D; Schuetze, Pamela; Colder, Craig R; Huestis, Marilyn A

Prenatal exposure to tobacco has consistently predicted later problem behavior for children. However, little is known about developmental mechanisms underlying this association. We examined a conceptual model for the association between prenatal tobacco exposure and child problem behavior in toddlerhood via indirect paths through fetal growth, maternal depression, and maternal aggressive disposition in early infancy and via maternal warmth and sensitivity and infant negative affect in later infancy. The sample consisted of 258 mother-child dyads recruited during pregnancy and assessed periodically at 2, 9, and 16months of child age. Pathways via maternal depression and infant negative affect to toddler problem behavior were significant. Further, combined tobacco and marijuana exposure during pregnancy and reduced fetal growth also demonstrated important associations with infant negative affect and subsequent problem behavior. These results highlight the importance of considering the role of maternal negative affect and poor fetal growth as risk factors in the context of prenatal exposure. Copyright © 2016. Published by Elsevier Inc.

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice.

PubMed

Ito, Naoki; Hirose, Eiji; Ishida, Tatsuya; Hori, Atsushi; Nagai, Takayuki; Kobayashi, Yoshinori; Kiyohara, Hiroaki; Oikawa, Tetsuro; Hanawa, Toshihiko; Odaguchi, Hiroshi

2017-05-03

Kososan, a Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. However, evidence for the antidepressant efficacy of kososan and potential mechanisms are lacking. Recently, it has been recognized that stress triggers neuroinflammation and suppresses adult neurogenesis, leading to depression and anxiety. Here, we examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS. In the CSDS paradigm, C57BL/6J mice were exposed to 10 min of social defeat stress from an aggressive CD-1 mouse for 10 consecutive days (days 1-10). Kososan extract (1.0 g/kg) was administered orally once daily for 12 days (days 1-12). On day 11, the social avoidance test was performed to examine depressive- and anxious-like behaviors. To characterize the impacts of kososan on neuroinflammation and adult neurogenesis, immunochemical analyses and ex vivo microglial stimulation assay with lipopolysaccharide (LPS) were performed on days 13-15. Oral administration of kososan extract alleviated social avoidance, depression- and anxiety-like behaviors, caused by CSDS exposure. CSDS exposure resulted in neuroinflammation, as indicated by the increased accumulation of microglia, the resident immune cells of the brain, and their activation in the hippocampus, which was reversed to normal levels by treatment with kososan extract. Additionally, in ex vivo studies, CSDS exposure potentiated the microglial pro-inflammatory response to a subsequent LPS challenge, an effect that was also blunted by kososan extract treatment. Indeed, the modulatory effect of kososan extract on neuroinflammation appears to be due to a hippocampal increase in an anti-inflammatory phenotype of microglia while sparing an increased pro-inflammatory phenotype of microglia caused by CSDS. Moreover, reduced adult hippocampal neurogenesis in defeated mice was recovered by kososan extract treatment. Our findings suggest that kososan extract prevents a social avoidant behavior in socially defeated mice that is partially mediated by the downregulation of hippocampal neuroinflammation, presumably by the relative increased anti-inflammatory microglia and regulation of adult hippocampal neurogenesis. Our present study also provides novel evidence for the beneficial effects of kososan on depression/anxiety and the possible underlying mechanisms.

Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection.

PubMed

Bai, Yongtao; Song, Lihua; Dai, Guoliang; Xu, Meijuan; Zhu, Lijing; Zhang, Weidong; Jing, Wen; Ju, Wenzheng

2018-07-01

Evidence showed that the stress hormone corticosterone (CORT) injection resulted in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis implicated in major depressive disorder. Magnolol, main constituent identified in the barks of Magnolia officinalis, exerted antidepressant effects in a rat model of depression induced by chronic unpredictable mild stress in previous studies. However, its antidepressant-like effects and mechanisms have never been studied in depression model induced by CORT administration in rodents. This study aimed to investigate the antidepressant-like effects and possible mechanisms of magnolol in CORT-treated mice by utilizing a combination of behavioral and biochemical analysis. The depressive model was developed by subcutaneous injection of CORT for 21 days at a dose of 20 mg/kg. CORT administration formed depressive-like behaviors in mice, as indicated by increased immobility time in the forced swim test (FST) and tail suspension test (TST), as well as decreased sucrose intake in sucrose preference test (SPT). Moreover, we also found that CORT levels in serum were significantly increased, along with the decrease of brain-derived neurotrophic factor (BDNF) mRNA, BDNF protein, 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels in the hippocampus. Treatment with magnolol alleviated depressive-like behaviors, reduced the levels of CORT, and improved the levels of BDNF protein, 5-HT, and NE compared with those in CORT-treated mice. These findings indicated that magnolol possessed antidepressant effects in mice exposed to CORT, which might be partially related to modulate HPA axis, up-regulate BDNF expression and increase neurotransmitters levels in the hippocampus. Copyright © 2018 Elsevier Inc. All rights reserved.

Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression

PubMed Central

Meylan, E M; Breuillaud, L; Seredenina, T; Magistretti, P J; Halfon, O; Luthi-Carter, R; Cardinaux, J-R

2016-01-01

Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression. PMID:27404284

Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.

PubMed

Meylan, E M; Breuillaud, L; Seredenina, T; Magistretti, P J; Halfon, O; Luthi-Carter, R; Cardinaux, J-R

2016-07-12

Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1(-/-) mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1(-/-) mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1(-/-) prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1(-/-) mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1(-/-) mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

PubMed Central

Pandya, Chirayu D; Hoda, Nasrul; Crider, Amanda; Peter, Diya; Kutiyanawalla, Ammar; Kumar, Sanjiv; Ahmed, Anthony O; Turecki, Gustavo; Hernandez, Caterina M; Terry, Alvin V

2016-01-01

Serotonin (5-HT) and brain derived neurotrophic factor (BDNF) are two signaling molecules that play important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B) levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of transglutaminase 2 (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the postmortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2 overexpressed mice. Taken together, these postmortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression. PMID:27620841

National study of the role of recent illicit substance use on the relationship between depressive symptoms and sexual risk behavior among child welfare-involved adolescents.

PubMed

Traube, Dorian; Holloway, Ian; Zhang, Jinjin

2013-07-01

The present study examined the association between early-adolescent depressive symptoms and lifetime sexual risk behavior and whether that association was moderated by recent illicit substance use among adolescents reported for maltreatment. Data came from Waves 1 (baseline) and 4 (36-month follow-up) of the National Survey of Child and Adolescent Well-Being, a national probability study of youths undergoing investigation for abuse or neglect (n = 861). Multivariate logistic regression was used to explore main effects and moderation models among baseline depressive symptoms, lifetime sexual risk behavior, and recent illicit substance use. Baseline depressive symptoms and recent illicit drug use played little role in predicting ever having intercourse, age at first intercourse, or pregnancy. Recent use of illicit substances moderated the relationship between early-adolescent depressive symptoms and condom use behavior (odds ratio = 0.85, p < .001) such that individuals who were more depressed at baseline and who used illicit drugs within the last 30 days were less likely to have often/always used condoms. Conversely, individuals with higher levels of depressive symptoms at baseline who had not engaged in illicit substance use in the last 30 days were more likely to often use condoms during sexual activity. Results suggest that among adolescents reported for maltreatment, use of illicit substances may moderate the relationship between elevated levels of depressive symptoms during early adolescence and condom use as children age thorough adolescence. Interventions for child welfare-engaged youths should focus on prevention and treatment of depression and substance use.

Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression.

PubMed

Li, Lu-Fan; Yang, Jie; Ma, Shi-Ping; Qu, Rong

2013-07-05

Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain. Copyright © 2013 Elsevier B.V. All rights reserved.

PhenoWorld: a new paradigm to screen rodent behavior

PubMed Central

Castelhano-Carlos, M; Costa, P S; Russig, H; Sousa, N

2014-01-01

Modeling depression in animals has inherent complexities that are augmented by intrinsic difficulties to measure the characteristic features of the disorder. Herein, we describe the PhenoWorld (PhW), a new setting in which groups of six rats lived in an ethological enriched environment, and have their feeding, locomotor activity, sleeping and social behavior automatically monitored. A battery of emotional and cognitive tests was used to characterize the behavioral phenotype of animals living in the PhW and in standard conditions (in groups of six and two rats), after exposure to an unpredictable chronic mild stress paradigm (uCMS) and antidepressants. Data reveal that animals living in the PhW displayed similar, but more striking, behavioral differences when exposed to uCMS, such as increased behavioral despair shown in the forced swimming test, resting/sleep behavior disturbances and reduced social interactions. Moreover, several PhW-cage behaviors, such as spontaneous will to go for food or exercise in running wheels, proved to be sensitive indicators of depressive-like behavior. In summary, this new ethological enriched paradigm adds significant discriminative power to screen depressive-like behavior, in particularly rodent's hedonic behavior. PMID:26126181

Evaluation of the Neurobehavioral Properties of Naringin in Swiss Mice.

PubMed

Ben-Azu, Benneth; Nwoke, Ekene Enekabokom; Umukoro, Solomon; Aderibigbe, Adegbuyi Oladele; Ajayi, Abayomi Mayowa; Iwalewa, Ezekiel O

2018-03-12

This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice. The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test. Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice. These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice. © Georg Thieme Verlag KG Stuttgart · New York.

Animal models of extinction-induced depression: loss of reward and its consequences.

PubMed

Huston, Joseph P; Silva, Maria A de Souza; Komorowski, Mara; Schulz, Daniela; Topic, Bianca

2013-11-01

The absence or loss of rewards or reinforcers holds a major role in the development of depression in humans. In spite of the prevalence of extinction-induced depression (EID) in humans, few attempts have been made to establish animal models thereof. Here we present the concept of extinction-related depression and summarize the results of two sets of studies in our attempt to create animal models of EID, one set based on extinction after positive reinforcement in the Skinner-box, the other on extinction after negative reinforcement - escape from water. We found various behaviors emitted during the extinction trials that responded to treatment with antidepressant drugs: Accordingly, the important behavioral marker for EID during extinction of escape from the water was immobility. During extinction after positive reinforcement the important indices for extinction-induced depression are the withdrawal from the former site of reward, biting behavior and rearing up on the hind legs. Avoidance behavior and biting may model aspects of human depressive behavior, which may include withdrawal or avoidance as well as aggressive-like behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Maternal neglect with reduced depressive-like behavior and blunted c-fos activation in Brattleboro mothers, the role of central vasopressin.

PubMed

Fodor, Anna; Klausz, Barbara; Pintér, Ottó; Daviu, Nuria; Rabasa, Cristina; Rotllant, David; Balazsfi, Diana; Kovacs, Krisztina B; Nadal, Roser; Zelena, Dóra

2012-09-01

Early mother-infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c-fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking-grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim-stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Depression in heart failure: Intricate relationship, pathophysiology and most updated evidence of interventions from recent clinical studies.

PubMed

Ghosh, Raktim K; Ball, Somedeb; Prasad, Vinita; Gupta, Anjan

2016-12-01

Heart failure (HF) is a burgeoning chronic health condition affecting more than 20million people worldwide. Patients with HF have a significant (17.1%) 30-day readmission rate, which invites substantial penalty in payment to hospitals from Centers for Medicare and Medicaid Services, as per the newly introduced Hospital Readmissions Reduction Program. Depression is one of the important risk factors for readmission in HF patients. It has a significant prevalence in patients with HF and contributes to the overall poor quality of life in them. Several behavioral (smoking, obesity, lack of exercise and medication noncompliance) and pathophysiological factors (hypercortisolism, elevated inflammatory biomarkers, fibrinogen, and atherosclerosis) have been found responsible for the adverse outcome in patients with HF and concomitant depression. Hippocampal volume loss noted in patients with acute HF exacerbations may contribute to the development of depressive symptoms in them. Screening for depression in HF patients continues to be challenging due to a considerable overlap in symptoms. Published trials on the use of antidepressants and cognitive behavioral therapy (CBT) have shown variable outcomes. Newer modalities like internet-based CBT have been tried in small studies, with promising results. A recent meta-analysis observed the beneficial role of aerobic exercise training in patients with HFrEF. Future long-term prospective studies may contribute to the formulation of a detailed screening and management guideline for patients with HF and depression. Our review is aimed to summarize the intricate relationship between depression and heart failure, with respect to their epidemiology, pathophysiological aspects, and optimal management approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition.

PubMed

Grieco, Steven F; Cheng, Yuyan; Eldar-Finkelman, Hagit; Jope, Richard S; Beurel, Eléonore

2017-01-04

An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803-mts was sufficient to up-regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non-depressed) and those that were susceptible (depressed). Non-depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression-like behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition

PubMed Central

Grieco, Steven F.; Cheng, Yuyan; Eldar-Finkelman, Hagit; Jope, Richard S.; Beurel, Eléonore

2016-01-01

An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10 mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803-mts was sufficient to up-regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non-depressed) and those that were susceptible (depressed). Non-depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression-like behavior. PMID:27542584

Startle response memory and hippocampal changes in adult zebrafish pharmacologically-induced to exhibit anxiety/depression-like behaviors.

PubMed

Pittman, Julian T; Lott, Chad S

2014-01-17

Zebrafish (Danio rerio) are rapidly becoming a popular animal model for neurobehavioral and psychopharmacological research. While startle testing is a well-established assay to investigate anxiety-like behaviors in different species, screening of the startle response and its habituation in zebrafish is a new direction of translational biomedical research. This study focuses on a novel behavioral protocol to assess a tapping-induced startle response and its habituation in adult zebrafish that have been pharmacologically-induced to exhibit anxiety/depression-like behaviors. We demonstrated that zebrafish exhibit robust learning performance in a task adapted from the mammalian literature, a modified plus maze, and showed that ethanol and fluoxetine impair memory performance in this maze when administered after training at a dose that does not impair motor function, however, leads to significant upregulation of hippocampal serotoninergic neurons. These results suggest that the maze associative learning paradigm has face and construct validity and that zebrafish may become a translationally relevant study species for the analysis of the mechanisms of learning and memory changes associated with psychopharmacological treatment of anxiety/depression. © 2013.

Housing environment influences stress-related hippocampal substrates and depression-like behavior.

PubMed

Ashokan, Archana; Hegde, Akshaya; Balasingham, Anushanthy; Mitra, Rupshi

2018-03-15

Rats are widely used animal models for biological psychiatry and neuroscience. Laboratory rats are typically housed in impoverished sensory environments. The lack of species-typical sensory environment might radically change the response of individual animals to stressful and/or threatening episodes. In this report, we demonstrate that behavioral and neural sequelae of chronic stress were modified by sensory environment of adult male rats. This includes effects of stress on the density of spines on CA3 hippocampal neurons, hippocampal neurogenesis and abundance of glucocorticoid or mineralocorticoid receptors. Enrichment also reduced depression-like behavior in a forced swim task. Stress and sensory enrichment evoked opposing effects on all the above endpoints. The sensory enrichment used in this report is of a relatively short duration provided during adulthood. This period excludes critical windows of greater plasticity during pre- and peripubertal stages. Our results suggest that standard housing practices for laboratory rats remain austere concerning sensory requirements of this species. Thus, even a moderate sensory enrichment is capable of reducing high stress-sensitivity and depressive-like behavior in standard laboratory rats. Copyright © 2018. Published by Elsevier B.V.

Conceptualizations of postpartum depression by public-sector health care providers in Mexico.

PubMed

Place, Jean Marie S; Billings, Deborah L; Blake, Christine E; Frongillo, Edward A; Mann, Joshua R; deCastro, Filipa

2015-04-01

In this article we describe the knowledge frameworks that 61 physicians, nurses, social workers, and psychologists from five public-sector health care facilities in Mexico used to conceptualize postpartum depression. We also demonstrate how providers applied social and behavioral antecedents in their conceptualizations of postpartum depression. Using grounded theory, we identify two frameworks that providers used to conceptualize postpartum depression: biochemical and adjustment. We highlight an emerging model of the function of social and behavioral antecedents within the frameworks, as well as the representation of postpartum depression by symptoms of distress and the perception among providers that these symptoms affected responsibilities associated with motherhood. The results provide a foundation for future study of how providers' conceptualizations of postpartum depression might affect detection and treatment practices and might be useful in the development of training materials to enhance the quality of care for women who experience any form of distress in the postpartum period. © The Author(s) 2014.

A history of major depressive disorder and the response to stress.

PubMed

Ilgen, Mark A; Hutchison, Kent E

2005-06-01

The occurrence of Major Depressive Disorder (MDD) has been linked to an increased vulnerability to stress. However, the specific behavioral and affective aspects that may underlie this vulnerability to stress have not been well studied. This study examined sensitivity to a stress manipulation in 62 participants, 30 with and 32 without a previous episode of MDD. Comparisons were made between those with a history of depression and those without, randomized to either the high or low stress conditions on self-report measures of affect and behavior measures of performance. A significant interaction was found between depression history and level of stress on measures of self-report tension and behavioral performance on the experimental task. Specifically, those with a history of MDD in the high stress condition reported significantly more tension than other participants. Additionally, participants in the high stress condition without a history of MDD responded to uncontrollable stress by responding at a significantly higher rate on the task while those individuals with a history of MDD responded to uncontrollable stress by maintaining a relatively low level of responding. No differences in self-report depressed affect were found. The study utilized a laboratory stressor in a sample composed primarily of college students. A history of MDD appears to be associated with an increased sensitivity to uncontrollable stress. This vulnerability may manifest itself in the subjective state of individuals (i.e., tension) or in their behavioral responses to stress.

Feeling Thanks and Saying Thanks: A Randomized Controlled Trial Examining If and How Socially Oriented Gratitude Journals Work.

PubMed

O'Connell, Brenda H; O'Shea, Deirdre; Gallagher, Stephen

2017-10-01

This study examined the effect of a reflective interpersonal gratitude journal, a reflective-behavioral interpersonal gratitude journal and an active control journal, on primary qualities of well-being and depression. Participants (n = 192; 67.2% female) completed this 3-month longitudinal randomized controlled design. Participants in the reflective-behavioral condition experienced the greatest improvements in affect balance and reductions in depression at immediate posttest. Both gratitude interventions improved affect balance at 1 month, compared to the control. Changes in affect balance for those in the reflective-behavioral condition were mediated by the rate at which people expressed gratitude in their existing relationships. This effect was moderated by participant's baseline depressive status. Expressing felt gratitude to others appears to be a crucial step in deriving benefits, and these benefits may not be limited to the emotionally healthy. Given the applied popularity of gratitude interventions, understanding not only if but also how they work is essential. © 2017 Wiley Periodicals, Inc.

Serotonin Signaling through Prefrontal Cortex 5-HT1A Receptors during Adolescence Can Determine Baseline Mood-Related Behaviors.

PubMed

Garcia-Garcia, Alvaro L; Meng, Qingyuan; Canetta, Sarah; Gardier, Alain M; Guiard, Bruno P; Kellendonk, Christoph; Dranovsky, Alex; Leonardo, E David

2017-01-31

Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT 1A receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT 1A receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT 1A heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A Cross-Sectional Study of Depressive Symptoms and Risky Alcohol Use Behaviors Among HIV Primary Care Patients in New York City.

PubMed

Algur, Yasemin; Elliott, Jennifer C; Aharonovich, Efrat; Hasin, Deborah S

2018-05-01

An association between problem drinking and depression among HIV-infected individuals has been previously demonstrated; however, which specific risky drinking behaviors are associated with higher levels of depression has not yet been investigated. Using an adult sample of HIV-infected primary care patients (78% male, 94% Black or Hispanic), we investigated whether depressive symptoms are associated with various risky drinking behaviors. Participants were administered the Beck Depression Inventory-II to assess depressive symptoms, and the Alcohol Use Disorders and Associated Disabilities Interview Schedule-IV to evaluate alcohol involvement. Participants with depressive symptoms (26%) were at higher risk for alcohol dependence [adjusted odds ratio (AOR) 3.8; 95% CI 2.0-7.2], regular binge drinking (AOR 2.0; 95% CI 1.1-3.8), and regular daytime drinking (AOR 2.1; 95% CI 1.2-3.8), in comparison with their non-depressed counterparts. Because both depression and unhealthy drinking negatively affect medication adherence and clinical outcomes, a better understanding of the association between depression and certain risky drinking behaviors among HIV-infected individuals is vital to improving their care and prognoses.

Maternal depressive symptoms and child obesity in low-income urban families.

PubMed

Gross, Rachel S; Velazco, Nerissa K; Briggs, Rahil D; Racine, Andrew D

2013-01-01

To characterize the relationship between maternal depressive symptoms and child weight status, obesity-promoting feeding practices, and activity-related behaviors in low-income urban families. We conducted a cross-sectional survey of mothers with 5-year-old children receiving pediatric care at a federally qualified community health center. We used regression analyses to examine the relationship between maternal depressive symptoms (trichotomized: none, mild, moderate to severe) and 1) child weight status; 2) obesity-promoting feeding practices, including mealtime practices and feeding styles; and 3) activity-related behaviors, including sleep time, screen time, and outdoor playtime. The sample included 401 mother-child pairs (78.3% response rate), with 23.4% of mothers reporting depressive symptoms (15.7% mild, 7.7% moderate to severe). Mothers with moderate to severe depressive symptoms were more likely to have overweight and obese children than mothers without depressive symptoms (adjusted odds ratio 2.62; 95% confidence interval 1.02-6.70). Children of mildly depressed mothers were more likely to consume sweetened drinks and to eat out at restaurants and were less likely to eat breakfast than children of nondepressed mothers. Mothers with depressive symptoms were less likely to set limits, to use food as a reward, to restrict their child's intake, and to model healthy eating than nondepressed mothers. Children with depressed mothers had less sleep and outdoor playtime per day than children of nondepressed mothers. Maternal depressive symptoms are associated with child overweight and obese status and with several obesity-promoting practices. These results support the need for maternal depression screening in pediatric obesity prevention programs. Further research should explore how to incorporate needed mental health support. Copyright © 2013 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Affective changes during the postpartum period: Influences of genetic and experiential factors.

PubMed

Agrati, Daniella; Lonstein, Joseph S

2016-01-01

This article is part of a Special Issue "Parental Care". The postpartum period involves some truly transformational changes in females' socioemotional behaviors. For most female laboratory rodents and women, these changes include an improvement in their affective state, which has positive consequences for their ability to sensitively care for their offspring. There is heterogeneity among females in the likelihood of this positive affective change, though, and some women experience elevated anxiety or depression (or in rodents anxiety- or depression-related behaviors) after giving birth. We aim to contribute to the understanding of this heterogeneity in maternal affectivity by reviewing selected components of the scientific literatures on laboratory rodents and humans examining how mothers' physical contact with her infants, genetics, history of anxiety and depression and early-life and recent-life experiences contribute to individual differences in postpartum affective states. These studies together indicate that multiple biological and environmental factors beyond female maternal state shape affective responses during the postpartum period, and probably do so in an interactive manner. Furthermore, the similar capacity of some of these factors to modulate anxiety and depression in human and rodent mothers suggests cross-species conservation of mechanisms regulating postpartum affectivity. Copyright © 2015 Elsevier Inc. All rights reserved.

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

PubMed

Thakare, Vishnu N; Aswar, Manoj K; Kulkarni, Yogesh P; Patil, Rajesh R; Patel, Bhoomika M

2017-10-01

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone. Copyright © 2017 Elsevier Inc. All rights reserved.

Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior

PubMed Central

Melendez-Ferro, Miguel; Perez-Costas, Emma; Glover, Matthew E.; Jackson, Nateka L.; Stringfellow, Sara A.; Pugh, Phyllis C.; Fant, Andrew D.; Clinton, Sarah M.

2016-01-01

Individual differences in human temperament can increase risk for psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. Using transcriptome profiling, the present study uncovered vast gene expression differences in the early postnatal HR versus LR limbic brain, including changes in genes involved in cellular metabolism. These data led us to hypothesize that rats prone to high (versus low) anxiety/depression-like behavior exhibit distinct patterns of brain metabolism during the first weeks of life, which may reflect disparate patterns of synaptogenesis and brain circuit development. Thus, in a second experiment we examined activity of Cytochrome C Oxidase (COX), an enzyme responsible for ATP production and a correlate of metabolic activity, to explore functional energetic differences in HR/LR early postnatal brain. We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes. PMID:26979051

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

PubMed

Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a gender-specific HPA axis enhanced activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Adolescents Transitioning to High School: Sex Differences in Bullying Victimization Associated With Depressive Symptoms, Suicide Ideation, and Suicide Attempts.

PubMed

Williams, Susan G; Langhinrichsen-Rohling, Jennifer; Wornell, Cory; Finnegan, Heather

2017-12-01

Adolescents transitioning to high school may be at greater risk of depression and suicide if they are victims of bullying behavior. This study explored sex differences in bullying victimization (physical, verbal/social, and cyberbullying) and the impact on depressive symptoms and suicidal behaviors in ninth-grade students ( N = 233). Females reported significantly more verbal/social and cyberbullying than male students. There were no significant sex differences in physical bullying; male students who reported physical bullying victimization were more likely to experience depressive symptoms. Verbal/social bullying predicted depressive symptoms in males and females. Females who reported being victims of cyberbullying were more likely to report depressive symptoms, suicide ideation, and suicide attempts. Eighteen students reported suicide attempts, and each also experienced verbal/social bullying. School nurses are positioned to reach out to transitioning students, screen for mental health issues, provide a safe place to talk about bullying experiences, and promote positive mental health.

Insomnia and suicidal ideation and behaviors in former and current U.S. service members: Does depression mediate the relations?

PubMed

Allan, Nicholas P; Conner, Kenneth R; Pigeon, Wilfred R; Gros, Daniel F; Salami, Temilola K; Stecker, Tracy

2017-06-01

Insomnia is a risk factor for Suicidal Ideation (SI) and Behavior (SB), yet the nature of the relations is unclear, including the potential mediating role of cognitive and affective/somatic symptoms of depression. It was hypothesized that the impact of insomnia on SI would be mediated through depressive symptoms and that insomnia would directly impact SB. Current and former military service members (N =405; M age =31.6 years, SD =7.3; 90.4% male, 76.5% White) who endorsed recent suicidal ideation and/or a history of suicide attempt completed measures of insomnia, depression, SI, and SB at baseline and at month 12 follow-up. Mediation models were conducted using structural equation modeling. Significant mediation from insomnia to baseline SI and month 12 SI was found through cognitive/affective depression. Insomnia was directly related to SB occurring between baseline and month 12 follow-up. These findings suggest that cognitive/affective depression mediates the association with SI but not SB. Results build on research showing the importance of depressive symptoms in SI in particular. The direct and indirect pathways from insomnia to SI/SB suggest that clinicians should be aware of these relations when treating patients reporting insomnia. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The Effects of Parental Depressive Symptoms, Appraisals, and Physical Punishment on Later Child Externalizing Behavior

PubMed Central

Callender, Kevin A.; Olson, Sheryl L.; Choe, Daniel E.; Sameroff, Arnold J.

2014-01-01

Examined a cognitive-behavioral pathway by which depressive symptoms in mothers and fathers increase risk for later child externalizing problem behavior via parents’ appraisals of child behavior and physical discipline. Participants were 245 children (118 girls) at risk for school-age conduct problems, and their parents and teachers. Children were approximately 3 years old at Time 1 (T1) and 5 ½ years old at Time 2 (T2). At T1, mothers and fathers reported their depressive symptoms, perceptions of their child’s reciprocal affection and responsiveness, frequency of physical punishment, and child externalizing problems. Mothers, fathers, and teachers provided ratings of externalizing behavior at T2. Structural equation modeling revealed that parents’ negative attributions mediated positive relations between their depressive symptoms and frequency of physical punishment for both fathers and mothers. More frequent physical punishment, in turn, predicted increased child externalizing behavior at T2. In future research, transactional mechanisms underlying effects of clinical depression on child conduct problems should be explored at multiple stages of development. For parents showing depressive symptoms, restructuring distorted perceptions about their children’s behavior may be an important component of intervention programs. PMID:21947616

The effects of parental depressive symptoms, appraisals, and physical punishment on later child externalizing behavior.

PubMed

Callender, Kevin A; Olson, Sheryl L; Choe, Daniel E; Sameroff, Arnold J

2012-04-01

Examined a cognitive-behavioral pathway by which depressive symptoms in mothers and fathers increase risk for later child externalizing problem behavior via parents' appraisals of child behavior and physical discipline. Participants were 245 children (118 girls) at risk for school-age conduct problems, and their parents and teachers. Children were approximately 3 years old at Time 1 (T1) and 5 ½ years old at Time 2 (T2). At T1, mothers and fathers reported their depressive symptoms, perceptions of their child's reciprocal affection and responsiveness, frequency of physical punishment, and child externalizing problems. Mothers, fathers, and teachers provided ratings of externalizing behavior at T2. Structural equation modeling revealed that parents' negative attributions mediated positive relations between their depressive symptoms and frequency of physical punishment for both fathers and mothers. More frequent physical punishment, in turn, predicted increased child externalizing behavior at T2. In future research, transactional mechanisms underlying effects of clinical depression on child conduct problems should be explored at multiple stages of development. For parents showing depressive symptoms, restructuring distorted perceptions about their children's behavior may be an important component of intervention programs.

Neuroprotective, Neurotrophic and Anti-oxidative Role of Bacopa monnieri on CUS Induced Model of Depression in Rat.

PubMed

Kumar, Sourav; Mondal, Amal Chandra

2016-11-01

Major depression is a life threatening neuropsychiatric disorder that produces mental illness and major cause of morbidity. The present study was conducted to evaluate the neuroprotective, neurotrophic and antioxidant potential of Bacopa monnieri extract (BME) on chronic unpredictable stress (CUS) induced behavioral depression in rats. Behavioral tests were carried out for investigation of antidepressant like effects of BME, and potential mechanism was assessed by determining neurotrophin level and hippocampal neurogenesis. Depressive-like behavior was assessed by shuttle-box escape test, forced swim test and tail suspension test. Effect of BME on hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring the plasma level of adrenocorticotropic hormone (ACTH) and corticosterone. The expression of brain derived neurotrophic factor (BDNF), neuronal marker doublecortin (DCX) in the hippocampus were measured and hippocampal neurogenesis was investigated by 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN). In addition, effects of BME on oxidative stress markers were also measured in the hippocampus of CUS exposed rats. The results indicated that BME significantly able to attenuate the depressive-like behaviors, normalized the levels of ACTH, corticosterone, and up-regulate the expression of BDNF, DCX and BrdU/NeuN in CUS induced rats compared to BME treated rats. It is also found that BME significantly increased the activity of antioxidant enzymes on CUS induced rats. These findings revealed that BME exerted neuroprotective effects possibly by promoting hippocampal neurogenesis with elevation of BDNF level and antioxidant defense against oxidative stress.

Maternal separation increases later immobility during forced swim in guinea pig pups: evidence for sensitization of a depressive-like state.

PubMed

Hennessy, Michael B; Schreibeis, Amanda D; Schiml, Patricia A; Deak, Terrence

2017-01-01

Early-life stress is thought to increase later vulnerability for developing depressive illness by sensitizing underlying stress-responsive systems. Guinea pig pups separated from their mother and isolated in a novel cage for 3 hr exhibit a sensitized depressive-like behavioral response when separated again the following day as well as weeks later. The behavioral response and its sensitization appear to be mediated by inflammatory factors. To determine if this sensitization is specific to the separation response or if it reflects a broader underlying depressive-like state, guinea pig pups that had either been separated for 3 hr or remained with their mothers were observed in the forced swim test the following 3 days. Earlier separation was found to increase the duration of immobility, a measure sensitive to antidepressant treatment. These results support the use of the guinea pig as a model for examining mechanisms of inflammatory-mediated sensitization of depression following stress in early life. © 2016 Wiley Periodicals, Inc.

Selective breeding for infant rat separation-induced ultrasonic vocalizations: developmental precursors of passive and active coping styles.

PubMed

Brunelli, Susan A; Hofer, Myron A

2007-09-04

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate "anxious"/"depressed" phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an "aggressive" phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting "coping styles" with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation.

Earlier parental set bedtimes as a protective factor against depression and suicidal ideation.

PubMed

Gangwisch, James E; Babiss, Lindsay A; Malaspina, Dolores; Turner, J Blake; Zammit, Gary K; Posner, Kelly

2010-01-01

To examine the relationships between parental set bedtimes, sleep duration, and depression as a quasi-experiment to explore the potentially bidirectional relationship between short sleep duration and depression. Short sleep duration has been shown to precede depression, but this could be explained as a prodromal symptom of depression. Depression in an adolescent can affect his/her chosen bedtime, but it is less likely to affect a parent's chosen set bedtime which can establish a relatively stable upper limit that can directly affect sleep duration. Multivariate cross-sectional analyses of the ADD Health using logistic regression. United States nationally representative, school-based, probability-based sample in 1994-96. Adolescents (n = 15,659) in grades 7 to 12. Adolescents with parental set bedtimes of midnight or later were 24% more likely to suffer from depression (OR = 1.24, 95% CI 1.04-1.49) and 20% more likely to have suicidal ideation (1.20, 1.01-1.41) than adolescents with parental set bedtimes of 10:00 PM or earlier, after controlling for covariates. Consistent with sleep duration and perception of getting enough sleep acting as mediators, the inclusion of these variables in the multivariate models appreciably attenuated the associations for depression (1.07, 0.88-1.30) and suicidal ideation (1.09, 0.92-1.29). The results from this study provide new evidence to strengthen the argument that short sleep duration could play a role in the etiology of depression. Earlier parental set bedtimes could therefore be protective against adolescent depression and suicidal ideation by lengthening sleep duration.

Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles.

PubMed

Zhang, Xin; Xu, Yan; Zhou, Lian; Zhang, Chengcheng; Meng, Qingtao; Wu, Shenshen; Wang, Shizhi; Ding, Zhen; Chen, Xiaodong; Li, Xiaobo; Chen, Rui

2015-12-09

Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al₂O₃ ultrafine particles. In the present study, male and female mice were exposed to Al₂O₃ nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al₂O₃ NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals.

The Association between the Parent-Child Relationship and Symptoms of Anxiety and Depression: The Roles of Attachment and Perceived Spouse Attachment Behaviors.

PubMed

Bradford, Angela B; Burningham, Kayla L; Sandberg, Jonathan G; Johnson, Lee N

2017-04-01

Research shows that the parent-child relationship affects attachment security, which correlates with anxiety and depression in adulthood. Additional research shows that romantic attachment behaviors may supersede individual attachment security and buffer against negative processes. Using data from 680 married couples in the general population, we examined whether attachment mediates the link between the parent-child relationship and depressive and anxiety symptoms in adulthood. In addition, we tested whether perceived spouse attachment behaviors moderate the effects of attachment insecurity. There was an indirect effect of poor parent-child relationships on symptoms via insecure attachment. Perception of spouse's attachment behaviors was related to depression for both spouses, and they moderated the effect of attachment insecurity on depressive symptoms for husbands. Clinical implications are discussed. © 2016 American Association for Marriage and Family Therapy.

Affect and eating behavior in obese adults with and without elevated depression symptoms.

PubMed

Goldschmidt, Andrea B; Crosby, Ross D; Engel, Scott G; Crow, Scott J; Cao, Li; Peterson, Carol B; Durkin, Nora

2014-04-01

Although there is a modest relation between obesity and depression, mechanisms that contribute to this co-occurrence are unclear. This study examined mood and eating behavior among obese adults with and without elevated depression symptoms. Obese adults (N = 50) were subtyped according to a Beck Depression Inventory (BDI) cutoff of 14, indicating "probable depression." Participants with (BDI ≥ 14; n = 15) and without (BDI < 14; n = 35) elevated depression symptoms were compared on affect- and eating-related variables measured via questionnaire and ecological momentary assessment (EMA) using ANCOVA and mixed model regression. After adjusting for group differences in body mass index (BMI; p = .03), participants with elevated depression symptoms reported greater emotional eating via self-report questionnaire [F(1,50) = 4.3; p = .04], as well as more frequent binge eating (Wald χ(2)  = 13.8; p < .001) and higher daily negative affect (Wald χ(2)  = 7.7; p = .005) on EMA recordings. Emotional eating mediated the relationship between depression status and BMI (indirect effect estimate = 3.79; 95% CI = 1.02-7.46). Emotional eating and binge eating were more commonly reported by obese adults with elevated depression symptoms compared to those without and may occur against a general backdrop of overall low mood. Intervention and prevention programs for obesity and/or depression should address disordered eating to prevent or minimize adverse health consequences. Copyright © 2013 Wiley Periodicals, Inc.

Popularity among same-sex and cross-sex peers: A process-oriented examination of links to aggressive behaviors and depressive affect

PubMed Central

Troop-Gordon, Wendy; Ranney, John D.

2014-01-01

Popularity has been linked to heightened aggression and fewer depressive symptoms. The current study extends this literature by examining the unique contributions of same-sex and cross-sex popularity to children’s development, as well as potential mediating processes. Third-and fourth-graders (212 boys, 250 girls) provided data at three time points over two school years. Data included peer-reported popularity, social exclusion, friendships, peer victimization, and aggression, and self-reported social self-esteem and depressive affect. Same-sex and cross-sex popularity independently contributed to the prediction of aggression and depressive affect. Popularity was associated with heightened aggression through reduced social exclusion and was indirectly related to lower levels of depressive affect through increased friendships. For boys only, same-sex popularity was further associated with dampened depressive affect through reduced social exclusion and peer victimization and increased social self-esteem. Findings are discussed in light of the potential tradeoffs associated with popularity in preadolescence. PMID:24684714

Major depressive disorder in children and adolescents after renal transplantation.

PubMed

Ghanizadeh, A; Mansoori, Y; Ashkani, H; Fallahzadeh, M H; Derakhshan, A; Shokrpour, N; Akhondzadeh, S

2009-06-01

This cross-sectional study evaluated the prevalence of major depressive disorder and depressive symptoms in children and adolescents after renal transplantation. A total of 71 patients who had undergone renal transplantation were interviewed in person using the Farsi (Persian) version of the Kiddie Schedule for Affective Disorders and Schizophrenia and Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria. Major depressive disorder, depressive symptoms, and suicidal behaviors were assessed. The rate of major depressive disorder was 2.8%; two-thirds of the patients had irritability; and approximately 40% had recurrent thoughts of death and suicidal ideation. The rate of major depressive disorder was lower than in other chronic diseases such as thallasemia or hemophilia; however, the rate of suicidal behaviors was high.

Garcinia mangostana Linn displays antidepressant-like and pro-cognitive effects in a genetic animal model of depression: a bio-behavioral study in the Flinders Sensitive Line rat.

PubMed

Oberholzer, Inge; Möller, Marisa; Holland, Brendan; Dean, Olivia M; Berk, Michael; Harvey, Brian H

2018-04-01

There is abundant evidence for both disorganized redox balance and cognitive deficits in major depressive disorder (MDD). Garcinia mangostana Linn (GM) has anti-oxidant activity. We studied the antidepressant-like and pro-cognitive effects of raw GM rind in Flinders Sensitive Line (FSL) rats, a genetic model of depression, following acute and chronic treatment compared to a reference antidepressant, imipramine (IMI). The chemical composition of the GM extract was analysed for levels of α- and γ-mangostin. The acute dose-dependent effects of GM (50, 150 and 200 mg/kg po), IMI (20 mg/kg po) and vehicle were determined in the forced swim test (FST) in FSL rats, versus Flinders Resistant Line (FRL) control rats. Locomotor testing was conducted using the open field test (OFT). Using the most effective dose above coupled with behavioral testing in the FST and cognitive assessment in the novel object recognition test (nORT), a fixed dose 14-day treatment study of GM was performed and compared to IMI- (20 mg/kg/day) and vehicle-treated animals. Chronic treated animals were also assessed with respect to frontal cortex and hippocampal monoamine levels and accumulation of malondialdehyde. FSL rats showed significant cognitive deficits and depressive-like behavior, with disordered cortico-hippocampal 5-hydroxyindole acetic acid (5-HIAA) and noradrenaline (NA), as well as elevated hippocampal lipid peroxidation. Acute and chronic IMI treatment evoked pronounced antidepressant-like effects. Raw GM extract contained 117 mg/g and 11 mg/g α- and γ-mangostin, respectively, with acute GM demonstrating antidepressant-like effects at 50 mg/kg/day. Chronic GM (50 mg/kg/d) displayed significant antidepressant- and pro-cognitive effects, while demonstrating parity with IMI. Both behavioral and monoamine assessments suggest a more prominent serotonergic action for GM as opposed to a noradrenergic action for IMI, while both IMI and GM reversed hippocampal lipid peroxidation in FSL animals. Concluding, FSL rats present with cognitive deficits and depressive-like behaviors that are reversed by acute and chronic GM treatment, similar to that of IMI.

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior.

PubMed

Sun, Dong; Sun, Xiang-Dong; Zhao, Lu; Lee, Dae-Hoon; Hu, Jin-Xia; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Zhu, Xiao-Juan; Xiong, Wen-Cheng

2018-01-08

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

Disruption of the HPA-axis through corticosterone-release pellets induces robust depressive-like behavior and reduced BDNF levels in mice.

PubMed

Demuyser, Thomas; Bentea, Eduard; Deneyer, Lauren; Albertini, Giulia; Massie, Ann; Smolders, Ilse

2016-07-28

The corticosterone mouse model is widely used in preclinical research towards a better understanding of mechanisms of major depression. One particular administration procedure is the subcutaneous implantation of corticosterone slow-release pellets. In this report we want to provide basic evidence, regarding behavioral changes, neurotransmitter and -modulator levels and some other relevant biomolecules after hypothalamic-pituitary-adrenal-axis distortion. We show that three weeks of corticosterone pellet exposure robustly induces depressive-like but not anxiety-like behavior in mice, accompanied by a significant decrease in hippocampal brain-derived neurotrophic factor levels, at five weeks after the start of treatment. Furthermore there is an overall decrease in plasma corticosterone levels after three weeks of treatment that lasts up until the five weeks' time point. On the other hand, no differences are observed in total monoamine, glutamate or d-serine levels, nor in glucocorticoid receptor expression, in various depression-related brain areas. Altogether this characterization delivers vital information, supplementary to existing literature, regarding the phenotyping of pellet-induced hypothalamic-pituitary-adrenal-axis disruption in mice following three weeks of continuous corticosterone exposure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mothers' depressive symptoms predict both increased and reduced negative reactivity: aversion sensitivity and the regulation of emotion.

PubMed

Dix, Theodore; Moed, Anat; Anderson, Edward R

2014-07-01

This study examined whether, as mothers' depressive symptoms increase, their expressions of negative emotion to children increasingly reflect aversion sensitivity and motivation to minimize ongoing stress or discomfort. In multiple interactions over 2 years, negative affect expressed by 319 mothers and their children was observed across variations in mothers' depressive symptoms, the aversiveness of children's immediate behavior, and observed differences in children's general negative reactivity. As expected, depressive symptoms predicted reduced maternal negative reactivity when child behavior was low in aversiveness, particularly with children who were high in negative reactivity. Depressive symptoms predicted high negative reactivity and steep increases in negative reactivity as the aversiveness of child behavior increased, particularly when high and continued aversiveness from the child was expected (i.e., children were high in negative reactivity). The findings are consistent with the proposal that deficits in parenting competence as depressive symptoms increase reflect aversion sensitivity and motivation to avoid conflict and suppress children's aversive behavior. © The Author(s) 2014.

Cognitive Behavioral Development in Children Following Maternal Postpartum Depression: A Review Article

PubMed Central

Mirhosseini, Hamid; Moosavipoor, Seyed Ahmad; Nazari, Mohammad Ali; Dehghan, Ahmad; Mirhosseini, Sara; Bidaki, Reza; Yazdian-anari, Pouria

2015-01-01

Mothers’ constitute is a very important part of infants’ social environment and mediate their experience with the surrounding world. Postpartum depression, which is considered one of the most common and important psychiatric disorders, affects 10–15% of mothers, its causes are different. By investigating various sources, some effects of this disorder have been observed on the cognitive development of children, particularly among boys, such as language, intelligence quotient (IQ), and behavioral problems. Thus, it is imperative to study the effects of postpartum depression on children’s growth and development and to identify methods of reducing these effects. This review indicates that postpartum depression in mothers reduces children’s cognitive performance. The adverse effects of postpartum depression on children’s development seem to be mediated by the mother’s interpersonal behavior and the infant gender. The review of previous studies shows that postpartum depression reduces children’s cognitive performance by impairing maternal mental and behavioral care. PMID:26816593

Early maternal depressive symptom trajectories: Associations with 7-year maternal depressive symptoms and child behavior.

PubMed

Buckingham-Howes, Stacy; Oberlander, Sarah E; Wang, Yan; Black, Maureen M

2017-06-01

This study examines potential mechanisms linking maternal depressive symptoms over 2 years postpartum with child behavior problems at school-age in a sample of adolescent mothers and their first-born child. Potential mechanisms include: mother-reported caregiving engagement at 6 months; observed parental nurturance and control, and child competence and affect at 24 months; and mother-reported resilience at 7 years based on achievement of adult developmental tasks. One hundred eighteen low-income African American adolescent mothers were recruited at delivery and followed through child age 7 years. Maternal depressive symptom trajectories over 24 months were estimated (low, medium, and high) based on mother-reported depressive symptoms. Direct and indirect associations between depressive symptom trajectories with 7-year maternal depressive symptoms and child behavior problems were examined. The high maternal depressive symptom trajectory was associated with 7-year maternal depressive symptoms (b = 5.52, SE = 1.65, p < .01) and child internalizing problems (b = 7.60, SE = 3.12, p = .02) and externalizing problems (b = 6.23, SE = 3.22, p = .05). Caregiving engagement among high depressive symptom trajectory mothers was significantly associated with observed child affect (b = -0.21, SE = 0.11, p = 0.05). Parental nurturance in toddlerhood mediated the association between high maternal depressive symptom trajectory and child internalizing problems at 7 years (indirect effect b = 2.33, 95% CI: 0.32-5.88). Findings suggest that family based interventions to promote parenting and adolescent resiliency strengthening may be beneficial in this population. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

(-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia.

PubMed

Voorhees, Jaymie R; Remy, Matthew T; Cintrón-Pérez, Coral J; El Rassi, Eli; Khan, Michael Z; Dutca, Laura M; Yin, Terry C; McDaniel, Latisha N; Williams, Noelle S; Brat, Daniel J; Pieper, Andrew A

2017-11-06

In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD. Published by Elsevier Inc.

Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats.

PubMed

Kang, Seungwoo; Li, Jing; Bekker, Alex; Ye, Jiang-Hong

2018-02-01

Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naïve rats; this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. This reduction was restored by systemic administration of ceftriaxone, a β-lactam antibiotic known to increase GLT-1 expression. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1's function in the LHb is critical. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal. Copyright © 2017 Elsevier Ltd. All rights reserved.