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Sample records for mild stress-induced depressive-like

  1. 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.

  2. Etazolate, a phosphodiesterase 4 inhibitor reverses chronic unpredictable mild stress-induced depression-like behavior and brain oxidative damage.

    PubMed

    Jindal, Ankur; Mahesh, Radhakrishnan; Bhatt, Shvetank

    2013-04-01

    Etazolate, a pyrazolopyridine class compound is selective inhibitor of type 4 phosphodiesterase (PDE4). Previous study in our laboratory has demonstrated that etazolate produced antidepressant-like effect in rodent models of behavioral despair. The present study was designed to investigate whether etazolate could affect the chronic unpredictable mild stress (CUMS)-induced depression in mice. The effect of etazolate on CUMS-induced depression was examined by measuring behavioral parameters and oxidant/antioxidant status of brain tissue. Mice were subjected to different stress paradigms daily for a period of 28days to induce depressive-like behavior. The results showed that CUMS caused depression-like behavior in mice, as indicated by significant (p<0.05) decrease in sucrose consumption and increase in duration of immobility. Moreover, CUMS also significantly (p<0.05) increased the oxidative stress markers and decreased the antioxidant enzymes activity. Chronic administration of etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) significantly (p<0.05) inhibited the CUMS-induced behavioral (decreased sucrose consumption and increased duration of immobility) and biochemical (increased lipid peroxidation and nitrite level; decreased glutathione, superoxide dismutase and catalase activity) changes. No alteration was observed in locomotor activity. Additionally, in the present study, the efficacy of etazolate (1mg/kg., p.o.) on the behavioral and biochemical paradigms was found comparable to that of fluoxetine, used as standard antidepressant. In conclusion, the results of the present study suggested that etazolate alleviated the CUMS-induced depression in mice, which is at least in part mediated by modulating oxidative-nitrosative stress status in mice brain.

  3. Chronic mild stress-induced depression-like symptoms in rats and abnormalities in catecholamine uptake in small arteries.

    PubMed

    Bouzinova, Elena V; Møller-Nielsen, Nina; Boedtkjer, Donna B; Broegger, Torbjoern; Wiborg, Ove; Aalkjaer, Christian; Matchkov, Vladimir V

    2012-04-01

    Major depression and cardiovascular diseases have a strong comorbidity; however, the reason for this is unknown. In the chronic mild stress (CMS) model of depression, only a fraction of rats develop a major feature of depression-anhedonia-like behavior, whereas other rats are stress resilient. Previous studies suggested that CMS rats also have increased total peripheral vascular resistance. On the basis of CMS-induced changes of sucrose intake, a reliable measure for anhedonia, rats were divided into "resilient" and "anhedonic" groups. An interaction between hedonic status and vascular function was studied after 4 and 8 weeks of CMS exposure in vitro in wire myograph on saphenous arteries and mesenteric small arteries (MSAs) from these rats. When comparing the different experimental rat groups, arterial sensitivities to noradrenaline (NA) were similar under control conditions, but in the presence of the neuronal reuptake inhibitor cocaine, arteries from anhedonic rats were more sensitive to NA. No change in perivascular innervation was found, but elevated expression of neuronal NA transporter was detected. Inhibition of extraneuronal uptake with corticosterone (1 μM) suggests that this transport is diminished in MSAs after CMS. The corticosterone-sensitive transporter organic cation cotransporter 2 was shown to be reduced in MSAs after CMS. No CMS-induced changes in the corticosterone-sensitive transport were found in saphenous arteries. Our results indicate that CMS-induced depression-like symptoms in rats are associated with changes in catecholamine uptake pathways in the vascular wall, which potentially modulates the effect of sympathetic innervation of resistance arteries.

  4. Retracted: Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced mice via RIP140/NF-κB pathway.

    PubMed

    Chunhua, Ma; Lingdong, Kong; Hongyan, Long; Zhangqiang, Ma

    2016-10-05

    The above article from IUBMB Life, published online on October 5th, 2016 in Wiley Online Library (http://wileyonlinelibrary.com), has been retracted by agreement between the authors, the Journal Editors-in-Chief, Dr. Angelo Azzi and Dr. William Whelan, and Wiley Periodicals, Inc. The retraction has been agreed because the article was submitted and approved for publication by Chunhua Ma and Long Hongyan without consent in any form by the named Corresponding Author, Kong Lingdong. Chunhua, M., Lingdong, K., Hongyan, L. and Zhangqiang, M. (2016), Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced mice via RIP140/NF-κB pathway. IUBMB Life. doi:10.1002/iub.1570 © 2017 IUBMB Life, 69(9):767-767, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  5. Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats.

    PubMed

    Wang, Y; Ma, Y; Hu, J; Cheng, W; Jiang, H; Zhang, X; Li, M; Ren, J; Li, X

    2015-08-20

    Chronic stress during critical periods of human fetal brain development is associated with cognitive, behavioral, and mood disorders in later life. Altered glutamate receptor (GluR) expression has been implicated in the pathogenesis of stress-dependent disorders. To test whether prenatal chronic mild stress (PCMS) enhances offspring's vulnerability to stress-induced behavioral and neurobiological abnormalities and if this enhanced vulnerability is sex-dependent, we measured depression-like behavior in the forced swimming test (FST) and regional changes in GluR subunit expression in PCMS-exposed adult male and female rats. Both male and female PCMS-exposed rats exhibited stronger depression-like behavior than controls. Males and females exhibited unique regional changes in GluR expression in response to PCMS alone, FST alone (CON-FST), and PCMS with FST (PCMS-FST). In females, PCMS alone did not alter N-methyl-d-aspartate receptor (NMDAR) or metabotropic glutamate receptor (mGluR) expression, while in PCMS males, higher mGluR2/3, mGluR5, and NR1 expression levels were observed in the prefrontal cortex. In addition, PCMS altered the change in GluR expression induced by acute stress (the FST test), and this too was sex-specific. Male PCMS-FST rats expressed significantly lower mGluR5 levels in the hippocampus, lower mGluR5, NR1, postsynaptic density protein (PSD)95, and higher mGluR2/3 in the prefrontal cortex, and higher mGluR5 and PSD95 in the amygdala than male CON-FST rats. Female PCMS-FST rats expressed lower NR1 in the hippocampus, lower NR2B and PSD95 in the prefrontal cortex, lower mGluR2/3 in the amygdala, and higher PSD95 in the amygdala than female CON-FST rats. PCMS may increase the offspring's vulnerability to depression by altering sex-specific stress-induced changes in glutamatergic signaling.

  6. Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats.

    PubMed

    Zhang, Lin; Luo, Junxia; Zhang, Minghua; Yao, Wei; Ma, Xuelian; Yu, Shu Yan

    2014-05-01

    Depression is a neuropsychiatric disease associated with wide ranging disruptions in neuronal plasticity throughout the brain. Curcumin, a natural polyphenolic compound of curcuma loga, has been demonstrated to be effective in the treatment of depressive-like disorders. The present study aimed to investigate the mechanisms underlying the antidepressant-like effects of curcumin in a rat model of chronic, unpredictable, mild, stress (CUMS) -induced depression. The results showed that CUMS produced depressive-like behaviours in rats, which were associated with ultra-structural changes in neurons within the lateral amygdala (LA). In addition, the expression of synapse-associated proteins such as brain-derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were significantly decreased in the LA of CUMS-treated rats. Chronic administration of curcumin (40 mg/kg, i.p. 6 wk) before stress exposure significantly prevented these neuronal and biochemical alterations induced by CUMS, and suppressed depressive-like behaviours, suggesting that this neuronal dysregulation may be related to the depressive-like behaviours caused by CUMS. Together with our previous results, the current findings demonstrate that curcumin exhibits neuroprotection and antidepressant-like effects in the CUMS-induced depression model. Furthermore, this antidepressant-like action of curcumin appears to be mediated by modulating synapse-associated proteins within the LA. These findings provide new insights into the underlying mechanisms leading to neural dysfunction in depression and reveal the therapeutic potential for curcumin use in clinical trials.

  7. Cytisine, a Partial Agonist of α4β2 Nicotinic Acetylcholine Receptors, Reduced Unpredictable Chronic Mild Stress-Induced Depression-Like Behaviors

    PubMed Central

    Han, Jing; Wang, Dong-sheng; Liu, Shui-bing; Zhao, Ming-gao

    2016-01-01

    Cytisine (CYT), a partial agonist of α4β2-nicotinic receptors, has been used for antidepressant efficacy in several tests. Nicotinic receptors have been shown to be closely associated with depression. However, little is known about the effects of CYT on the depression. In the present study, a mouse model of depression, the unpredictable chronic mild stress (UCMS), was used to evaluate the activities of CYT. UCMS caused significant depression-like behaviors, as shown by the decrease of total distances in open field test, and the prolonged duration of immobility in tail suspension test and forced swimming test. Treatment with CYT for two weeks notably relieved the depression-like behaviors in the UCMS mice. Next, proteins related to depressive disorder in the brain region of hippocampus and amygdala were analyzed to elucidate the underlying mechanisms of CYT. CYT significantly reversed the decreases of 5-HT1A, BDNF, and mTOR levels in the hippocampus and amygdala. These results imply that CYT may act as a potential anti-depressant in the animals under chronic stress. PMID:27098858

  8. Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced rats by attenuating neuronal apoptosis via regulating ROCK/Akt pathway.

    PubMed

    Qin, Tingting; Fang, Fang; Song, Meiting; Li, Ruipeng; Ma, Zhanqiang; Ma, Shiping

    2017-01-15

    There is increasing evidence that major depressive disorder (MDD) is also a progressive neurodegeneration disorder and neuronal damage is the major pathology of MDD. Umbelliferone, a coumarin derivative, was found in a range of plants with proved anti-oxidative, anti-inflammatory and neuroprotective effects. The primary purpose of this investigation was to evaluate whether umbelliferone could confer an antidepressant-like effect on the depressive model in rats developed by chronic unpredictable mild stress (CUMS) and explore the possible mechanism involved in its neuroprotective effects. We found that treatments with umbelliferone (15mg/kg, 30mg/kg) significantly ameliorated CUMS-induced depressive-like behaviors, such as decreased sucrose consumption, reduced locomotor activity and prolonged immobility time. Rats under CUMS stimulation treated with umbelliferone (15mg/kg, 30mg/kg) showed reduced neuronal apoptosis, as well as inhibited inflammatory cytokines levels by down-regulating Rho-associated protein kinase (ROCK) signaling and up-regulating protein kinase B (Akt) signaling. In conclusion, umbelliferone showed neuroprotective effects on CUMS-induced model of depression, which was associated with the inhibition of neuronal apoptosis modulated by ROCK/Akt pathway.

  9. Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: involving the inhibition of cyclooxygenase-2 in rat brain.

    PubMed

    Li, Yu-Cheng; Shen, Ji-Duo; Li, Jing; Wang, Rui; Jiao, Shuo; Yi, Li-Tao

    2013-01-10

    Baicalin, a major constituent of flavonoids isolated from Scutellariae Radix, has been previously confirmed to decrease the duration of immobility in mice exposed to the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms are still seldom studied in chronic mild stress (CMS) model of depression. In the present study, we attempted to investigate the effects of baicalin on the depressive-like behavior, the mRNA expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E(2) (PGE(2)) levels in the frontal cortex and hippocampus. Moreover, the serum corticosterone levels were also examined. We found that CMS procedure not only decreased the sucrose preference and increased serum corticosterone levels, but also elevated the activity and mRNA expression of COX-2, and increased PGE(2) levels in rat brain regions. Treatment with baicalin (10, 20, 40 mg/kg) prevented these abnormalities induced by CMS. These results confirmed that baicalin exerted antidepressant-like effects, and suggested its mechanisms at least partially related to decease COX-2 activity and expression, subsequently resulted in reduction of PGE(2) levels in brain. Our findings may provide a new aspect to understand the antidepressant action of baicalin, which is targeted on the COX-2 system in brain. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Agmatine attenuates chronic unpredictable mild stress-induced anxiety, depression-like behaviours and cognitive impairment by modulating nitrergic signalling pathway.

    PubMed

    Gawali, Nitin B; Bulani, Vipin D; Gursahani, Malvika S; Deshpande, Padmini S; Kothavade, Pankaj S; Juvekar, Archana R

    2017-05-15

    Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28days. Agmatine (20 and 40mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15mg/kg, i.p.) and l-arginine (400mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in Morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15mg/kg) potentiated the effect of agmatine whereas l-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative-nitrergic stress, CORT and BDNF levels. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis.

    PubMed

    Kreisel, T; Frank, M G; Licht, T; Reshef, R; Ben-Menachem-Zidon, O; Baratta, M V; Maier, S F; Yirmiya, R

    2014-06-01

    The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

  12. 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

  13. Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice.

    PubMed

    Mineur, Yann S; Belzung, Catherine; Crusio, Wim E

    2006-11-25

    The widely accepted stress-diathesis hypothesis of depression postulates that genetic factors contribute to biological vulnerability. Based on this concept, the unpredictable chronic mild stress (UCMS) animal model was developed. Most effects of UCMS can be reversed by antidepressant agents, illustrating a strong predictive validity. In rodents, UCMS also has good face validity as it can elicit depression-like symptoms. While abundant for rats, the UCMS literature on mice is relatively limited. Reports sometimes are contradictory, making it difficult to establish a clear profile of stress-induced depression-like behaviors in mice. As different groups often use different strains for their experiments, differential strain susceptibility to UCMS may provide at least a partial explanation of these discrepancies. Moreover, differences in testing methodology add another level of complexity. Very little is known about the role of genetic factors and their interactions with the environment in the development of stress-induced behavioral changes relevant to depression, though recent studies unequivocally demonstrated the effects of specific gene polymorphisms on stress-induced depressive symptoms, as well as the effects of stress on gene expression. In the present study, we investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in three behaviorally and genetically distinct inbred strains. The goals of these experiments are to obtain a clearer behavioral profile of genetically/phenotypically distant mouse strains after UCMS treatment and to evaluate the limitations and strengths of the UCMS model in mice.

  14. Gestational stress induces persistent depressive-like behavior and structural modifications within the postpartum nucleus accumbens.

    PubMed

    Haim, Achikam; Sherer, Morgan; Leuner, Benedetta

    2014-12-01

    Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Pregnancy stress enhances vulnerability to PPD and has also been shown to increase depressive-like behavior in postpartum rats. Thus, gestational stress may be an important translational risk factor that can be used to investigate the neurobiological mechanisms underlying PPD. Here we examined the effects of gestational stress on depressive-like behavior during the early/mid and late postpartum periods and evaluated whether this was accompanied by altered structural plasticity in the nucleus accumbens (NAc), a brain region that has been linked to PPD. We show that early/mid (postpartum day 8) postpartum female rats exhibited more depressive-like behavior in the forced swim test as compared with late postpartum females (postpartum day 22). However, 2 weeks of restraint stress during pregnancy increased depressive-like behavior regardless of postpartum timepoint. In addition, dendritic length, branching and spine density on medium spiny neurons in the NAc shell were diminished in postpartum rats that experienced gestational stress although stress-induced reductions in spine density were evident only in early/mid postpartum females. In the NAc core, structural plasticity was not affected by gestational stress but late postpartum females exhibited lower spine density and reduced dendritic length. Overall, these data not only demonstrate structural changes in the NAc across the postpartum period, they also show that postpartum depressive-like behavior following exposure to gestational stress is associated with compromised structural plasticity in the NAc and thus may provide insight into the neural changes that could contribute to PPD.

  15. Gestational stress induces persistent depressive-like behavior and structural modifications within the postpartum nucleus accumbens

    PubMed Central

    Haim, Achikam; Sherer, Morgan; Leuner, Benedetta

    2015-01-01

    Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Pregnancy stress enhances vulnerability to PPD and has also been shown to increase depressive-like behavior in postpartum rats. Thus, gestational stress may be an important translational risk factor that can be used to investigate the neurobiological mechanisms underlying PPD. Here we examined the effects of gestational stress on depressive-like behavior during the early/mid and late postpartum periods and evaluated whether this was accompanied by altered structural plasticity in the nucleus accumbens (NAc), a brain region that has been linked to PPD. We show that early/mid (PD8) postpartum female rats exhibited more depressive-like behavior in the forced swim test as compared to late postpartum females (PD22). However, two weeks of restraint stress during pregnancy increased depressive-like behavior regardless of postpartum timepoint. In addition, dendritic length, branching, and spine density on medium spiny neurons in the NAc shell were diminished in postpartum rats that experienced gestational stress although stress-induced reductions in spine density were evident only in early/mid postpartum females. In the NAc core, structural plasticity was not affected by gestational stress but late postpartum females exhibited lower spine density and reduced dendritic length. Overall, these data not only demonstrate structural changes in the NAc across the postpartum period, they also show that postpartum depressive-like behavior following exposure to gestational stress is associated with compromised structural plasticity in the NAc and thus may provide insight into the neural changes that could contribute to PPD. PMID:25359225

  16. Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior.

    PubMed

    Brachman, Rebecca A; McGowan, Josephine C; Perusini, Jennifer N; Lim, Sean C; Pham, Thu Ha; Faye, Charlene; Gardier, Alain M; Mendez-David, Indira; David, Denis J; Hen, René; Denny, Christine A

    2016-05-01

    Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test. These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. Ketamine as a prophylactic against stress-induced depressive-like behavior

    PubMed Central

    Brachman, Rebecca A.; McGowan, Josephine C.; Perusini, Jennifer N.; Lim, Sean C.; Pham, Thu Ha; Faye, Charlene; Gardier, Alain M.; Mendez-David, Indira; David, Denis J.; Hen, René; Denny, Christine A.

    2015-01-01

    Background Stress exposure is one of the greatest risk factors for psychiatric illnesses like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Methods Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine (K) could protect against depressive-like behavior. Mice were administered a single dose of saline (Sal) or ketamine and then one week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. Results SD robustly and reliably induced depressive-like behavior in control (Ctrl) mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test (FST) and in the dominant interaction (DI) test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training—and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the FST, novelty suppressed feeding (NSF) paradigm, and the sucrose splash test (ST). Conclusions These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders. PMID:26037911

  18. Effect of (4a) a novel 5-HT3 receptor antagonist on chronic unpredictable mild stress induced depressive-like behavior in mice: an approach using behavioral tests battery.

    PubMed

    Kurhe, Yeshwant; Mahesh, Radhakrishnan; Gupta, Deepali; Thangaraj, Devadoss

    2015-01-01

    The inconsistent therapeutic outcome necessitates designing and identifying novel therapeutic interventions for depression. Hence, the present study deals with the investigation of antidepressant-like effects of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations. Animals were subjected to different stressors for a period of 28 days. On day 15 after the subsequent stress procedure, mice were administered with (4a) (2 and 4 mg/kg p.o.), escitalopram (10 mg/kg p.o.), or vehicle (10 mL/kg p.o.) until day 28 along with the CUMS. Thereafter, behavioral battery tests like locomotor score, sucrose preference test, forced swim test (FST), tail suspension test (TST), and elevated plus maze (EPM) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were estimated in the mice brain homogenate. (4a) Dose dependently attenuated the behavioral alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the open arm number of entries and time in EPM. Furthermore, biochemical alterations were reversed by (4a) as examined by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD. (4a) exhibits antidepressant potential by reversing the CUMS induced behavioral and biochemical changes in mice.

  19. Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

    PubMed

    Tao, Weiwei; Dong, Yu; Su, Qiang; Wang, Hanqing; Chen, Yanyan; Xue, Wenda; Chen, Chang; Xia, Baomei; Duan, Jinao; Chen, Gang

    2016-07-15

    Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) content was reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin (5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

  20. The antidepressant roles of Wnt2 and Wnt3 in stress-induced depression-like behaviors

    PubMed Central

    Zhou, W-J; Xu, N; Kong, L; Sun, S-C; Xu, X-F; Jia, M-Z; Wang, Y; Chen, Z-Y

    2016-01-01

    Wnts-related signaling pathways have been reported to play roles in the pathogenesis of stress-induced depression-like behaviors. However, there is relatively few direct evidence to indicate the effect of Wnt ligands on this process. Here, we investigated the role of Wnts in mediating chronic restraint stress (CRS)-induced depression-like behaviors. We found that CRS induced a significant decrease in the expression of Wnt2 and Wnt3 in the ventral hippocampus (VH) but not in the dorsal hippocampus. Knocking down Wnt2 or Wnt3 in the VH led to impaired Wnt/β-catenin signaling, neurogenesis deficits and depression-like behaviors. In contrast, overexpression of Wnt2 or Wnt3 reversed CRS-induced depression-like behaviors. Moreover, Wnt2 and Wnt3 activated cAMP response element-binding protein (CREB) and there was CREB-dependent positive feedback between Wnt2 and Wnt3. Finally, fluoxetine treatment increased Wnt2 and Wnt3 levels in the VH and knocking down Wnt2 or Wnt3 abolished the antidepressant effect of fluoxetine. Taken together, our study indicates essential roles for Wnt2 and Wnt3 in CRS-induced depression-like behaviors and antidepressant. PMID:27622936

  1. [Molecular changes in inbred mice with individual vulnerability vs resilience to stress-induced depressive-like state].

    PubMed

    Strekalova, T V; Kholod, N S; Bachurin, S O; Koval'zon, V M

    2011-08-01

    The C57BL/6 mice were subjected to a chronic combined stress which resulted in the induction of a depressive-like state. The occurrence of a depressive-like state was defined by a decrease in sensitivity to the reward determined by the diminished preference of sweetened solutions over regular drinking water. Such decrease is generally considered as a sign of an unhedonic-like state: one of the key features of clinical depression. Applied here, the paradigm in mice allows unhedonia induction in a subpopulation of stressed animals (54% in the current study); remaining mice are regarded as resilient to stress-induced hedonic deficit. The resilient subgroup is taken, therefore, as a "functional control" for those effects of stress that are not accompanied by development of the stress-induced depressive-like state in mice. The analysis of the mRNA extracted from the hippocampi of stress-subjected and home-cage control mice enabled the assessment of gene expression level of over 13 000 genes. This study showed that unhedonic mice are characterized by an up-regulation of 278 and down-regulation of 174 genes related mostly to the CNS development and functions, inter-cellular interactions and signalling, neurological disorders, apoptosis and behavioural regulation. Resilient animals demonstrated up-regulation of 924 and down-regulation of only 29 genes that control formation of cell assemblies, molecular transport, CNS functioning, neurological disorders and various biochemical reactions. Thus, gene expression profiles in the hippocampus of susceptible vs resilient to stress-induced unhedonia inbred subgroups of animals are strictly distinct in both quantity and quality.

  2. Antidepressant-like Effect of l-perillaldehyde in Stress-induced Depression-like Model Mice through Regulation of the Olfactory Nervous System

    PubMed Central

    Ito, N.; Nagai, T.; Oikawa, T.; Yamada, H.; Hanawa, T.

    2011-01-01

    Perillae Herba (a leaf of Perilla frutescens) has been prescribed as one of the component herbs in certain Kampo (Japanese herbal) medicines that are used clinically for the improvement of depressive mood. l-Perillaldehyde (PAH) is a major component in the essential oil containing in Perillae Herba, but its antidepressant-like effect has not been reported. To clarify the antidepressant-like effect of PAH, the inhaled effect of PAH on stress-induced depression-like model mice prepared by subjection to a combination of forced swimming and chronic mild stresses was investigated. The degree of the depression-like state was measured by the animal's duration of immobility using a forced swimming test. Inhalation of PAH (0.0965 and 0.965 mg/mouse/day, 9 days) significantly shortened the duration of immobility of the depression-like model mice and did not affect locomotor activity. However, another odor substance, cinnamaldehyde containing in Cinnamomi Cortex, exhibited no reduction in the immobility. The reduction in the immobility induced by the inhalation of PAH was prevented on anosmia-induced mice prepared by intranasal irrigation with zinc sulfate. These results suggest that the inhalation of PAH shows antidepressant-like activity through the olfactory nervous function. PMID:18955354

  3. Monoacylglycerol Lipase Inhibition Blocks Chronic Stress-Induced Depressive-Like Behaviors via Activation of mTOR Signaling

    PubMed Central

    Zhong, Peng; Wang, Wei; Pan, Bin; Liu, Xiaojie; Zhang, Zhen; Long, Jonathan Z; Zhang, Han-ting; Cravatt, Benjamin F; Liu, Qing-song

    2014-01-01

    The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling. PMID:24476943

  4. TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors.

    PubMed

    Choi, Juli; Kim, Ji-eun; Kim, Tae-Kyung; Park, Jin-Young; Lee, Jung-Eun; Kim, Hannah; Lee, Eun-Hwa; Han, Pyung-Lim

    2015-10-01

    Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up-regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated suppression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA.

  5. 24-hour-restraint stress induces long-term depressive-like phenotypes in mice

    PubMed Central

    Zhou, Ying; Hu, Zhiqiang; Lou, Jingyu; Song, Wei; Li, Jing; Liang, Xiao; Chen, Chen; Wang, Shuai; Yang, Beimeng; Chen, Lei; Zhang, Xu; Song, Jinjing; Dong, Yujie; Chen, Shiqing; He, Lin; Xie, Qingguo; Chen, Xiaoping; Li, Weidong

    2016-01-01

    There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders. PMID:27609090

  6. 24-hour-restraint stress induces long-term depressive-like phenotypes in mice.

    PubMed

    Chu, Xixia; Zhou, Ying; Hu, Zhiqiang; Lou, Jingyu; Song, Wei; Li, Jing; Liang, Xiao; Chen, Chen; Wang, Shuai; Yang, Beimeng; Chen, Lei; Zhang, Xu; Song, Jinjing; Dong, Yujie; Chen, Shiqing; He, Lin; Xie, Qingguo; Chen, Xiaoping; Li, Weidong

    2016-09-09

    There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders.

  7. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice.

    PubMed

    Iñiguez, Sergio D; Riggs, Lace M; Nieto, Steven J; Dayrit, Genesis; Zamora, Norma N; Shawhan, Kristi L; Cruz, Bryan; Warren, Brandon L

    2014-05-01

    Abstract Exposure to stress is highly correlated with the emergence of mood-related illnesses. Because major depressive disorder often emerges in adolescence, we assessed the effects of social defeat stress on responses to depressive-like behaviors in juvenile mice. To do this, postnatal day (PD) 35 male c57BL/6 mice were exposed to 10 days of social defeat stress (PD35-44), while control mice were handled daily. Twenty-four hours after the last episode of defeat (PD45), separate groups of mice were tested in the social interaction, forced swimming, sucrose preference, and elevated plus-maze behavioral assays (n = 7-12 per group). Also, we examined body weight gain across days of social defeat and levels of blood serum corticosterone 40 min after the last episode of defeat stress. Our data indicates that defeated mice exhibited a depressive-like phenotype as inferred from increased social avoidance, increased immobility in the forced swim test, and reduced sucrose preference (a measure of anhedonia), when compared to non-defeated controls. Defeated mice also displayed an anxiogenic-like phenotype when tested on the elevated plus-maze. Lastly, stressed mice displayed lower body weight gain, along with increased blood serum corticosterone levels, when compared to non-stressed controls. Overall, we show that in adolescent male c57BL/6 mice, social defeat stress induces a depression- and anxiety-like phenotype 24 h after the last episode of stress. These data suggest that the social defeat paradigm may be used to examine the etiology of stress-induced mood-related disorders during adolescence.

  8. Vulnerability to chronic subordination stress-induced depression-like disorders in adult 129SvEv male mice.

    PubMed

    Dadomo, Harold; Sanghez, Valentina; Di Cristo, Luisana; Lori, Andrea; Ceresini, Graziano; Malinge, Isabelle; Parmigiani, Stefano; Palanza, Paola; Sheardown, Malcolm; Bartolomucci, Alessandro

    2011-08-01

    Exposure to stressful life events is intimately linked with vulnerability to neuropsychiatric disorders such as major depression. Pre-clinical animal models offer an effective tool to disentangle the underlying molecular mechanisms. In particular, the 129SvEv strain is often used to develop transgenic mouse models but poorly characterized as far as behavior and neuroendocrine functions are concerned. Here we present a comprehensive characterization of 129SvEv male mice's vulnerability to social stress-induced depression-like disorders and physiological comorbidities. We employed a well characterized mouse model of chronic social stress based on social defeat and subordination. Subordinate 129SvEv mice showed body weight gain, hyperphagia, increased adipose fat pads weight and basal plasma corticosterone. Home cage phenotyping revealed a suppression of spontaneous locomotor activity and transient hyperthermia. Subordinate 129SvEv mice also showed marked fearfulness, anhedonic-like response toward a novel but palatable food, increased anxiety in the elevated plus maze and social avoidance of an unfamiliar male mouse. A direct measured effect of the stressfulness of the living environment, i.e. the amount of daily aggression received, predicted the degree of corticosterone level and locomotor activity but not of the other parameters. This is the first study validating a chronic subordination stress paradigm in 129SvEv male mice. Results demonstrated remarkable stress vulnerability and establish the validity to use this mouse strain as a model for depression-like disorders.

  9. Naloxone exacerbates memory impairments and depressive-like behavior after mild traumatic brain injury (mTBI) in mice with upregulated opioid system activity.

    PubMed

    Lesniak, Anna; Leszczynski, Pawel; Bujalska-Zadrozny, Magdalena; Pick, Chaim G; Sacharczuk, Mariusz

    2017-03-08

    The neuroprotective role of the endogenous opioid system in the pathophysiological sequelae of brain injury remains largely ambiguous. Noteworthy, almost no data is available on how its genetically determined activity influences the outcome of mild traumatic brain injury. Thus, the aim of our study was to examine the effect of opioid receptor blockage on cognitive impairments produced by mild traumatic brain injury in mice selectively bred for high (HA) and low (LA) swim-stress induced analgesia that show innate divergence in opioid system activity. Mild traumatic brain injury was induced with a weight-drop device on anaesthetized mice. Naloxone (5mg/kg) was intraperitoneally delivered twice a day for 7days to non-selectively block opioid receptors. Spatial memory performance and manifestations of depressive-like behavior were assessed using the Morris Water Maze and tail suspension tests, respectively. Mild traumatic brain injury resulted in a significant deterioration of spatial memory performance and severity of depressive-like behavior in the LA mouse line as opposed to HA mice. Opioid receptor blockage with naloxone unmasked cognitive deficits in HA mice but was without effect in the LA line. The results suggest a protective role of genetically predetermined enhanced opioid system activity in suppression of mild brain trauma-induced cognitive impairments. Mice selected for high and low swim stress-induced analgesia might therefore be a useful model to study the involvement of the opioid system in the pathophysiology and neurological outcome of traumatic brain injury.

  10. Decreased Glycogen Content Might Contribute to Chronic Stress-Induced Atrophy of Hippocampal Astrocyte volume and Depression-like Behavior in Rats

    PubMed Central

    Zhao, Yunan; Zhang, Qiang; Shao, Xiao; Ouyang, Liufeng; Wang, Xin; Zhu, Kexuan; Chen, Lin

    2017-01-01

    The involvement of brain glycogen in the progress of chronic stress-induced impairment of hippocampal astrocyte structural plasticity and depression-like behavior is yet to be clarified. The present study designed three experiments to determine the role of brain glycogen in the plasticity and behavioral consequences of chronic stress. Time course studies on brain glycogen, astrocytes, and behavioral responses to stress were conducted in Experiment 1. Chronic stress decreased the hippocampal glycogen levels, reduced astrocytic size and protrusion length in the hippocampus, and induced depression-like behavior. Glycogen synthase 1 mRNA in the hippocampus was silenced by lentiviral vector-based RNA interference (RNAi) in Experiment 2. This RNAi produced a lack of glycogen in the hippocampus, decreased the hippocampal astrocyte size, and induced depressive behavior in rats. The mechanisms of chronic stress-induced brain glycogen decrease were investigated in Experiment 3. Chronic stress promoted hippocampal glycogen breakdown and increased hippocampal glycogen synthesis. Results suggest that decreased glycogen content was associated with chronic stress-induced atrophy of hippocampal astrocyte size and depression-like behavior. Furthermore, the decrease of glycogen content in the hippocampus might be due to the compensation of glycogen synthesis for breakdown in an insufficient manner. PMID:28233800

  11. 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.

  12. NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation

    PubMed Central

    Zhang, Yi; Liu, Lei; Liu, Yun-Zi; Shen, Xiao-Liang; Wu, Teng-Yun; Zhang, Ting; Wang, Wei; Wang, Yun-Xia

    2015-01-01

    Background: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1β. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. Methods: To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress. Results: Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1β levels, and hippocampal active interleukin-1β protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1β protein and significantly moderated the depressive-like behaviors induced by chronic mild stress. Conclusions: These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression. PMID:25603858

  13. Possible Involvement of µ Opioid Receptor in the Antidepressant-Like Effect of Shuyu Formula in Restraint Stress-Induced Depression-Like Rats

    PubMed Central

    Wang, Fu-rong; Qiao, Ming-qi; Xue, Ling; Wei, Sheng

    2015-01-01

    Recently μ opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants. PMID:25821488

  14. Honokiol abrogates chronic restraint stress-induced cognitive impairment and depressive-like behaviour by blocking endoplasmic reticulum stress in the hippocampus of mice.

    PubMed

    Jangra, Ashok; Dwivedi, Shubham; Sriram, Chandra Shaker; Gurjar, Satendra Singh; Kwatra, Mohit; Sulakhiya, Kunjbihari; Baruah, Chandana C; Lahkar, Mangala

    2016-01-05

    The primary objective of our study is to investigate the neuroprotective efficacy of honokiol and imipramine against restraint stress (RS)-induced cognitive impairment and depressive-like behaviour in mice. We examined whether the neuroprotective activity of honokiol and imipramine mediates through the inhibition of endoplasmic reticulum stress. Adult Swiss albino mice were restrained for 6h/day for 28 days. Honokiol (3 and 10mg/kg) and Imipramine (10 and 30mg/kg) were administered for last 7 days to the different groups. Cognitive function was assessed by Morris water maze and novel object recognition test. Forced swimming test and tail suspension test were performed to evaluate the restraint stress-induced depressive-like behaviour. Proinflammatory cytokines, brain-derived neurotrophic factor, and ER stress markers i.e. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) were quantified in the hippocampus. We observed cognitive impairment and depressive-like behaviour in RS-exposed animals. Honokiol (10mg/kg) treated group depicted marked reduction in cognitive impairment and depressive-like behaviour. However, imipramine (10 and 30mg/kg) prevented the depressive-like behaviour but failed to prevent RS-induced cognitive impairment. Moreover, proinflammatory cytokines, GRP78 and CHOP were elevated in the hippocampus of stressed mice as compared to unstressed mice. Honokiol (10mg/kg) significantly prevented the RS-induced elevated levels of proinflammatory cytokines and endoplasmic reticulum stress markers. Our results clearly suggest the beneficial potential of honokiol in restraint stress through inhibition of proinflammatory cytokines and endoplasmic reticulum stress. Honokiol could be an intriguing therapeutic approach in endoplasmic reticulum stress related neuro-pathophysiological conditions. Copyright © 2015. Published by Elsevier B.V.

  15. Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression.

    PubMed

    Bouzinova, Elena V; Norregaard, Rikke; Boedtkjer, Donna M B; Razgovorova, Irina A; Moeller, Anaïs M J; Kudryavtseva, Olga; Wiborg, Ove; Aalkjaer, Christian; Matchkov, Vladimir V

    2014-05-01

    Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient. After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine-preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups. Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)-dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX-2-dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase- and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca-activated K channels. Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization-like relaxation despite up-regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major

  16. Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus.

    PubMed

    Zheng, Yu; Fan, Weidong; Zhang, Xianquan; Dong, Erbo

    2016-01-01

    Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression.

  17. Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

    PubMed Central

    Zheng, Yu; Fan, Weidong; Zhang, Xianquan; Dong, Erbo

    2016-01-01

    ABSTRACT Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression. PMID:26890656

  18. Deletion of TRIM32 protects mice from anxiety- and depression-like behaviors under mild stress.

    PubMed

    Ruan, Chun-Sheng; Wang, Shu-Fen; Shen, Yan-Jun; Guo, Yi; Yang, Chun-Rui; Zhou, Fiona H; Tan, Li-Tao; Zhou, Li; Liu, Jian-Jun; Wang, Wen-Yue; Xiao, Zhi-Cheng; Zhou, Xin-Fu

    2014-08-01

    Chronic stress causes a variety of psychiatric disorders such as anxiety and depression, but its mechanism is not well understood. Tripartite motif-containing protein 32 (TRIM32) was strongly associated with autism spectrum disorder, attention deficit hyperactivity disorder, anxiety and obsessive compulsive disorder based on a study of copy number variation, and deletion of TRIM32 increased neural proliferation and reduced apoptosis. Here, we propose that TRIM32 is involved in chronic stress-induced affective behaviors. Using a chronic unpredictable mild stress mouse depression model, we studied expression of TRIM32 in brain tissue samples and observed behavioral changes in Trim32 knockout mice. The results showed that TRIM32 protein but not its mRNA was significantly reduced in hippocampus in a time-dependent manner within 8 weeks of chronic stress. These stress-induced affective behaviors and reduction of TRIM32 protein expression were significantly reversed by antidepressant fluoxetine treatment. In addition, Trim32 knockout mice showed reduced anxiety and depressive behaviors and hyperactivities compared with Trim32 wild-type mice under normal and mild stress conditions. We conclude that TRIM32 plays important roles in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress.

  19. The role of hepcidin in chronic mild stress-induced depression.

    PubMed

    Farajdokht, Fereshteh; Soleimani, Mansoureh; Mehrpouya, Sara; Barati, Mahmood; Nahavandi, Arezo

    2015-02-19

    Depression is one of the most prevalent challenges of mental conditions. Yet its exact etiology has not been clear. Chronic stress increases the production of cytokines, which can lead to depression. Hepcidin, an iron modulator, is involved in the inflammation process as well as iron homeostasis. This study was designed to investigate the role of hepcidin, on stress-induced depression. 60 male wistar rats were entered the experiment. We used a chronic unpredictable mild stress (for 28 days) as a rat model of depression. In stressed group, three subgroups were treated with three different doses of dalteparin (a hepcidin inhibitor): 70IU/kg, 100IU/kg and 140IU/kg daily, for 4 weeks. The animals in the stressed group had more depressive-like behavior than the control group. Moreover, chronic mild stress produced an increased serum interleukin-6 levels. These effects were accompanied by an obvious increase in hepcidin mRNA level and iron content in the hippocampus. These changes were blocked by the injection of dalteparin. In conclusion, inhibition of hepcidin may reduce many pathological changes seen in stress-induced depressive disorders.

  20. Prior chronic stress induces persistent polyI:C-induced allodynia and depressive-like behavior in rats: Possible involvement of glucocorticoids and microglia.

    PubMed

    Chijiwa, Takeharu; Oka, Takakazu; Lkhagvasuren, Battuvshin; Yoshihara, Kazufumi; Sudo, Nobuyuki

    2015-08-01

    When animals suffer from viral infections, they develop a set of symptoms known as the "sickness response." Recent studies suggest that psychological stress can modulate the sickness response. However, it remains uncertain whether acute and chronic psychosocial stresses have the same effect on viral infection-induced sickness responses. To address this question, we compared changes in polyI:C-induced sickness responses, such as fever, change of body weight and food intake, mechanical allodynia, and depressive-like behavior, in rats that had been pre-exposed to single and repeated social defeat stresses. Intraperitoneal injection of polyI:C induced a maximal fever of 38.0°C 3h after injection. Rats exposed to prior social defeat stress exhibited blunted febrile responses, which were more pronounced in the repeated stress group. Furthermore, only the repeated stress group showed late-onset and prolonged mechanical allodynia lasting until 8days after injection in the von Frey test and prolonged immobility time in the forced swim test 9days post-injection. To assess the role of glucocorticoids and microglia in the delayed and persistent development of these sickness responses in rats exposed to repeated stress, we investigated the effect of pretreatment with RU486, a glucocorticoid receptor antagonist, and minocycline, an inhibitor of microglial activation, on polyI:C-induced allodynia and depressive-like behavior. Pretreatment with either drug inhibited both the delayed allodynia and depressive-like behavior. The present study demonstrates that repeated, but not single, social defeat stress followed by systemic polyI:C administration induced prolonged allodynia and depressive-like behavior in rats. Our results show that even though a single-event psychosocial stress does not have any effect by itself, animals may develop persistent allodynia and depressive-like behavior when they suffer from an infectious disease if they are pre-exposed to repeated or chronic

  1. [Establishment of Social Stress Induced Depression-like Animal Model in Mice of C57BL/6 Strain and Behavioral Assessments].

    PubMed

    Li, Mi-hui; Wu, Xiao; Wei Ying; Dong, Jing-cheng

    2016-02-01

    To establish social stress induced depression-like model in mice of C57BL/6 strain, and to assess its reliability using differenf behavioral methods. Totally 20 male mice of C57BL/6 strain were divided into the normal group and the stress model group by random digit table,10 in each group. Another 10 CD1 mice were subjected to social stress. Mice in the normal control group received no stress, while those in the model group received social stress for 10 successive days. Behavioral assessment was performed using social interaction test (SIT), the elevated plus-maze (EPM) test, tail suspension test (TST), respectively. Serum cortisol level was detected by ELISA to assess the reliability of the model. In the social interaction test when the social target (CDI mice) was inexistent, mice in the normal control group spent longer time in the social interaction zone and less time in the corner zone (P < 0.05); mice in the model group spent less time in the social interaction zone and more time in the corner zone (P < 0.05). Compared with the normal group when CDI mice existed, mice in the model group spent less time in the social interaction zone and more time in the corner zone (P < 0.05). Compared with the normal control group, the total times for entry into open arms, close arms, and the maze were obviously reduced (P < 0.05), and the proportion of entering open arms was significantly reduced (P < 0.05) in the model group. In TST, the motionless time within the last 4 mm was prolonged in the model group (P < 0.05). The serum cortisol level in the model group was obviously elevated (P < 0.01). Social stress induced depression-like animal model in mice of C57BL/6 straineasquite reliable and possibly suitable to be used in integrative medicine research of combination of disease and syndrome model.

  2. Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice

    PubMed Central

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

    Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and left adrenal glands. SI showed lower mRNA levels of the BDNF-7 splice variant, c-Fos, Arc, and Egr-1 in both hippocampus and prefrontal cortex compared to GH mice. Finally, SI mice exhibited selectively reduced mGluR1 and mGluR2 levels in the prefrontal cortex. Altogether, these results suggest that anxious- and depressive-like behavior induced by social isolation stress correlates with reduction of several neuroplasticity-related genes in the hippocampus and prefrontal cortex of adult male mice. PMID:26881124

  3. Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice.

    PubMed

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

    Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and left adrenal glands. SI showed lower mRNA levels of the BDNF-7 splice variant, c-Fos, Arc, and Egr-1 in both hippocampus and prefrontal cortex compared to GH mice. Finally, SI mice exhibited selectively reduced mGluR1 and mGluR2 levels in the prefrontal cortex. Altogether, these results suggest that anxious- and depressive-like behavior induced by social isolation stress correlates with reduction of several neuroplasticity-related genes in the hippocampus and prefrontal cortex of adult male mice.

  4. Increased expression of the anti-apoptotic protein Bcl-xL in the brain is associated with resilience to stress-induced depression-like behavior.

    PubMed

    Dygalo, Nikolay N; Kalinina, Tatyana S; Bulygina, Veta V; Shishkina, Galina T

    2012-07-01

    Clinical observations and the results of animal studies have implicated changes in neuronal survival and plasticity in both the etiology of mood disorders, especially stress-induced depression, and anti-depressant drug action. Stress may predispose individuals toward depression through down-regulation of neurogenesis and an increase in apoptosis in the brain. Substantial individual differences in vulnerability to stress are evident in humans and were found in experimental animals. Recent studies revealed an association between the brain anti-apoptotic protein B cell lymphoma like X, long variant (Bcl-xL) expression and individual differences in behavioral vulnerability to stress. The ability to increase Bcl-xL gene expression in the hippocampus in response to stress may be an important factor for determining the resistance to the development of stress-induced depression. Treatment with anti-depressant drugs may change Bcl-xL response properties. In the rat brainstem, expression of this anti-apoptotic gene becomes sensitive to swim stress during the long-term fluoxetine treatment, an effect that appeared concomitantly with the anti-depressant-like action of the drug in the forced swim test, suggesting that Bcl-xL may be a new target for depression therapy. The processes and pathways linking stress stimuli to behavior via intracellular anti-apoptotic protein are discussed here in the context of Bcl-xL functions in the mechanisms of individual differences in behavioral resilience to stress and anti-depressant-induced effects on the behavioral despair.

  5. The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

    PubMed Central

    García-Rojo, Gonzalo; Fresno, Cristóbal; Vilches, Natalia; Díaz-Véliz, Gabriela; Mora, Sergio; Aguayo, Felipe; Pacheco, Aníbal; Parra-Fiedler, Nicolás; Parra, Claudio S.; Rojas, Paulina S.; Tejos, Macarena; Aliaga, Esteban

    2017-01-01

    Abstract Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity. PMID:27927737

  6. Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice.

    PubMed

    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

  7. 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

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

    PubMed

    Bajwa, Nikita M; Halavi, Shina; 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.

  9. 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

  10. Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like behaviors via targeting cyclooxygenase-2 in mid-aged rats.

    PubMed

    Yao, Ying; Huang, Hai-Ying; Yang, Yuan-Xiao; Guo, Jian-You

    2015-03-13

    COX-2 has been considered as a potent molecular target for prevention and therapy of depression. However, a recent study showed that COX-2 inhibitor does not improve depressive symptoms in persons aged 70 and over. Therefore, whether treatments targeting COX-2 have a clinical efficacy in depression, especially elderly individuals, remains unclear. Cinnamic aldehyde is a major constituent of Cinnamomum cassia, which has exhibited excellent anti-inflammatory activities as a COX-2 inhibitor. To investigate the potential antidepressant effect of cinnamic aldehyde in mid-aged rats. The depressive-like behaviors were measured after the rats exposed to chronic unexpected mild stress (CUMS). Cinnamic aldehyde was administrated by oral gavage to stressed rats (22.5, 45, 90 mg/kg, respectively) for 21 days. The mRNA, protein expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E2 (PGE2) levels were measured in the frontal cortex and hippocampus of stressed animals. We found that CUMS procedure not only decreased the sucrose preference, but also elevated the COX-2 activity, mRNA and protein levels, and increased PGE2 concentration in rat brain regions. Treatment with high doses of cinnamic aldehyde (45, 90 mg/kg) reversed the behavioral abnormalities, and decreased the COX-2 protein and activity (but not COX-2 mRNA expression) and PGE2 concentration in frontal cortex and hippocampus of stressed rats. Cinnamic aldehyde exerted antidepressant-like effects in stressed mid-aged rats, and its mechanism of action appears to decrease COX-2 protein and activity. The current findings suggest that targeting COX-2 system might be benefit to the depression, especially elderly individuals and cinnamic aldehyde might be a promising medicine to treat the subjects in the depression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Impaired GABA synthesis, uptake and release are associated with depression-like behaviors induced by chronic mild stress

    PubMed Central

    Ma, K; Xu, A; Cui, S; Sun, M-R; Xue, Y-C; Wang, J-H

    2016-01-01

    Major depression is a prevalent emotion disorder. Chronic stressful life in genetically susceptible individuals is presumably a major etiology that leads to neuron and synapse atrophy in the limbic system. Molecular mechanisms underlying the pathological changes remain elusive. Mice were treated by chronic unpredictable mild stress (CUMS) until they demonstrated depression-like behavior. GABA release in the medial prefrontal cortex was evaluated by cell electrophysiology and imaging. Molecular profiles related to GABA synthesis and uptake were investigated by the high-throughput sequencings of microRNAs and mRNAs as well as western blot analysis in this cortical area. In CUMS-induced depression mice, there appear the decreases in the innervation and function of GABAergic axons and in the levels of mRNAs and proteins of glutamate decarboxylase-67, vesicular GABA transporter and GABA transporter-3. miRNA-15b-5p, miRNA-144-3p, miRNA-582-5p and miRNA-879-5p that directly downregulate such mRNAs increase in this cortex. Our results suggest that chronic mild stress impairs GABA release and uptake by upregulating miRNAs and downregulating mRNAs and proteins, which may constitute the subcellular and molecular mechanisms for the lowered GABA tone in major depression. PMID:27701406

  12. Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress.

    PubMed

    Chen, Xue-Qin; Chen, Shu-Jiao; Liang, Wen-Na; Wang, Miao; Li, Cheng-Fu; Wang, Shuang-Shuang; Dong, Shu-Qi; Yi, Li-Tao; Li, Can-Dong

    2017-09-25

    Accumulating studies have shown that a traditional Chinese decoction Chaihu-Shugan-San produced the antidepressant-like effects in rodents including in perimenopausal. Previous studies and our preliminary study indicated that saikosaponin A, one of the main constituents of Chaihu-Shugan-San, enhanced brain-derived neurotrophic factor (BDNF) expression in rats. Herein, this study aimed to evaluate the antidepressant-like effects of saikosaponin A in perimenopausal rats exposed to chronic unpredictable mild stress (CUMS). The sucrose preference test, novelty-suppressed feeding test and forced swimming test were performed after administration of saikosaponin A for 4 weeks. Serum corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone levels, as well as hypothalamus CRH and hippocampal glucocorticoid receptor were measured. In addition, pro-inflammatory cytokines such as interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the hippocampus were detected for evaluation of the neuroinflammation. Further, BDNF levels and its receptor TrkB were also determined. Our results indicated that four-week treatment with saikosaponin A increased sucrose preference, decreased latency to feed in the novelty-suppressed feeding test and reduced the immobility time in the forced swimming test. In addition, saikosaponin A restored the dsyregulation of HPA axis and neuroinflammation in rats exposed to CUMS. Moreover, saikosaponin A promoted BDNF-TrkB signaling in the hippocampus. This study demonstrates that saikosaponin A produced the antidepressant-like effects in rats, which may be mediated by restoration of neuroendocrine, neuroinflammation and neurotrophic systems in the hippocampus during perimenopausal. Copyright © 2017. Published by Elsevier B.V.

  13. Electroacupuncture relieves depression-like symptoms in rats exposed to chronic unpredictable mild stress by activating ERK signaling pathway.

    PubMed

    Li, Weidong; Zhu, Yan; Saud, Shakir M; Guo, Qiujun; Xi, Shengyan; Jia, Baohui; Jiao, Shuang; Yang, Xiuyan; Lu, Jun; Song, Sihong; Tu, Ya

    2017-03-06

    Electroacupuncture (EA) has been shown to alleviate the symptoms associated with major depressive disorder; however, the underlying mechanisms remain unclear. While the mainstay treatment for depression are pharmacological agents that modulate serotonergic and/or noradrenergic activity of the brain, recent data suggest that, neurotrophins may play a larger role in the pathogenesis of depression and may offer better therapeutic potential in alleviating symptoms associated with depression. One downstream target of neurotrophins is the extracellular signal-regulated kinase (ERK)/Mitogen-activated protein kinase (MAPK) cascade, a major mediator of cellular stress often associated with clinical depression. In this study, we assessed whether the efficacy of EA is due to regulation of these novel pathways using an animal model of depression induced by chronic unpredictable mild stress (CUMS). We found that EA stimulation at specific locations, Baihui (GV20), and Yintang (GV29) ameliorated the behavioral responses of CUMS, which included reduced locomotion, decreased sucrose intake and weight loss. Furthermore, EA increased the activation of ERK and ribosomal s6 kinase (RSK) levels under stress. Both the behavioral and biochemical responses to EA were attenuated with administration of ERK inhibitor, suggesting that EA improves depression-like symptoms in stressed rats, in part, by activation of ERK signaling.

  14. Catalase activity as a biomarker for mild-stress-induced robustness in Bacillus weihenstephanensis.

    PubMed

    den Besten, Heidy M W; Effraimidou, Styliani; Abee, Tjakko

    2013-01-01

    Microorganisms are able to survive and grow in changing environments by activating stress adaptation mechanisms which may enhance bacterial robustness. Stress-induced enhanced robustness complicates the predictability of microbial inactivation. Using psychrotolerant Bacillus weihenstephanensis strain KBAB4 as a model, we investigated the impact of the culturing temperature on mild-oxidative-stress-induced (cross-)protection toward multiple stresses, including severe oxidative, heat, and acid stresses. Culturing at a refrigeration temperature (7°C) compared to the optimal growth temperature (30°C) affected both the robustness level of B. weihenstephanensis and the oxidative stress adaptive response. Scavengers of reactive oxygen species have a crucial role in adaptation to oxidative stresses, and this points to a possible predictive role in mild-oxidative-stress-induced robustness. Therefore, the catalase activity was determined upon mild oxidative stress treatment and was demonstrated to be significantly correlated with the robustness level of mild-stress-treated cells toward severe oxidative and heat stresses but not toward severe acid stress for cells grown at both refrigeration and optimal temperatures. The quantified correlations supported the predictive quality of catalase activity as a biomarker and also underlined that the predictive quality is stress specific. Biomarkers that are able to predict stress-induced enhanced robustness can be used to better understand stress adaptation mechanisms and might allow the design of effective combinations of hurdles to control microbial behavior.

  15. Two weeks of predatory stress induces anxiety-like behavior with co-morbid depressive-like behavior in adult male mice.

    PubMed

    Burgado, Jillybeth; Harrell, Constance S; Eacret, Darrell; Reddy, Renuka; Barnum, Christopher J; Tansey, Malú G; Miller, Andrew H; Wang, Huichen; Neigh, Gretchen N

    2014-12-15

    Psychological stress can have devastating and lasting effects on a variety of behaviors, especially those associated with mental illnesses such as anxiety and depression. Animal models of chronic stress are frequently used to elucidate the mechanisms underlying the relationship between stress and mental health disorders and to develop improved treatment options. The current study expands upon a novel chronic stress paradigm for mice: predatory stress. The predatory stress model incorporates the natural predator-prey relationship that exists among rats and mice and allows for greater interaction between the animals, in turn increasing the extent of the stressful experience. In this study, we evaluated the behavioral effects of exposure to 15 days of predatory stress on an array of behavioral indices. Up to 2 weeks after the end of stress, adult male mice showed an increase of anxiety-like behaviors as measured by the open field and social interaction tests. Animals also expressed an increase in depressive-like behavior in the sucrose preference test. Notably, performance on the novel object recognition task, a memory test, improved after predatory stress. Taken as a whole, our results indicate that 15 exposures to this innovative predatory stress paradigm are sufficient to elicit robust anxiety-like behaviors with evidence of co-morbid depressive-like behavior, as well as changes in cognitive behavior in male mice.

  16. Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway

    PubMed Central

    Zhang, Jin-qiang; Wu, Xiao-hui; Feng, Yi; Xie, Xiao-fang; Fan, Yong-hua; Yan, Shuo; Zhao, Qiu-ying; Peng, Cheng; You, Zi-li

    2016-01-01

    Aim: Major depressive disorder (MDD) is a debilitating mental disorder associated with dysfunction of the neurotransmitter-neuroendocrine system and neuroinflammatory responses. Salvianolic acid B (SalB) has shown a variety of pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects. In this study, we examined whether SalB produced antidepressant-like actions in a chronic mild stress (CMS) mouse model, and explored the mechanisms underlying the antidepressant-like actions of SalB. Methods: Mice were subjected to a CMS paradigm for 6 weeks. In the last 3 weeks the mice were daily administered SalB (20 mg·kg−1·d−1, ip) or a positive control drug imipramine (20 mg·kg−1·d−1, ip). The depressant-like behaviors were evaluated using the sucrose preference test, the forced swimming test (FST), and the tail suspension test (TST). The gene expression of cytokines in the hippocampus and cortex was analyzed with RT-PCR. Plasma corticosterone (CORT) and cerebral cytokines levels were assayed with an ELISA kit. Neural apoptosis and microglial activation in brain tissues were detected using immunofluorescence staining. Results: Administration of SalB or imipramine reversed the reduced sucrose preference ratio of CMS-treated mice, and significantly decreased their immobility time in the FST and TST. Administration of SalB significantly decreased the expression of pro-inflammatory cytokines IL-1β and TNF-α, and markedly increased the expression of anti-inflammatory cytokines IL-10 and TGF-β in the hippocampus and cortex of CMS-treated mice, and normalized their elevated plasma CORT levels, whereas administration of imipramine did not significantly affect the imbalance between pro- and anti-inflammatory cytokines in the hippocampus and cortex of CMS-treated mice. Finally, administration of SalB significantly decreased CMS-induced apoptosis and microglia activation in the hippocampus and cortex, whereas administration of

  17. Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2

    PubMed Central

    Birey, Fikri; Kloc, Michelle; Chavali, Manideep; Hussein, Israa; Wilson, Michael; Christoffel, Daniel J.; Chen, Tony; Frohman, Michael A.; Robinson, John K.; Russo, Scott J.; Maffei, Arianna; Aguirre, Adan

    2015-01-01

    SUMMARY NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders. PMID:26606998

  18. Comparison of stress-induced and LPS-induced depressive-like behaviors and the alterations of central proinflammatory cytokines mRNA in rats.

    PubMed

    Guan, Xi-Ting; Lin, Wen-Juan; Tang, Ming-Ming

    2015-09-01

    Although proinflammatory cytokine changes in depression have been studied widely, few investigations have searched for specific and common changes in cytokines. In the present study, two animal models of depression were compared: a chronic stress model using forced swim stress and an immune activation model using repeated central lipopolysaccharide (LPS) infusion. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 mRNA were examined in the brain regions of the prefrontal cortex, amygdala, and hippocampus using real-time polymerase chain reaction (RT-PCR). It was found that both chronic swim stress and repeated central LPS infusion induced depressive-like behaviors, including decreased body weight, reduced saccharin preference, and increased immobility time or shortened latency of immobility in the tail suspension test. Central TNF-α mRNA expression was elevated in both models and central IL-6 mRNA expression was unchanged in both models. Central IL-1β mRNA expression was increased only in the chronic immune activation model. The findings from this study suggest that TNF-α may be a common risk factor for inflammation in depressive disorders.

  19. Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2.

    PubMed

    Birey, Fikri; Kloc, Michelle; Chavali, Manideep; Hussein, Israa; Wilson, Michael; Christoffel, Daniel J; Chen, Tony; Frohman, Michael A; Robinson, John K; Russo, Scott J; Maffei, Arianna; Aguirre, Adan

    2015-12-02

    NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders.

  20. Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats

    PubMed Central

    Benelli, A; Filaferro, M; Bertolini, A; Genedani, S

    1999-01-01

    S-adenosyl-L-methionine (SAMe) is the most important methyl donor in the brain and is essential for polyamine synthesis. Methyl group deficiency in the brain has been implicated in depression; on the other hand, polyamines enhance phosphorylation processes, and phosphorylation of functional proteins in neurons is involved in the therapeutic mechanisms of antidepressants. The effect of SAMe in an animal model of ‘depression', the chronic mild stress-induced anhedonia, was studied using long-term castrated male and female Lister hooded rats. Chronic daily exposure to an unpredictable sequence of mild stressors produced, within 3 weeks, a significant reduction of the consumption of a sucrose solution. SAMe (100, 200 or 300 mg kg−1 daily i.m.) while having no influence on sucrose intake in non-stressed animals, dose-dependently reinstated sucrose consumption within the first week of treatment, both in male and in female stressed rats. Imipramine (10 mg kg−1 daily i.p.) produced a similar effect after a 3 week treatment. Similarly, a palatable food reward-induced place preference conditioning was developed in SAMe (200 or 300 mg kg−1 daily i.m.)- and in imipramine (10 mg kg−1 daily i.p.)-treated chronically stressed animals (males and females), whilst it could not be obtained in vehicle-treated rats. Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory activity and curiosity for the environment (rearing), in the open-field test. While imipramine caused a blockade of the growth throughout the treatment, SAMe produced only a transient growth arrest during the first week of treatment. These results show that SAMe reverses an experimental condition of ‘depression-like' behaviour in rats, the effect being more rapid and complete than that of imipramine, and without apparent side effects. PMID:10401554

  1. Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice

    PubMed Central

    Wang, Zhen-Zhen; Yang, Wei-Xing; Zhang, Yi; Zhao, Nan; Zhang, You-Zhi; Liu, Yan-Qin; Xu, Ying; Wilson, Steven P.; O'Donnell, James M.; Zhang, Han-Ting; Li, Yun-Feng

    2015-01-01

    Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices. PMID:26161529

  2. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes.

    PubMed

    Bhutani, Mohit Kumar; Bishnoi, Mahendra; Kulkarni, Shrinivas K

    2009-03-01

    Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

  3. Unpredictable chronic mild stress induced behavioral deficits: a comparative study in male and female rats.

    PubMed

    Farhan, Muhammad; Ikram, Huma; Kanwal, Sumera; Haleem, Darakhshan Jabeen

    2014-07-01

    Stress is an important precipitant factor for depression. Changes in various body systems that occur in depression are similar to those observed in response to stress. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Unpredictable chronic mild stress (UCMS) also produces alteration in the serotonergic (5-HT; 5-hydroxytryptamine) neurotransmission. Unpredictable chronic mild stress (UCMS) could be used as an animal model of depression. Neurochemical and behavioral effects of UCMS can be reversed by antidepressant agents, suggesting an important role of serotonin. In rodents, UCMS can elicit depression-like symptoms. The objective of the present study was to evaluate and compare the behavioral deficits induced by chronic mild stress in male and female rats and finding out the vulnerability of the two groups. Male and female rats exposed to UCMS exhibited a significant decrease in cumulative food intake as well as in growth rate. Loco motor activity in home cage and open field was also decreased. Results may contribute to our understanding of the interaction between stress and behavioral functions have to depressive disorders.

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

    PubMed Central

    Yang, Jin Ling; Liu, De Xiang; Jiang, Hong; Pan, Fang; Ho, Cyrus SH; Ho, Roger CM

    2016-01-01

    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. PMID:27739518

  5. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

    PubMed Central

    Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

  6. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats.

    PubMed

    Kushwah, Neetu; Jain, Vishal; Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state.

  7. Effects of Electroacupuncture on Chronic Unpredictable Mild Stress Rats Depression-Like Behavior and Expression of p-ERK/ERK and p-P38/P38

    PubMed Central

    Xu, Jian; She, Yanling; Su, Ning; Zhang, Ruixin; Lao, Lixing; Xu, Shifen

    2015-01-01

    We investigate the antidepressant-like effect and mechanism of electroacupuncture (EA) on a chronic unpredictable mild stress rats depression-like behavior. In our study, depression in rats was induced by unpredictable chronic mild stress (UCMS) and isolation for four weeks. Male Sprague-Dawley rats were randomly divided into four groups: Normal, Model, EA, and Sham EA. EA treatment was administered for two weeks, once a day for five days a week. Two acupoints, Yintang (EX-HN3) and Baihui (GV20), were selected. For sham EA, acupuncture needles were inserted shallowly into the acupoints: EX-HN3 and GV20. No electrostimulator was connected. The antidepressant-like effect of the electroacupuncture treatment was measured by sucrose intake test, open field test, and forced swimming test in rats. The protein levels of phosphorylated extracellular regulated protein kinases (p-ERK1/2)/ERK1/2 and p-P38/P38 in the hippocampus (HP) were examined by Western blot analysis. Our data demonstrate that EA treatment decreased the immobility time of forced swimming test and improved the sucrose solution intake in comparison to unpredictable chronic mild stress and placebo sham control. Electroacupuncture may act on depression by enhancing p-ERK1/2 and p-p38 in the hippocampus. PMID:26366182

  8. MDMA Pretreatment Leads to Mild Chronic Unpredictable Stress-induced Impairments in Spatial Learning

    PubMed Central

    Cunningham, Jacobi I.; Raudensky, Jamie; Tonkiss, John; Yamamoto, Bryan K.

    2009-01-01

    3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse world-wide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. While MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT. PMID:19824774

  9. Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats.

    PubMed

    Fu, Wan; Xie, Heng; Laudon, Moshe; Zhou, Shouhong; Tian, Shaowen; You, Yong

    2016-06-01

    Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer's disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear. The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. Rats were exposed randomly to chronic mild stressors for 7 weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50 mg/kg) was administered daily during the last 2 weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus. We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine. Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits.

  10. 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

  11. Melatonin produces a rapid onset and prolonged efficacy in reducing depression-like behaviors in adult rats exposed to chronic unpredictable mild stress.

    PubMed

    Sun, Xiaoran; Wang, Mengting; Wang, Yiqiang; Lian, Bo; Sun, Hongwei; Wang, Gang; Li, Qi; Sun, Lin

    2017-03-06

    The present study was aimed at evaluating the rapidity and duration of melatonin as an antidepressant in a rat model of depression. The rats were subjected to a six-week period of unpredictable mild stress followed by melatonin treatment. Three groups of rats were included in this study: Controls (CON - no stress exposure), Chronic Unpredictable Mild Stress (CUS) and CUS followed by melatonin (MT). Stressors consisted of exposure to rotation on a shaker, placement in a chamber maintained at 4°C, lights off for 3h, lights on overnight, exposure to an aversive odor, 45° tilted cages, food and water deprivation and crowding and isolated housing. Subsequently, the saline vehicle (CUS) or melatonin was administered at a dose of 10mg/kg for 14days period. Body weight and behavioral tests were used to evaluate depression-like behavior and its recovery following melatonin treatment. While body weight increases were significantly lower in rats exposed to CUS versus CON, body weights of the MT group increased significantly following melatonin treatment as compared with the CUS group. With regard to results obtained with behavioral assays indicative of depression, rapid and long-term functional recoveries in depression were observed in the MT as compared to the CUS group. The results indicate that not only does melatonin induce an antidepressant-like action within this rat model of depression, but does so with a rapid onset and prolonged efficacy. As most current treatments for depression require an extended period of administration, our current results suggest that melatonin may prove to be a particularly effect agent to promote a rapid onset and prolonged behavioral benefits in the treatment of depression. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Effect of serotonergic and catecholaminergic antagonists on mild-stress-induced excessive grooming in the rat.

    PubMed

    Rodríguez Echandía, E L; Broitman, S T; Fóscolo, M R

    1983-12-01

    Excessive grooming was induced in male rats by two ip injections of physiological saline. This mild stressful procedure did not modify open-field locomotion in 5-min trials. Methysergide (15 mg/kg) and pizotifene (5 mg/kg), serotonergic blockers, selectively prevented the grooming response to saline without affecting locomotion. Haloperidol (.4 mg/kg) also prevented the excessive grooming. However, this dopaminergic blocker impaired locomotion. The alpha- or beta-adrenoceptor antagonists phentolamine (20 mg/kg) and l-propranolol (20 mg/kg) did not prevent the excessive grooming in response to saline and did not affect locomotion. The results suggest that some serotonergic pathways in the brain are involved in the grooming response to a mild stress and support previous findings on the role of dopaminergic systems on this activity.

  13. Mild Lipid Stress Induces Profound Loss of MC4R Protein Abundance and Function

    PubMed Central

    Cragle, Faith K.

    2014-01-01

    Food intake is controlled at the central level by the melanocortin pathway in which the agonist α-MSH binds to melanocortin 4 receptor (MC4R), a Gs-coupled G protein-coupled receptor expressed by neurons in the paraventricular nuclei of the hypothalamus, which signals to reduce appetite. Consumption of a high-fat diet induces hypothalamic accumulation of palmitate, endoplasmic reticulum (ER) stress, apoptosis, and unresponsiveness to prolonged treatment with MC4R agonists. Here we have modeled effects of lipid stress on MC4R by using mHypoE-42 immortalized hypothalamic neurons expressing endogenous MC4R and Neuro2A cells expressing a tagged MC4R reporter, HA-MC4R-GFP. In the hypothalamic neurons, exposure to elevated palmitate in the physiological range induced splicing of X-box binding protein 1, but it did not activate C/EBP-homologous protein or induce increased levels of cleaved caspase-3, indicating mild ER stress. Such mild ER stress coexisted with a minimal loss of MC4R mRNA and yet a profound loss of cAMP signaling in response to incubation with the agonist. These findings were mirrored in the Neuro2A cells expressing HA-MC4R-GFP, in which protein abundance of the tagged receptor was decreased, whereas the activity per receptor number was maintained. The loss of cAMP signaling in response to α-MSH by elevated palmitate was corrected by treatment with a chemical chaperone, 4-phenylbutyrate in both mHypoE-42 hypothalamic neurons and in Neuro2A cells in which protein abundance of HA-MC4R-GFP was increased. The data indicate that posttranscriptional decrease of MC4R protein contribute to lower the response to α-MSH in hypothalamic neurons exposed to even a mild level of lipid stress and that a chemical chaperone corrects such a defect. PMID:24506538

  14. Protective effects of a novel 5-HT3 receptor antagonist, N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) against chronic unpredictable mild stress-induced behavioral changes and biochemical alterations.

    PubMed

    Bhatt, Shvetank; Mahesh, Radhakrishnan; Jindal, Ankur; Devadoss, Thangaraj

    2014-07-01

    Stimulation of high oxidative stress in the brain is considered as an important factor for neurotoxicity towards the pathophysiology of chronic stress-induced depression disorder. In the present research, a potential 5-HT₃ receptor antagonist N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) having good Log P (2.60) and pA₂ (7.7) values was examined for its effect on the behavioral and biochemical changes induced by the chronic unpredictable mild stress (CUMS) model. In the current investigation mice were introduced to different stress procedures daily for a period of 28 days to induce a depressive-like behavior. The results show that CUMS caused a depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and locomotor activity and increase in immobility in the forced swim test (FST). Moreover, it was found that oxidative stress markers such as lipid peroxide and nitrite levels were significantly increased, whereas, antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in the brain tissue of CUMS-subjected mice. "Compound 6o" (1 and 2 mg/kg, p.o.) and fluoxetine treatment (20 mg/kg, p.o.) for a period of 21 days altered the CUMS-induced behavioral (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxide, increased brain nitrite; decreased GSH, SOD and CAT levels) alterations. Moreover normal mice treated with "compound 6o" (2 mg/kg, p.o.) showed a significant decrease in the duration of immobility in FST as compared to normal vehicle treated mice. In conclusion, "compound 6o" produced antidepressant-like effects in behavioral despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity.

  15. Chronic mild stress induces variations in locomotive behavior and metabolic rates in high fat fed rats.

    PubMed

    García-Díaz, D F; Campion, J; Milagro, F I; Lomba, A; Marzo, F; Martínez, J A

    2007-12-01

    Chronic mild stress (CMS) has been often associated to the pathogenesis of many diseases including obesity. Indeed, visceral obesity has been linked to the development of metabolic syndrome features and constitutes a serious risk factor for cardiovascular diseases and diabetes. In order to study possible mechanistic relationships between stress and the onset of obesity, we developed during 11 weeks a model of high-fat dietary intake (cafeteria diet) together with a CMS regimen in male Wistar rats. During the experimental period, basal metabolism by indirect calorimetry, rectal temperature, food intake, and locomotive markers were specifically analyzed. After 77 days, animals were sacrificed and body, adiposity and plasma biochemical profiles were also examined. As expected, cafeteria diet in unstressed animals induced a significative increase in body weight, adiposity, and insulin resistance markers. Locomotive variables, specifically distance, rearing and meander, were significantly increased by CMS on the first weeks of stress. Moreover, this model of CMS in Wistar rats increased significantly energy expenditure, and apparently interplayed with the dietary treatment on the muscle weight/fat weight ratio. In summary, this chronic stress model did not affected weight gain in control and high fat fed animals, but induced an interaction concerning the metabolic muscle/fat repartitioning.

  16. Electroacupuncture Restores 5-HT System Deficit in Chronic Mild Stress-Induced Depressed Rats

    PubMed Central

    Tu, Ya; Yang, Xiuyan; Liu, Ping

    2016-01-01

    Objective. The current study is designed to investigate the antidepressant efficacy of electroacupuncture (EA) treatment by evaluating its effect on the synthesis, metabolism, reuptake, and receptors of 5-hydroxytryptamine (5-HT), so as to clarify the molecular mechanisms of EA for antidepression. Materials and Methods. Solitary combined with the chronic unpredictable mild stress (CUMS) was used to establish the rat model with depression. The depressed rats were supplied with EA treatment for 4 weeks, and the behavior change and the following indices including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase A (MAO-A), tryptophan hydroxylase (TPH), 5-HT transporter (SERT), 5-HT1A, and 5-HT2A in hippocampus and prefrontal cortex were examined. Results. EA treatment significantly improved the behavior of rats and increased 5-HT level in hippocampus of depressed rats. Similarly, EA treatment could significantly increase protein and mRNA expression of TPH and 5-HT1A during 5-HT synthesis process in hippocampus of depressed rats. However, EA treatment had no effect on the activity of MAO-A and the expression of SERT protein and mRNA. Conclusion. Antidepressant efficacy of EA treatment can be accomplished through enhancing 5-HT synthesis, upregulating 5-HT1A level, and improving 5-HT content in brain and synaptic gaps. PMID:27994633

  17. Electroacupuncture Restores 5-HT System Deficit in Chronic Mild Stress-Induced Depressed Rats.

    PubMed

    Duan, Dongmei; Tu, Ya; Yang, Xiuyan; Liu, Ping

    2016-01-01

    Objective. The current study is designed to investigate the antidepressant efficacy of electroacupuncture (EA) treatment by evaluating its effect on the synthesis, metabolism, reuptake, and receptors of 5-hydroxytryptamine (5-HT), so as to clarify the molecular mechanisms of EA for antidepression. Materials and Methods. Solitary combined with the chronic unpredictable mild stress (CUMS) was used to establish the rat model with depression. The depressed rats were supplied with EA treatment for 4 weeks, and the behavior change and the following indices including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase A (MAO-A), tryptophan hydroxylase (TPH), 5-HT transporter (SERT), 5-HT1A, and 5-HT2A in hippocampus and prefrontal cortex were examined. Results. EA treatment significantly improved the behavior of rats and increased 5-HT level in hippocampus of depressed rats. Similarly, EA treatment could significantly increase protein and mRNA expression of TPH and 5-HT1A during 5-HT synthesis process in hippocampus of depressed rats. However, EA treatment had no effect on the activity of MAO-A and the expression of SERT protein and mRNA. Conclusion. Antidepressant efficacy of EA treatment can be accomplished through enhancing 5-HT synthesis, upregulating 5-HT1A level, and improving 5-HT content in brain and synaptic gaps.

  18. Can Ocimum basilicum relieve chronic unpredictable mild stress-induced depression in mice?

    PubMed

    Ayuob, Nasra Naeim; Firgany, Alaa El-Din L; El-Mansy, Ahmed A; Ali, Soad

    2017-08-18

    Depression is one of the important world-wide health problems. This study aimed to assess the ameliorative effect of Ocimum basilicum (OB) essential oil on the behavioral, biochemical and histopathological changes resulted from exposure to chronic unpredictable mild stress (CUMS). It also aimed to investigate the underlying mechanism in an animal model of depression. Forty male Swiss albino mice were divided into four groups (n=10): control, CUMS (exposed to CUMS for 4weeks), CUMS plus fluoxetine, and CUMS plus OB. At the end of the experiment, behavioral changes, serum corticosterone level, protein and gene expressions of brain derived neurotropic factor (BDNF) and glucocorticoid receptors (GR) in the hippocampus was all assessed. Immunoexpression of surface makers of glial fibrillary acidic protein (GFAP), Ki67, Caspase-3, BDNF and GR in the hippocampus were estimated. Data were analyzed by using the statistical package for the social sciences (SPSS). OB alleviated both behavioral and biochemical changes recorded in mice after exposure to CUMS. It also reduced neuronal atrophy observed in the hippocampal region III cornu ammonis (CA3) and dentate gyrus and restored back astrocyte number. OB decreased apoptosis in both neurons and glial cells and increased neurogenesis in the dentate gyrus in a pattern comparable to that of fluoxetine. Increased BDNF and GR gene and protein expressions seems to be behind the antidepressant-like effect of OB. Ocimum basilicum ameliorates the changes induced after exposure to the chronic stress. Assessing Ocimum basilicum efficacy on human as antidepressant is recommended in further studies. Copyright © 2017. Published by Elsevier Inc.

  19. Behavioural and neurochemical evaluation of Perment an herbal formulation in chronic unpredictable mild stress induced depressive model.

    PubMed

    Ramanathan, M; Balaji, B; Justin, A

    2011-04-01

    Perment, a polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The aim of the present study was to explore the behavioural effects and to understand possible mode of action of Perment in stress induced depressive model. Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour. Using standard protocols plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant action than anxiolytic activity. Further Perment increased the plasma noradrenaline and serotonin levels in stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with Perment treatment. However the adrenal corticosterone level is decreased with Perment. It can be concluded that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic activity, which may be mediated through adrenergic and serotonergic system activation. Currently the formulation is clinically used as anxiolytic but the present results suggest that the formulation can also be indicated in patients affected with depression.

  20. Protective Effect of Irbesartan an Angiotensin (AT1) Receptor Antagonist in Unpredictable Chronic Mild Stress Induced Depression in Mice.

    PubMed

    Ayyub, M; Najmi, A K; Akhtar, M

    2017-01-01

    Objective: Oxidative stress and alternation of renin-angiotensin system has been implicated in the pathophysiology of various cardio vascular, endocrine including mood and anxiety disorders. The present study evaluated the role of irbesartan in stress induced different models of depression. Materials and method: Mice were treated with irbesartan (40 mg/kg), fluoxetine (25 mg/kg) alone in combination orally. Drugs treatment started after 2 weeks from the beginning of the unpredictable mild stress (UCMS) protocol. Behavioural tests were performed on week 6, at least 24 h after the last treatment. Modified forced swim test (MFST), tail suspension test (TST) and open field test (OFT) were used followed by antioxidant markers and 5-HT levels determination. Result: Irbesartan increased swimming, climbing and decreased immobility times in MFST, decrease immobility time in TST. Irbesartan also increased no. of field crossings; rearings and also increased time spent in the centre of OFT. Thus, antidepressant like activity in UCMS mice was observed. Combination of irbesartan with fluoxetine showed potentiating effect of behavioural parameters in all animal models. Combination groups also showed antioxidant effects and elevated the 5-HT levels in UCMS mice. Conclusion: Chronic administration of Irbesartan exerted antidepressant like effect, reduced oxidative stress and elevated brain 5-HT levels.

  1. Beneficial effect of a symbiotic preparation with S. boulardii lysate in mild stress-induced gut hyper-permeability.

    PubMed

    Takadanohara, Hiroshi; Catanzaro, Roberto; Chui, De Hua; He, Fengtian; Yadav, Hariom; Ganguli, Abhijit; Sakata, Yasuhiko; Solimene, Umberto; Minelli, Emilio; Kobayashi, Riyichi; Nagamachi, Yoko; Marotta, Francesco

    2012-12-01

    Increased intestinal permeability has been advocated as one of the likely causes of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Thus, the aim of the present study was to test a symbiotic preparation containing microbial lysates (KC-1317, Named, Italy) against stress-induced derangement of gut mucosa permeability. Sprague Dawley rats were allocated into control (n=20) and stress (n=20) group. Stress was implemented by 1h of water avoidance stress daily for 10 days. Body weight, food and water intake and passage of stool pellet during stress session were recorded throughout the experiment. On the 11th day, fluorescent iso-thiocyanate dextran solution was injected into small intestinal loops. One hour after the injection, rats were sacrificed. Jejunum and ileum were taken for histopathology. Blood was collected from the abdominal aorta to measure intestinal permeability. In stress group, stool pellets during stress session was significantly higher than control group (p < 0.01). Villus height (p < 0.01), crypt depth (p < 0.01), number of goblet cells in villus (p < 0.01) and crypt (p < 0.05) decreased significantly in jejunum as compared to control. These phenomena were significantly prevented by KC-1317 (p < 0.05). Ileum also showed atrophy but villus height and the number of goblet cells in the villi did not significantly differ. Plasma-concentration of brain-gut peptides (substance P, thyrotropin-releasing hormone, cholecystokinin and motilin) were affected by stress (p < 0.001) and this effect did not change during supplementation with KC-1317. Polymorphonuclear neutrophil counting was significantly higher in stress group as compared to control (p < 0.01) but this phenomenon was abolished in the ileum (p < 0.01) or partly but significantly reduced by KC-1317 supplementation (p < 0.05). Accordingly, intestinal permeability was significantly enhanced in stress group as compared to control (p < 0.01) and prevented by KC

  2. Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g) on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice

    PubMed Central

    Bhatt, Shvetank; Radhakrishnan, Mahesh; Jindal, Ankur; Devadoss, Thangaraj; Dhar, Arghya Kusum

    2014-01-01

    Aim: The aim of the study was to evaluate a novel 5 HT3 receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body's reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants. Materials and Methods: In the present study, a novel and potential 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) with good Log P (3.08) value and pA2(7.5) values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS)-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. Results: The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05) decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05) increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. ‘6g’ (1 and 2 mg/kg, p.o., 21 days) and fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly (P < 0.05) reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities). However fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly decreased the nitrite level in the brain while ‘6g’ (1 and 2 mg/kg, p.o., 21 days) did not show significant (P < 0.05) effect on the

  3. Disturbance of hippocampal H2S generation contributes to CUMS-induced depression-like behavior: involvement in endoplasmic reticulum stress of hippocampus.

    PubMed

    Tan, Huiying; Zou, Wei; Jiang, Jiamei; Tian, Ying; Xiao, Zhifang; Bi, Lili; Zeng, Haiying; Tang, Xiaoqing

    2015-04-01

    The chronic unpredictable mild stress (CUMS) model is a widely used experimental model of depression. Exogenous stress-induced neuronal cell death in the hippocampus is closely associated with the pathogenesis of depression. Excessive and prolonged endoplasmic reticulum (ER) stress triggers cell death. Hydrogen sulfide (H2S), the third endogenous signaling gasotransmitter, plays an important role in brain functions as a neuromodulator and a neuroprotectant. We hypothesized that the disturbance of endogenous H2S generation and ER stress in the hippocampus might be involved in CUMS-induced depression-like behaviors. Thus, the present study focused on whether CUMS disturbs the generation of endogenous H2S and up-regulates ER stress in the hippocampus and whether exogenous H2S prevents CUMS-induced depressive-like behaviors. Results showed that CUMS-treated rats exhibit depression-like behavior and hippocampal ER stress responses including up-regulated levels of glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and cleaved caspase-12 expression, while the endogenous generation of H2S in the hippocampus is suppressed in CUMS-treated rats. Furthermore, exogenous H2S prevents CUMS-induced depression-like behavior. These data indicated that CUMS-induced depression-like behaviors are related to the disturbance of endogenous H2S generation and ER stress in the hippocampus and suggested that endogenous H2S and ER stress are novel treatment targets of depression.

  4. Antidepressant-like effects of Marasmius androsaceus metabolic exopolysaccharides on chronic unpredictable mild stress-induced rat model.

    PubMed

    Song, Jia; Wang, Xue; Huang, Yu; Qu, Yidi; Teng, Lesheng; Wang, Di; Meng, Zhaoli

    2017-10-01

    Marasmius androsaceus (M. androsaceus), a medicinal fungus, has various pharmacological activities including antidepression. The present study investigated the effects of exopolysaccharides obtained during M. androsaceus submerged fermentation in a chronic unpredictable mild stress (CUMS)‑induced depression rat model. Similar to fluoxetine (positive drug), 4‑week administration of M. androsaceus exopolysaccharides (MEPS) at doses of 6, 30 and 150 mg/kg strongly enhanced bodyweight gain and sucrose consumption, and reduced the immobility time in forced swimming test and tail suspension test in CUMS rats. MEPS resulted in significant enhancement on the levels of noradrenalin, dopamine, 5‑hydroxytryptamine (5‑HT), and 5‑hydroxyindoleacetic acid in the serum and hypothalamus of CUMS rats, as detected by ELISA. Western blotting results revealed that MEPS upregulated the protein expression levels of tyrosine hydroxylase in the hypothalamus of CUMS rats. In conclusion, these results confirmed the antidepressant‑like effects of MEPS, and suggested that the monoamine neurotransmitter system is involved in its antidepressive effects in a CUMS rat model. The present study provided evidence for the clinical application of MEPS as an effective agent against depression.

  5. Possible involvement of stress hormones and hyperglycaemia in chronic mild stress-induced impairment of immune functions in diabetic mice.

    PubMed

    Rubinstein, M R; Cremaschi, G A; Oliveri, L M; Gerez, E N; Wald, M R; Genaro, A M

    2010-09-01

    Stress, an important aspect of modern life, has long been associated with an altered homeostatic state. Little is known about the effect of the life stress on the outcome of diabetes mellitus, especially related to the higher risk of infections. Here, we evaluate the effects of chronic mild stress (CMS) exposure on the evolution of type I diabetes induced by streptozotocin administration in BALB/c mice. Exposure of diabetic mice to CMS resulted in a significant reduction of survival and a sustained increase in blood glucose values. Concerning the immune response, chronic stress had a differential effect in mice with diabetes with respect to controls, showing a marked decrease in both T- and B-cell proliferation. No correlation was found between splenic catecholamine or circulating corticosterone levels and the proliferative response. However, a significant negative correlation was found between glucose levels and concanavalin A- and lipopolysaccharide-stimulated proliferative responses of T and B cells. A positive correlation between blood glucose and splenic catecholamine concentrations was found in diabetic mice but not in controls subjected to CMS. Hence, the present report shows that diabetic mice show a worse performance in immune function after stress exposure, pointing to the importance of considering life stress as a risk factor for patients with diabetes.

  6. Evaluation of cognitive function of fluoxetine, sertraline and tianeptine in isolation and chronic unpredictable mild stress-induced depressive Wistar rats.

    PubMed

    Ramanathan, M; Kumar, S N Ashok; Suresh, B

    2003-11-01

    Depressive illness is generally associated with cognitive impairment. Serotonergic selective antidepressant drugs, fluoxetine (FLX), sertraline (SER) and tianeptine (TIA), are claimed to have less or no effect on cholinergic system, the key system involved in memory. In the present study, these drugs were evaluated for their influence on cognitive behavior in both depressive and non-depressive animals. Depression was induced by two models, (i) 60 days social isolation of litter; and ii) by applying chronic unpredictable mild stress for 21 days. Depression in the rats was confirmed by behavioral despair test. Transfer latency on elevated plus maze and inflexion ratio in passive avoidance step through behavior were employed to assess learning and memory. The results indicated that administration of fluoxetine; sertraline and tianeptine attenuated the cognitive deficits observed in depressive rats. In non-depressive rats these drugs produced retention deficit, which was found to be parameter and model dependent. Data suggested that, FLX and SER (SSRI's) effectively attenuated the isolation-induced depression and cognitive deficit, whereas TIA (SSRE) produced better effect in stress-induced depressive conditions. It was concluded that behavioral profiles of fluoxetine, sertraline and tianeptine on cognition were model and parameter dependent.

  7. SCLM, total saponins extracted from Chaihu-jia-longgu-muli-tang, reduces chronic mild stress-induced apoptosis in the hippocampus in mice.

    PubMed

    Liu, Yadong; Ma, Shiping; Qu, Rong

    2010-08-01

    Increasing evidence demonstrates that stress or depression can lead to atrophy and cell loss in the hippocampus. In contrast, antidepressant treatment significantly reduces apoptosis in the dentate granule cell layer and subgranular zone in animal models of depression. In the present study, we investigated the neuroprotective action of SCLM, the total saponins extracted from Chaihu-jia-longgu-muli-tang, a traditional Chinese medicinal formula which was prescribed 1000 years ago, in the reduction of apoptosis in hippocampal neurons using an experimental chronic mild stress (CMS) model. Mice were subjected to the CMS procedure for a period of 21 consecutive days. SCLM (100 mg/kg, p.o.) or fluoxetine (20 mg/ kg, p.o.) was administered during the stress periods. CMS mice showed a decreased sucrose intake over 21 days, and an increase in the number of TUNEL-positive neurons as well as up-regulation of the apoptotic-related factors, such as Bax and caspase-3 in the hippocampus, compared with control mice. On the other hand, the administration of SCLM (100 mg/kg) and fluoxetine (20 mg/kg) reversed these effects induced by CMS, showing a significant increase of sucrose intake and a dramatic reduction of TUNEL-positive neurons and decreased expression of Bax and caspase-3 proteins. The present results suggest that SCLM possesses a significant antidepressant-like property, and this effect may be through protection against stress-induced neuronal apoptosis by affecting the expression of Bax and caspase-3 proteins in the hippocampus. These findings provide important information that the anti-apoptotic effect of herbal medicine therapy may be beneficial for the treatment of depression.

  8. Anti-depressant-like effect of peony: a mini-review.

    PubMed

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

    2012-01-01

    Depression is a common psychiatric disorder, yet the clinical efficacy of antidepression therapies is unsatisfactory. Thus, the search for new anti-depressants continues, and natural products remain a promising source of new therapeutic agents. The root part of Paeonia lactiflora Pall. (Ranunculaceae), known as peony, is often used in Chinese herbal prescriptions for the treatment of depression-like disorders. The objective of this review is to provide scientific evidence to support further research on peony as a potential anti-depressant drug. This review summarizes the results obtained in our laboratory, together with other literature data obtained through a comprehensive search in databases including PubMed, ScienceDirect, Scirus, and Web of Science. The peony extract is active in the mouse forced swim test and tail suspension test, and it produces anti-depressant effects in chronic unpredictable mild stress-induced depression model in mice and rats. The anti-depressant mechanisms of peony are likely mediated by the inhibition of monoamine oxidase activity, neuro-protection, modulation of the function of hypothalamic-pituitary-adrenal axis, inhibition of oxidative stress, and the up-regulation of neurotrophins. Peony is used clinically to treat depression-like symptoms in Chinese medicine, and it has been shown to possess anti-depressant property in a battery of test models using laboratory animals. Its effect is likely mediated by multiple targets. Further studies are warranted to delineate the molecular mechanisms of action, determine the pharmacokinetics, establish the toxicological profile, and assess the potentials of peony in clinical applications. Identification of the clinically active ingredient(s) is also warranted.

  9. Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors.

    PubMed

    Ruan, C S; Zhou, F H; He, Z Y; Wang, S F; Yang, C R; Shen, Y J; Guo, Y; Zhao, H B; Chen, L; Liu, D; Liu, J; Baune, B T; Xiao, Z C; Zhou, X F

    2015-05-07

    Mood disorders are a severe health burden but molecular mechanisms underlying mood dysfunction remain poorly understood. Here, we show that wild-type p53-induced phosphatase 1 (Wip1) negatively responds to the stress-induced negative mood-related behaviors. Specifically, we show that Wip1 protein but not its mRNA level was downregulated in the hippocampus but not in the neocortex after 4 weeks of chronic unpredictable mild stress (CUMS) in mice. Moreover, the CUMS-responsive WIP1 downregulation in the hippocampus was restored by chronic treatment of fluoxetine (i.p. 20 mg/kg) along with the CUMS procedure. In addition, Wip1 knockout mice displayed decreased exploratory behaviors as well as increased anxiety-like and depression-like behaviors in mice without impaired motor activities under the non-CUMS condition. Furthermore, the Wip1 deficiency-responsive anxiety-like but not depression-like behaviors were further elevated in mice under CUMS. Although limitations like male-alone sampling and multiply behavioral testing exist, the present study suggests a potential protective function of Wip1 in mood stabilization. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Early adversity contributes to chronic stress induced depression-like behavior in adolescent male rhesus monkeys.

    PubMed

    Zhang, Zhi-Yi; Mao, Yu; Feng, Xiao-Li; Zheng, Na; Lü, Long-Bao; Ma, Yuan-Ye; Qin, Dong-Dong; Hu, Xin-Tian

    2016-06-01

    Chronic stress is an important cause for depression. However, not everyone who is exposed to chronic stress will develop depression. Our previous studies demonstrated that early adversity can cause lasting changes in adolescent rhesus monkeys, but depressive symptoms have not been observed. Compared to adults, it is still unknown that whether adolescent rhesus monkeys experiencing early adversity are more likely to develop depressive symptoms. In this study, we investigated the long term relationship between early adversity, chronic stress and adolescent depression for the first time. Eight male rhesus monkeys were reared in maternal separation (MS) or mother-reared (MR) conditions. All of them went through unpredictable chronic stress for two months at their age four. The stressors included space restriction, intimidation, long illumination and fasting. Behavioral and physiological data were collected during the experiment. The results showed that, compared with the MR group, the locomotor activity of MS group was significantly decreased after one month of chronic stress while huddling up and stereotypical behaviors were significantly increased. Moreover, this trend continued and even worsened at the second month. Significantly higher hair cortisol levels and lower body weight were observed in MS group after two months of stress. These results indicate that early adversity is one of the environmental factors which can increase the susceptibility of depression when experiencing chronic stress in the later life. This will further clarify the important roles of early environmental factors in the development of adolescent depression and children rearing conditions should receive more attention.

  11. Alteration of Behavioral Changes and Hippocampus Galanin Expression in Chronic Unpredictable Mild Stress-Induced Depression Rats and Effect of Electroacupuncture Treatment

    PubMed Central

    Mo, Yuping; Yao, Haijiang; Song, Hongtao; Wang, Xin; Chen, Wanshun; Abulizi, Jiawula; Xu, Anping; Tang, Yinshan; Han, Xiangbo; Li, Zhigang

    2014-01-01

    To explore new noninvasive treatment options for depression, this study investigated the effects of electric acupuncture (EA) for depression rat models. Depression in rats was induced by unpredictable chronic mild stress (UCMS) combined with isolation for 21 days. Eighteen male Sprague-Dawley rats were randomly assigned into three groups: control, model, and EA groups. Rats were treated by EA once daily for 21 days. The results showed that body weight and sucrose consumption were significantly increased in EA group than in the model group. The crossing numbers and rearing numbers in the open field test significantly decreased in the model group but not in the EA group. And EA treatments upregulated levels of hippocampus galanin (Gal) in UCMS rats back to relative normal levels. The present study suggested that EA had antidepressant effects on UCMS model rats. The potential antidepressant effect may be related to upregulating Gal expression in hippocampus. PMID:25530777

  12. Possible involvement of corticosterone and serotonin in antidepressant and antianxiety effects of chromium picolinate in chronic unpredictable mild stress induced depression and anxiety in rats.

    PubMed

    Dubey, Vivek Kumar; Ansari, Faraha; Vohora, Divya; Khanam, Razia

    2015-01-01

    In the present study, we investigated the effects of chromium picolinate (CrP) on behavioural and biochemical parameters in chronic unpredictable mild stress (CUMS) induced depression and anxiety in rats. The normal and stressed male Swiss albino rats were administered CrP (8 and 16μg/mL in drinking water), they received stressors for seven days (each day one stressor) and this cycle was repeated three times for 21 days. On 22nd day, behaviour assessments followed by biochemical estimations were conducted. The results showed that treatment of CrP produced significant antidepressant effect, which has been evidenced by decrease in immobility time in modified forced swimming test (FST) in chronic unpredictable mild stress (CUMS) induced depression in rats. In elevated plus maze (EPM), CrP (16μg/mL) showed significant reduction in time spent in open arm. CrP (8μg/mL and 16μg/mL) also showed significant decrease in number of entries in open arm that shows antianxiety effect of CrP in CUMS rats. It was also found that CrP (8 and 16μg/mL) significantly increased 5-HT concentration in the discrete regions of brain (cortex and cerebellum). On the other hand, the plasma corticosterone level was significantly decreased with CrP (16μg/mL). The results suggested that increase in the concentration of 5-HT and decrease in plasma corticosterone levels could be responsible for improvement in symptoms of depression and anxiety in CUMS induced depression and anxiety in rats.

  13. Response of Mouse Zygotes Treated with Mild Hydrogen Peroxide as a Model to Reveal Novel Mechanisms of Oxidative Stress-Induced Injury in Early Embryos

    PubMed Central

    2016-01-01

    Our study aimed to develop embryo models to evaluate the impact of oxidative stress on embryo development. Mouse zygotes, which stayed at G1 phase, were treated with prepared culture medium (containing 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, or 0.1 mM hydrogen peroxide (H2O2)) for 30 min in experiment 1. The dose-effects of H2O2 on embryo development were investigated via comparisons of the formation rate at each stage (2- and 4-cell embryos and blastocysts). Experiment 2 was carried out to compare behaviors of embryos in a mild oxidative-stressed status (0.03 mM H2O2) with those in a control (0 mM H2O2). Reactive oxygen species (ROS) levels, variation of mitochondrial membrane potential (MMP), expression of γH2AX, and cell apoptosis rate of blastocyst were detected. We observed a dose-dependent decrease on cleavage and blastocyst rates. Besides, higher level of ROS, rapid reduction of MMP, and the appearance of γH2AX revealed that embryos are injured early in mild oxidative stress. Additionally, γH2AX may involve during DNA damage response in early embryos. And the apoptotic rate of blastocyst may significantly increase when DNA damage repair is inadequate. Most importantly, our research provides embryo models to study cell cycle regulation and DNA damage response under condition of different levels of oxidative stress. PMID:27738489

  14. The Antidepressant Effect of Angelica sinensis Extracts on Chronic Unpredictable Mild Stress-Induced Depression Is Mediated via the Upregulation of the BDNF Signaling Pathway in Rats

    PubMed Central

    2016-01-01

    Angelica sinensis (AS), a traditional Chinese herbal medicine, has pharmaceutical effects on menstrual illness, cerebrovascular diseases, cardiovascular diseases, and cognitive impairments. However, until recently, few studies had explored its antidepressant effect. The current study attempts to investigate the effect of AS extracts on chronic unpredictable mild stress- (CUMS-) induced depression in rats. Male SD rats were exposed to a CUMS-inducing procedure for 5 weeks, resulting in rodent depressive behaviors that included reduced sucrose consumption and lessened sucrose preference ratios in sucrose preference test, prolonged immobility times and decreased struggling time in force swim test, and decreased locomotor activity in open field test. Moreover, the expression of brain derived neurotrophic factor (BDNF) and the phosphorylation of cAMP-response element binding protein (CREB) and extracellular signal-regulated protein kinase (ERK 1/2) were markedly decreased in the hippocampus in depressed rats. However, chronically treating the depressed rats with AS (1 g/kg) normalized their depression-related behaviors and molecular profiles. In conclusion, in the present study, we show that AS extracts exerted antidepressant effects that were mediated by the BDNF signaling pathway: in AS-treated depressed rats, the expression of the BDNF protein and the phosphorylation of its downstream targets (ERK 1/2, CREB) were upregulated in the hippocampus. PMID:27642354

  15. Isolation stress and chronic mild stress induced immobility in the defensive burying behavior and a transient increased ethanol intake in Wistar rats.

    PubMed

    Vázquez-León, Priscila; Martínez-Mota, Lucía; Quevedo-Corona, Lucía; Miranda-Páez, Abraham

    2017-09-01

    Stress can be experienced with or without adverse effects, of which anxiety and depression are two of the most important due to the frequent comorbidity with alcohol abuse in humans. Historically, stress has been considered a cause of drug use, particularly alcohol abuse due to its anxiolytic effects. In the present work we exposed male Wistar rats to two different stress conditions: single housing (social isolation, SI), and chronic mild stress (CMS). We compared both stressed groups to group-housed rats and rats without CMS (GH) to allow the determination of a clear behavioral response profile related to their respective endocrine stress response and alcohol intake pattern. We found that SI and CMS, to a greater extent, induced short-lasting increased sucrose consumption, a transient increase in serum corticosterone level, high latency/immobility, and low burying behavior in the defensive burying behavior (DBB) test, and a transient increase in alcohol intake. Thus, the main conclusion was that stress caused by both SI and CMS induced immobility in the DBB test and, subsequently, induced a transient increased voluntary ethanol intake in Wistar rats with a free-choice home-cage drinking paradigm. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain.

    PubMed

    Li, Ruipeng; Wang, Xiangxiang; Qin, Tingting; Qu, Rong; Ma, Shiping

    2016-01-01

    Increasing evidence suggests that inflammation and oxidative stress may contribute to the development of major depressive disorder (MDD). Apigenin, a type of bioflavonoid widely found in citrus fruits, has a number of biological actions including anti-inflammatory and antioxidant effects. Although apigenin has potential antidepressant activity, the mechanisms of this effect remain unclear. The present study aims to investigate the effects of apigenin on behavioral changes and inflammatory responses induced by chronic unpredictable mild stress (CUMS) in rats. GW9662, a selective peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor, was administered 30 min before apigenin. We found that treatment with apigenin (20mg/kg, intragastrically) for three weeks remarkably ameliorated CUMS-induced behavioral abnormalities, such as decreased locomotor activity and reduced sucrose consumption. In response to oxidative stress, the NLRP3 inflammasome was activated and IL-1β secretion increased in the prefrontal cortex (PFC) of CUMS rats. However, apigenin treatment upregulated PPARγ expression and downregulated the expression of NLRP3, which subsequently downregulated the production of IL-1β. In addition, GW9662 diminished the inhibitory effects of apigenin on the NLRP3 inflammasome. In conclusion, our results demonstrate that apigenin exhibits antidepressant-like effects in CUMS rats, possibly by inhibiting IL-1β production and NLRP3 inflammasome expression via the up-regulation of PPARγ expression.

  17. Induction of depressive-like effects by subchronic exposure to cocaine or heroin in laboratory rats.

    PubMed

    Zilkha, Noga; Feigin, Eugene; Barnea-Ygael, Noam; Zangen, Abraham

    2014-08-01

    The effect of psychoactive drugs on depression has usually been studied in cases of prolonged drug addiction and/or withdrawal, without much emphasis on the effects of subchronic or recreational drug use. To address this issue, we exposed laboratory rats to subchronic regimens of heroin or cocaine and tested long-term effects on (i) depressive-like behaviors, (ii) brain-derived neurotrophic factor (BDNF) levels in reward-related brain regions, and (iii) depressive-like behavior following an additional chronic mild stress procedure. The long-term effect of subchronic cocaine exposure was a general reduction in locomotor activity whereas heroin exposure induced a more specific increase in immobility during the forced swim test. Both cocaine and heroin exposure induced alterations in BDNF levels that are similar to those observed in several animal models of depression. Finally, both cocaine and heroin exposure significantly enhanced the anhedonic effect of chronic mild stress. These results suggest that subchronic drug exposure induces depressive-like behavior which is accompanied by modifications in BDNF expression and increases the vulnerability to develop depressive-like behavior following chronic stress. Implications for recreational and small-scale drug users are discussed. In the present study, we examined the long-term effects of limited subchronic drug exposure on depressive-like symptoms. Our results demonstrate that short-term, subchronic administration of either cocaine or heroin promotes some depressive-like behaviors, while inducing alterations in BDNF protein levels similar to alterations observed in several animal models of depression. In addition, subchronic cocaine or heroin enhanced the anhedonic effect of chronic stress.

  18. Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons through NKCC1 Upregulation.

    PubMed

    Gao, Yonggang; Zhou, Jing-Jing; Zhu, Yun; Kosten, Therese; Li, De-Pei

    2017-01-01

    Prolonged and repeated stresses cause hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The corticotrophin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) are an essential component of the HPA axis. Chronic unpredictable mild stress (CUMS) was induced in Sprague-Dawley rats. GABA reversal potentials (EGABA) were determined by using gramicidin-perforated recordings in identified PVN-CRH neurons through expressing enhanced green fluorescent protein driven by the CRH promoter. Plasma corticosterone (CORT) levels were measured in rats implanted with a cannula targeting the lateral ventricles and PVN. Blocking the GABAA receptor in the PVN with gabazine significantly increased plasma CORT levels in unstressed rats but did not change CORT levels in CUMS rats. CUMS caused a depolarizing shift in EGABA in PVN-CRH neurons compared with EGABA in PVN-CRH neurons in unstressed rats. Furthermore, CUMS induced a long-lasting increase in expression levels of the cation chloride cotransporter Na+-K+-Cl--Cl- (NKCC1) in the PVN but a transient decrease in expression levels of K+-Cl--Cl- in the PVN, which returned to the basal level 5 days after CUMS treatment. The NKCC1 inhibitor bumetanide decreased the basal firing activity of PVN-CRH neurons and normalized EGABA and the gabazine-induced excitatory effect on PVN-CRH neurons in CUMS rats. In addition, central administration of bumetanide decreased basal circulating CORT levels in CUMS rats. These data suggest that chronic stress impairs GABAergic inhibition, resulting in HPA axis hyperactivity through upregulation of NKCC1. © 2016 S. Karger AG, Basel.

  19. Effect of fluoxetine and resveratrol on testicular functions and oxidative stress in a rat model of chronic mild stress-induced depression.

    PubMed

    Sakr, H F; Abbas, A M; Elsamanoudy, A Z; Ghoneim, F M

    2015-08-01

    Our objective was to investigate the effects of chronic unpredictable mild stress (CUMS) with or without selective serotonin reuptake inhibitor (fluoxetine) and anti-oxidant (resveratrol) on testicular functions and oxidative stress in rats. Fifty male rats were divided into 2 groups; control and CUMS. CUMS group was further subdivided into 4 subgroups administered water, fluoxetine, resveratrol and both. Sucrose intake, body weight gain, serum corticosterone, serotonin and testosterone levels, sperm count and motility, testicular malondialdehyde, superoxide dismutase (SOD), catalase, glutathione (GSH), and gene expression of steroidogenic acute-regulatory (StAR) protein and cytochrome P450 side chain cleavage (P450scc) enzyme were evaluated. CUMS decreased sucrose intake, weight gain, anti-oxidants (SOD, catalase, GSH), testosterone, serotonin, StAR and cytochrome P450scc gene expression, sperm count and motility and increased malondialdehyde and corticosterone. Fluoxetine increased malondialdehyde, sucrose intake, weight gain, serotonin and decreased anti-oxidants, StAR and cytochrome P450scc gene expression, sperm count and motility, testosterone, corticosterone in stressed rats. Administration of resveratrol increased anti-oxidants, sucrose intake, weight gain, serotonin, StAR and cytochrome P450scc gene expression, testosterone, sperm count and motility, and decreased malondialdehyde and corticosterone in stressed rats with or without fluoxetine. In conclusion, CUMS induces testicular dysfunctions and oxidative stress. While treatment of CUMS rats with fluoxetine decreases the depressive behavior, it causes further worsening of testicular dysfunctions and oxidative stress. Administration of resveratrol improves testicular dysfunctions and oxidative stress that are caused by CUMS and further worsened by fluoxetine treatment.

  20. Mild stress induces brain region-specific alterations of selective ER stress markers' mRNA expression in Wfs1-deficient mice.

    PubMed

    Altperery, A; Raud, S; Sütt, S; Reimets, R; Visnapuu, T; Toots, M; Vasar, E

    2017-09-26

    In this work, the effect of mild stress (elevated plus maze test, EPM) on the expression of endoplasmic reticulum (ER) stress markers in different brain areas of wild type (WT) and Wfs1-deficient (Wfs1KO) mice was investigated. The following ER stress markers were studied: activating transcription factor 6α (Atf6α), protein kinase-like ER kinase (Perk), X-box binding protein 1 (Xbp1) and its spliced form (Xbp1s), 78-kilodalton glucose regulated protein (Grp78), 94-kilodalton glucose regulated protein (Grp94), C/EBP homologous protein (Chop). Wfs1KO and WT mice, not exposed to EPM, had similar patterns of ER stress markers in the studied brain areas. The exploratory activity of Wfs1KO mice in the EPM was inhibited compared to WT mice, probably reflecting increased anxiety in genetically modified mice. In response to the EPM, activation of inositol-requiring transmembrane kinase and endonuclease 1α (Ire1α) ER stress pathway was seen in both genotypes, but in different brain areas. Such a brain region-specific Ire1α activation was linked with dominant behavioural trends in these mice as more anxious, neophobic Wfs1KO mice had increased ER stress markers expression in the temporal lobe, the brain region related to anxiety, and more curious WT mice had ER stress markers increased in the ventral striatum which is related to the exploratory drive. The molecular mechanism triggering respective changes in ER stress markers in these brain regions is likely related to altered levels of monoamine neurotransmitters (serotonin, dopamine) in Wfs1KO mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression.

    PubMed

    Kubera, Marta; Obuchowicz, Ewa; Goehler, Lisa; Brzeszcz, Joanna; Maes, Michael

    2011-04-29

    Recently, the inflammatory and neurodegenerative (I&ND) hypothesis of depression was formulated (Maes et al., 2009), i.e. the neurodegeneration and reduced neurogenesis that characterize depression are caused by inflammation, cell-mediated immune activation and their long-term sequels. The aim of this paper is to review the body of evidence that external stressors may induce (neuro)inflammation, neurodegeneration and reduced neurogenesis; and that antidepressive treatments may impact on these pathways. The chronic mild stress (CMS) and learned helplessness (LH) models show that depression-like behaviors are accompanied by peripheral and central inflammation, neuronal cell damage, decreased neurogenesis and apoptosis in the hippocampus. External stress-induced depression-like behaviors are associated with a) increased interleukin-(IL)1β, tumor necrosis factor-α, IL-6, nuclear factor κB, cyclooxygenase-2, expression of Toll-like receptors and lipid peroxidation; b) antineurogenic effects and reduced brain-derived neurotrophic factor (BDNF) levels; and c) apoptosis with reduced levels of Bcl-2 and BAG1 (Bcl-2 associated athanogene 1), and increased levels of caspase-3. Stress-induced inflammation, e.g. increased IL-1β, but not reduced neurogenesis, is sufficient to cause depression. Antidepressants a) reduce peripheral and central inflammatory pathways by decreasing IL-1β, TNFα and IL-6 levels; b) stimulate neuronal differentiation, synaptic plasticity, axonal growth and regeneration through stimulatory effects on the expression of different neurotrophic factors, e.g. trkB, the receptor for brain-derived neurotrophic factor; and c) attenuate apoptotic pathways by activating Bcl-2 and Bcl-xl proteins, and suppressing caspase-3. It is concluded that external stressors may provoke depression-like behaviors through activation of inflammatory, oxidative, apoptotic and antineurogenic mechanisms. The clinical efficacity of antidepressants may be ascribed to their

  2. Stress-induced flowering

    PubMed Central

    Wada, Kaede C

    2010-01-01

    Many plant species can be induced to flower by responding to stress factors. The short-day plants Pharbitis nil and Perilla frutescens var. crispa flower under long days in response to the stress of poor nutrition or low-intensity light. Grafting experiments using two varieties of P. nil revealed that a transmissible flowering stimulus is involved in stress-induced flowering. The P. nil and P. frutescens plants that were induced to flower by stress reached anthesis, fruited and produced seeds. These seeds germinated, and the progeny of the stressed plants developed normally. Phenylalanine ammonialyase inhibitors inhibited this stress-induced flowering, and the inhibition was overcome by salicylic acid (SA), suggesting that there is an involvement of SA in stress-induced flowering. PnFT2, a P. nil ortholog of the flowering gene FLOWERING LOCUS T (FT) of Arabidopsis thaliana, was expressed when the P. nil plants were induced to flower under poor-nutrition stress conditions, but expression of PnFT1, another ortholog of FT, was not induced, suggesting that PnFT2 is involved in stress-induced flowering. PMID:20505356

  3. 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

  4. Cellular and Molecular Basis for Stress-Induced Depression

    PubMed Central

    Seo, Ji-Seon; Wei, Jing; Qin, Luye; Kim, Yong; Yan, Zhen

    2016-01-01

    Chronic stress plays 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. PMID:27457815

  5. EXACERBATED MECHANICAL ALLODYNIA IN RATS WITH DEPRESSION-LIKE BEHAVIOR

    PubMed Central

    Zeng, Qing; Wang, Shuxing; Lim, Grewo; Yang, Liling; Mao, Ji; Sung, Backil; Chang, Yang; Lim, Jeong-Ae; Guo, Gongshe; Mao, Jianren

    2008-01-01

    Although a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report that both mechanical allodynia and depression-like behavior were significantly exacerbated after peripheral nerve injury in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats with demonstrable depression-like behavior. Administration of melatonin into the anterior cingular cortex contralateral to peripheral nerve injury prevented the exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in WKY rats. Moreover, there was a lower plasma melatonin concentration and a lower melatonin receptor expression in the anterior cingular cortex in WKY rats than in Wistar rats. These results suggest that there exists a reciprocal relationship between mechanical allodynia and depression-like behavior and the melotoninergic system in the anterior cingular cortex might play an important role in the interaction between pain and depression. PMID:18289511

  6. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition.

    PubMed

    Wong, M-L; Inserra, A; Lewis, M D; Mastronardi, C A; Leong, L; Choo, J; Kentish, S; Xie, P; Morrison, M; Wesselingh, S L; Rogers, G B; Licinio, J

    2016-06-01

    The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome activation causes the maturation of caspase-1 and activation of interleukin (IL)-1β and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota-inflammasome-brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota

  7. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition

    PubMed Central

    Wong, M-L; Inserra, A; Lewis, M D; Mastronardi, C A; Leong, L; Choo, J; Kentish, S; Xie, P; Morrison, M; Wesselingh, S L; Rogers, G B; Licinio, J

    2016-01-01

    The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome activation causes the maturation of caspase-1 and activation of interleukin (IL)-1β and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota–inflammasome–brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota

  8. Stress-induced cardiomyopathy

    PubMed Central

    Lisung, Fausto Gabriel; Shah, Ankit B; Levitt, Howard L; Coplan, Neil B

    2015-01-01

    A woman in her early 70s presented with chest pain, dyspnoea and diaphoresis 30 min after her husband expired in our hospital. Cardiac markers were elevated and there were acute changes in ECG suggestive for acute coronary syndrome. Echocardiogram showed apical akinesis, basal segment hyperkinesis with an ejection fraction of 30%. Cardiac catheterisation was performed showing non-obstructive coronary arteries, leading to the diagnosis of stress-induced cardiomyopathy. The patient improved with medical management. Repeat echocardiogram 2 months later showed resolution of heart failure with an ejection fraction of 65–70%. PMID:25858931

  9. Effects of hydrogen-rich water on depressive-like behavior in mice.

    PubMed

    Zhang, Yi; Su, Wen-Jun; Chen, Ying; Wu, Teng-Yun; Gong, Hong; Shen, Xiao-Liang; Wang, Yun-Xia; Sun, Xue-Jun; Jiang, Chun-Lei

    2016-03-30

    Emerging evidence suggests that neuroinflammation and oxidative stress may be major contributors to major depressive disorder (MDD). Patients or animal models of depression show significant increase of proinflammatory cytokine interleukin-1β (IL-1β) and oxidative stress biomarkers in the periphery or central nervous system (CNS). Recent studies show that hydrogen selectively reduces cytotoxic oxygen radicals, and hydrogen-rich saline potentially suppresses the production of several proinflammatory mediators. Since current depression medications are accompanied by a wide spectrum of side effects, novel preventative or therapeutic measures with fewer side effects might have a promising future. We investigated the effects of drinking hydrogen-rich water on the depressive-like behavior in mice and its underlying mechanisms. Our study show that hydrogen-rich water treatment prevents chronic unpredictable mild stress (CUMS) induced depressive-like behavior. CUMS induced elevation in IL-1β protein levels in the hippocampus, and the cortex was significantly attenuated after 4 weeks of feeding the mice hydrogen-rich water. Over-expression of caspase-1 (the IL-1β converting enzyme) and excessive reactive oxygen species (ROS) production in the hippocampus and prefrontal cortex (PFC) was successfully suppressed by hydrogen-rich water treatment. Our data suggest that the beneficial effects of hydrogen-rich water on depressive-like behavior may be mediated by suppression of the inflammasome activation resulting in attenuated protein IL-1β and ROS production.

  10. Effects of hydrogen-rich water on depressive-like behavior in mice

    PubMed Central

    Zhang, Yi; Su, Wen-Jun; Chen, Ying; Wu, Teng-Yun; Gong, Hong; Shen, Xiao-Liang; Wang, Yun-Xia; Sun, Xue-Jun; Jiang, Chun-Lei

    2016-01-01

    Emerging evidence suggests that neuroinflammation and oxidative stress may be major contributors to major depressive disorder (MDD). Patients or animal models of depression show significant increase of proinflammatory cytokine interleukin-1β (IL-1β) and oxidative stress biomarkers in the periphery or central nervous system (CNS). Recent studies show that hydrogen selectively reduces cytotoxic oxygen radicals, and hydrogen-rich saline potentially suppresses the production of several proinflammatory mediators. Since current depression medications are accompanied by a wide spectrum of side effects, novel preventative or therapeutic measures with fewer side effects might have a promising future. We investigated the effects of drinking hydrogen-rich water on the depressive-like behavior in mice and its underlying mechanisms. Our study show that hydrogen-rich water treatment prevents chronic unpredictable mild stress (CUMS) induced depressive-like behavior. CUMS induced elevation in IL-1β protein levels in the hippocampus, and the cortex was significantly attenuated after 4 weeks of feeding the mice hydrogen-rich water. Over-expression of caspase-1 (the IL-1β converting enzyme) and excessive reactive oxygen species (ROS) production in the hippocampus and prefrontal cortex (PFC) was successfully suppressed by hydrogen-rich water treatment. Our data suggest that the beneficial effects of hydrogen-rich water on depressive-like behavior may be mediated by suppression of the inflammasome activation resulting in attenuated protein IL-1β and ROS production. PMID:27026206

  11. Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning.

    PubMed

    Liu, Weina; Zhou, Chenglin

    2012-07-01

    Both chronic mild stress and an injection of corticosterone induce depression-like states in rodents. To further link mitochondrial dysfunction to the pathophysiology of major depression, here we describe two rat models of a depressive-like state induced by chronic unpredictable mild stress (CUMS) or corticosterone treatment (CORT). It is also a model that allows the simultaneous study of effects of exercise preconditioning on behavioral, electrophysiological, biochemical and molecular markers in the same animal. Exercise preconditioning ahead of CUMS and CORT treatment prevents many behavioral abnormalities resulted from CUMS. The changes in mitochondrial activity in brain and reduced expressions of superoxide dismutase (SOD1, SOD2), mitofusin (Mfn1, Mfn2) as well as brain-derived neurotrophic factor (BDNF) suggest that both CORT and CUMS may impair mitochondrial function and/or expressions of mitofusion and antioxidant enzymes that, in turn, may increase oxidative stress and reduce energy production in brain with depression-like behaviors. These findings suggest an underlying mechanism by which CORT, as well as CUMS, induces brain mitochondrial dysfunction that is associated with depressive-like states. Remarkably, physical exercise is identified as a helpful and preventive measure to promote mitochondrial function and expressions of mitofusin, BDNF and antioxidant enzymes in brain, so as to protect brain energy metabolism against CUMS, rather than the compound of corticosterone. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

    PubMed Central

    Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

    2015-01-01

    Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression. PMID:25875952

  13. 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.

  14. Neuropharmacological effect of novel 5-HT3 receptor antagonist, N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) on chronic unpredictable mild stress-induced molecular and cellular response: Behavioural and biochemical evidences.

    PubMed

    Bhatt, Shvetank; Mahesh, Radhakrishnan; Jindal, Ankur; Devadoss, Thangaraj

    2014-10-01

    Chronic unpredictable stressors can produce a situation similar to human depression and such animal models can be used for the preclinical evaluation of antidepressants. The 5-HT3 receptor antagonists modulate serotonergic pathways and show antidepressant-like effect in various animal models of depression. In this study, a novel and potential 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) with good Log P (2.52) value and pA2 (7.6) values, synthesized in our laboratory was explore to study the effects on CUMS-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. CUMS caused depression-like behaviour in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test (FST) while there was no significant effect on spontaneous locomotor activity (SLA) observed. In addition it was found that lipid peroxide and nitrite levels were significantly increased, whereas glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in brain tissue of CUMS-treated mice. Compound 6n (1 and 2mg/kg, po, 21 days) and fluoxetine treatment (20mg/kg, po, 21 days) significantly altered the CUMS-induced behavioural (increased immobility period, reduced sucrose preference) and biochemical (increased lipid peroxidation, increased brain nitrite; decreased GSH, SOD and CAT levels) parameters while there was no significant effect of observed on SLA. Compound 6n produced antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity up to significant level. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  15. Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression.

    PubMed

    Zhang, Yanli; Fan, Kai; Liu, Yanna; Liu, Gang; Yang, Xiaohan; Ma, Jianmei

    2017-06-16

    Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5 mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.

  16. Targeting Oxidative Stress, Cytokines and Serotonin Interactions Via Indoleamine 2, 3 Dioxygenase by Coenzyme Q10: Role in Suppressing Depressive Like Behavior in Rats.

    PubMed

    Abuelezz, Sally A; Hendawy, Nevien; Magdy, Yosra

    2016-10-11

    Depression is a major health problem in which oxidative stress and inflammation are inextricably connected in its pathophysiology. Coenzyme Q10 (CoQ10) is an important anti-oxidant compound with anti-inflammatory and neuro-protective properties. This study was designed to investigate the hypothesis that CoQ10 by its anti-oxidant and anti-inflammatory potentials can alleviate depressive- like behavior by restoring the balance of the tryptophan catabolites kynurenine/serotonin toward the serotonin pathway by down-regulation of hippocampal indoleamine 2,3-dioxygenase 1 (IDO-1). Depressive-like behavior was induced by chronic unpredictable mild stress (CUMS) protocol including food or water deprivation, cage tilting, reversed light cycle etc. Male Wistar rats were randomly divided into five groups; Control, CUMS, CUMS and CoQ10 (50,100 and 200 mg/kg/day i.p. respectively) groups. CoQ10 effects on different behavioral and biochemical tests were analyzed. CoQ10 showed significant antidepressant efficacy, as evidenced by significantly decreased stress induced changes to forced swimming challenge and open field test, as well as attenuating raised corticosterone level and adrenal glands weight. The anti-oxidant effect of CoQ10 was exhibited by its ability to significantly reduce hippocampal elevated malondialdehyde and 4-hydroxynonenal levels and elevate the reduced glutathione and catalase levels. CoQ10 significantly reduced different pro-inflammatory cytokines levels including interleukin (IL)-1β, IL-2, IL-6 and tumor necrosis factor-α. It suppressed hippocampal IDO-1 and subsequent production of kynurenine and enhanced the hippocampal contents of tryptophan and serotonin. Immunohistochemical analysis revealed that CoQ10 was able to attenuate the elevated microglial CD68 and elevate the astrocyte glial fibrillary acidic protein compared to CUMS group. CoQ10 exhibited antidepressant-like effects on rats exposed to CUMS. This could be attributed to its ability to reduce

  17. Inflammatory Factors Mediate Vulnerability to a Social Stress-Induced Depressive-like Phenotype in Passive Coping Rats.

    PubMed

    Wood, Susan K; Wood, Christopher S; Lombard, Calliandra M; Lee, Catherine S; Zhang, Xiao-Yan; Finnell, Julie E; Valentino, Rita J

    2015-07-01

    Coping strategy impacts susceptibility to psychosocial stress. The locus coeruleus (LC) and dorsal raphe (DR) are monoamine nuclei implicated in stress-related disorders. Our goal was to identify genes in these nuclei that distinguish active and passive coping strategies in response to social stress. Rats were exposed to repeated resident-intruder stress and coping strategy determined. Gene and protein expression in the LC and DR were determined by polymerase chain reaction array and enzyme-linked immunosorbent assay and compared between active and passive stress-coping and unstressed rats. The effect of daily interleukin (IL)-1 receptor antagonist before stress on anhedonia was also determined. Rats exhibited passive or active coping strategies based on a short latency (SL) or longer latency (LL) to assume a defeat posture, respectively. Stress differentially regulated 19 and 26 genes in the LC and DR of SL and LL rats, respectively, many of which encoded for inflammatory factors. Notably, Il-1β was increased in SL and decreased in LL rats in both the LC and DR. Protein changes were generally consistent with a proinflammatory response to stress in SL rats selectively. Stress produced anhedonia selectively in SL rats and this was prevented by IL-1 receptor antagonist, consistent with a role for IL-1β in stress vulnerability. This study highlighted distinctions in gene expression related to coping strategy in response to social stress. Passive coping was associated with a bias toward proinflammatory processes, particularly IL-1β, whereas active coping and resistance to stress-related pathology was associated with suppression of inflammatory processes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Immobility stress induces depression-like behavior in the forced swim test in mice: effect of magnesium and imipramine.

    PubMed

    Poleszak, Ewa; Wlaź, Piotr; Kedzierska, Ewa; Nieoczym, Dorota; Wyska, Elzbieta; Szymura-Oleksiak, Joanna; Fidecka, Sylwia; Radziwoń-Zaleska, Maria; Nowak, Gabriel

    2006-01-01

    Previously, we demonstrated antidepressant-like effect of magnesium (Mg) in the forced swim test (FST). Moreover, the joint administration of Mg and imipramine (IMI) at ineffective doses per se, resulted in a potent reduction in the immobility time in this test. In the present study, we examined the effect of immobility stress (IS), and Mg and/or IMI administration on FST behavior. IS induced enhancement of immobility time, which was reversed by Mg or IMI at doses ineffective in non-stressed mice (10 mg/kg and 15 mg/kg, respectively). The joint administration of Mg and IMI was effective in both IS and non-stressed animals in FST. IS did not significantly alter locomotor activity, while IMI or Mg + IMI treatment in IS mice reduced this activity. We also measured serum and brain Mg, IMI and its metabolite desipramine (DMI) concentration in mice subjected to FST and injected with Mg + IMI, both restrained and non-restrained. In the present study we demonstrated a significant increase (by 68%) in the brain IMI and a slight, non-significant reduction in DMI concentration in IS + Mg + IMI + FST vs. Mg + IMI + FST groups, which might indicate the reduction in brain IMI metabolism. The IS-induced reduction in brain IMI metabolism did not participate in the activity in FST, since no differences in such activity were noticed between IS + Mg + IMI + FST and Mg + IMI + FST groups. The present data suggest that IS-induced increase in immobility time in FST is more sensitive for detection antidepressant-like activity. However, further studies are needed to examine the effect of other antidepressants in such an experimental paradigm.

  19. Neuroprotective Role of L-NG-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour

    PubMed Central

    Deep, Satya Narayan; Baitharu, Iswar; Sharma, Apurva; Gurjar, Anoop Kishor Singh; Prasad, Dipti; Singh, Shashi Bala

    2016-01-01

    Improper neuroimmune responses following chronic stress exposure have been reported to cause neuronal dysfunctions leading to memory impairment, anxiety and depression like behaviours. Though several factors affecting microglial activation and consequent alteration in neuro-inflammatory responses have been well studied, role of NO and its association with microglia in stress induced depression model is yet to be explored. In the present study, we validated combination of chronic hypobaric hypoxia and crowding (CHC) as a stress model for depression and investigated the role of chronic stress induced elevated nitric oxide (NO) level in microglia activation and its effect on neuro-inflammatory responses in brain. Further, we evaluated the ameliorative effect of L-NG-Nitroarginine Methyl Ester (L-NAME) to reverse the stress induced depressive mood state. Four groups of male Sprague Dawley rat were taken and divided into control and CHC stress exposed group with and without treatment of L-NAME. Depression like behaviour and anhedonia in rats were assessed by Forced Swim Test (FST) and Sucrose Preference Test (SPT). Microglial activation was evaluated using Iba-1 immunohistochemistry and proinflammatory cytokines were assessed in the hippocampal region. Our result showed that exposure to CHC stress increased the number of active microglia with corresponding increase in inflammatory cytokines and altered behavioural responses. The inhibition of NO synthesis by L-NAME during CHC exposure decreased the number of active microglia in hippocampus as evident from decreased Iba-1 positive cells. Further, L-NAME administration decreased pro-inflammatory cytokines in hippocampus and improved behaviour of rats. Our study demonstrate that stress induced elevation of NO plays pivotal role in altered microglial activation and consequent neurodegenerative processes leading to depression like behaviour in rat. PMID:27082990

  20. Neuroprotective Role of L-NG-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour.

    PubMed

    Deep, Satya Narayan; Baitharu, Iswar; Sharma, Apurva; Gurjar, Anoop Kishor Singh; Prasad, Dipti; Singh, Shashi Bala

    2016-01-01

    Improper neuroimmune responses following chronic stress exposure have been reported to cause neuronal dysfunctions leading to memory impairment, anxiety and depression like behaviours. Though several factors affecting microglial activation and consequent alteration in neuro-inflammatory responses have been well studied, role of NO and its association with microglia in stress induced depression model is yet to be explored. In the present study, we validated combination of chronic hypobaric hypoxia and crowding (CHC) as a stress model for depression and investigated the role of chronic stress induced elevated nitric oxide (NO) level in microglia activation and its effect on neuro-inflammatory responses in brain. Further, we evaluated the ameliorative effect of L-NG-Nitroarginine Methyl Ester (L-NAME) to reverse the stress induced depressive mood state. Four groups of male Sprague Dawley rat were taken and divided into control and CHC stress exposed group with and without treatment of L-NAME. Depression like behaviour and anhedonia in rats were assessed by Forced Swim Test (FST) and Sucrose Preference Test (SPT). Microglial activation was evaluated using Iba-1 immunohistochemistry and proinflammatory cytokines were assessed in the hippocampal region. Our result showed that exposure to CHC stress increased the number of active microglia with corresponding increase in inflammatory cytokines and altered behavioural responses. The inhibition of NO synthesis by L-NAME during CHC exposure decreased the number of active microglia in hippocampus as evident from decreased Iba-1 positive cells. Further, L-NAME administration decreased pro-inflammatory cytokines in hippocampus and improved behaviour of rats. Our study demonstrate that stress induced elevation of NO plays pivotal role in altered microglial activation and consequent neurodegenerative processes leading to depression like behaviour in rat.

  1. Antidepressant-Like Effects of Fractions Prepared from Danzhi-Xiaoyao-San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic-Pituitary-Adrenal Axis, Arginine Vasopressin, and Neurotransmitters

    PubMed Central

    Wu, Li-Li; Liu, Yan; Pan, Yi; Su, Jun-Fang; Wu, Wei-Kang

    2016-01-01

    The aim of the present study was to investigate the antidepressant-like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA) and water-EtOH soluble fraction (Fraction B, FB) prepared from the Danzhi-xiaoyao-san (DZXYS) by using chronic unpredictable mild stress-induced depressive rat model. The results indicated that DZXYS could ameliorate the depression-like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant-like effect in chronically stressed rats. PMID:27413389

  2. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats

    PubMed Central

    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

  3. 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

  4. Depression-Like Effect of Prenatal Buprenorphine Exposure in Rats

    PubMed Central

    Hung, Chih-Jen; Wu, Chih-Cheng; Chen, Wen-Ying; Chang, Cheng-Yi; Kuan, Yu-Hsiang; Pan, Hung-Chuan; Liao, Su-Lan; Chen, Chun-Jung

    2013-01-01

    Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior. PMID:24367510

  5. Hyperactivity and depression-like traits in Bax KO mice.

    PubMed

    Krahe, Thomas E; Medina, Alexandre E; Lantz, Crystal L; Filgueiras, Cláudio C

    2015-11-02

    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.

  6. Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress

    PubMed Central

    Ma, Zegang; Wang, Guilin; Cui, Lin; Wang, Qimin

    2015-01-01

    Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus. PMID:26633366

  7. Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice.

    PubMed

    Walsh, Ryan M; Shen, Erica Y; Bagot, Rosemary C; Anselmo, Anthony; Jiang, Yan; Javidfar, Behnam; Wojtkiewicz, Gregory J; Cloutier, Jennifer; Chen, John W; Sadreyev, Ruslan; Nestler, Eric J; Akbarian, Schahram; Hochedlinger, Konrad

    2017-05-09

    PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of PHF8 have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a Phf8 knockout allele in mice to examine the consequences of Phf8 loss for development and behaviour. Phf8 deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of Phf8. We further observe misregulation of serotonin signalling within the prefrontal cortex of Phf8 deficient mice and identify the serotonin receptors Htr1a and Htr2a as direct targets of PHF8. Our results clarify the functional role of Phf8 in mammalian development and behaviour and establish a direct link between Phf8 expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.

  8. 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

  9. 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.

  10. 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

  11. Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models.

    PubMed

    Scheich, Bálint; Gaszner, Balázs; Kormos, Viktória; László, Kristóf; Ádori, Csaba; Borbély, Éva; Hajna, Zsófia; Tékus, Valéria; Bölcskei, Kata; Ábrahám, István; Pintér, Erika; Szolcsányi, János; Helyes, Zsuzsanna

    2016-02-01

    Somatostatin regulates stress-related behavior and its expression is altered in mood disorders. However, little is known about the underlying mechanisms, especially about the importance of its receptors (sst1-sst5) in anxiety and depression-like behavior. Here we analyzed the potential role of sst4 receptor in these processes, since sst4 is present in stress-related brain regions, but there are no data about its functional relevance. Genetic deletion of sst4 (Sstr4(-/-)) and its pharmacological activation with the newly developed selective non-peptide agonist J-2156 were used. Anxiety was examined in the elevated plus maze (EPM) and depression-like behavior in the forced swim (FST) and tail suspension tests (TST). Neuronal activation during the TST was monitored by Fos immunohistochemistry, receptor expression was identified by sst4(LacZ) immunostaining in several brain regions. Sstr4(-/-) mice showed increased anxiety in the EPM and enhanced depression-like behavior in the FST. J-2156 (100 μg/kg i.p.) exhibited anxiolytic effect in the EPM and decreased immobility in the TST. J-2156 alone did not influence Fos immunoreactivity in intact mice, but significantly increased the stress-induced Fos response in the dorsal raphe nucleus, central projecting Edinger-Westphal nucleus, periaqueductal gray matter, the magnocellular, but not the parvocellular part of the hypothalamic paraventricular nucleus, lateral septum, bed nucleus of the stria terminalis and the amygdala. Notably, sst4(LacZ) immunoreactivity occurred in the central and basolateral amygdala. Together, these studies reveal that sst4 mediates anxiolytic and antidepressant-like effects by enhancing the stress-responsiveness of several brain regions with special emphasis on the amygdala. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. CD4+CD25+ Regulatory T Cell Depletion Modulates Anxiety and Depression-Like Behaviors in Mice

    PubMed Central

    Kim, Soo-Jeong; Lee, Hyojung; Lee, Gihyun; Oh, Sei-Joong; Shin, Min-Kyu; Shim, Insop; Bae, Hyunsu

    2012-01-01

    Stress has been shown to suppress immune function and increase susceptibility to inflammatory disease and psychiatric disease. CD4+CD25+ regulatory T (Treg) cells are prominent in immune regulation. This study was conducted to determine if anti-CD25 antibody (Ab) mediated depletion of Treg cells in mice susceptibility to stress-induced development of depression-like behaviors, as well as immunological and neurochemical activity. To accomplish this, an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST) were used to examine depression-like behaviors upon chronic immobilization stress. Immune imbalance status was observed based on analysis of serum cytokines using a mouse cytometric bead array in conjunction with flow cytometry and changes in the levels of serotonin (5-HT) and dopamine (DA) in the brain were measured by high performance liquid chromatography (HPLC). The time spent in the open arms of the EPM decreased significantly and the immobility time in the FST increased significantly in the anti-CD25 Ab-treated group when compared with the non stressed wild-type group. In addition, interlukin-6 (IL-6), tumor necrosis factor-á (TNF-á), interlukin-2 (IL-2), interferon-gamma (IFN-γ), interlukin-4 (IL-4) and interlukin-17A (IL-17A) concentrations were significantly upregulated in the stressed anti-CD25 Ab-treated group when compared with the non stressed wild-type group. Furthermore, the non stressed anti-CD25 Ab-treated group displayed decreased 5-HT levels within the hippocampus when compared with the non stressed wild-type group. These results suggest that CD4+CD25+ Treg cell depletion modulated alterations in depressive behavior, cytokine and monoaminergic activity. Therefore, controlling CD4+CD25+ Treg cell function during stress may be a potent therapeutic strategy for the treatment of depression-like symptoms. PMID:22860054

  13. 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.

  14. 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.

  15. Repeated social defeat stress induces chronic hyperthermia in rats.

    PubMed

    Hayashida, Sota; Oka, Takakazu; Mera, Takashi; Tsuji, Sadatoshi

    2010-08-04

    Psychological stressors are known to increase core body temperature (T(c)) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T(c) returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T(c) are limited. Therefore, we measured T(c) changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests. In the stressed rats, the first social defeat experience induced a robust increase in T(c) (+1.3 degrees C). However, the T(c) of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+0.2-0.3 degree C) T(c) versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.

  16. 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.

  17. Chronic stress prior to pregnancy potentiated long-lasting postpartum depressive-like behavior, regulated by Akt-mTOR signaling in the hippocampus

    PubMed Central

    Xia, Baomei; Chen, Chang; Zhang, Hailou; Xue, Wenda; Tang, Juanjuan; Tao, Weiwei; Wu, Ruyan; Ren, Li; Wang, Wei; Chen, Gang

    2016-01-01

    Postpartum depression (PPD) affects over 10% of new mothers and adversely impacts the health of offspring. One of the greatest risk factors for PPD is prepregnancy stress but the underlying biological mechanism is unknown. Here we constructed an animal model which recapitulated prepregnancy stress induced PPD and tested the role of Akt-mTOR signaling in the hippocampus. Female virgin Balb/c mice received chronic restraint stress, followed by co-housing with a normal male mouse. We found that the chronic stress led to a transient depressive-like condition that disappeared within two weeks. However, prepregnantly stressed females developed long-term postpartum depressive-like (PPD-like) symptoms as indicated by deficient performance in tests of sucrose preference, forced swim, and novelty-suppressed feeding. Chronic stress induced transient decrease in Akt-mTOR signaling and altered expressions of glutamate receptor subunits NR1 and GluR1, in contrast to long-term deficits in Akt-mTOR signaling, GluR1/NR1 ratio, and hippocampal neurogenesis in PPD-like mice. Acute ketamine improved the molecular signaling abnormality, and reversed the behavioral deficits in PPD-like mice in a rapid and persistent manner, in contrast to ineffectiveness by chronic fluoxetine treatment. Taken together, we find that chronic prepregnancy stress potentiates a long-term PPD, in which Akt-mTOR signaling may play a crucial role. PMID:27756905

  18. 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

    Yusko, Brittany; Hawk, Kiel; Schiml, Patricia A; Deak, Terrence; Hennessy, Michael B

    2012-02-01

    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.

  19. 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.

  20. 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

  1. 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.

  2. HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice

    PubMed Central

    Hashikawa, Naoya; Utaka, Yuta; Ogawa, Takumi; Tanoue, Ryo; Morita, Yuna; Yamamoto, Sayumi; Yamaguchi, Satoru; Kayano, Masafumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2017-01-01

    Heat shock proteins (HSPs) are stress-induced chaperones that are involved in neurological disease. Although increasingly implicated in behavioral disorders, the mechanisms of HSP action, and the relevant functional pathways, are still unclear. We examined whether oral administration of geranylgeranylacetone (GGA), a known HSP inducer, produced an antidepressant effect in a social defeat stress model of depression in mice. We also investigated the possible molecular mechanisms involved, particularly focusing on hippocampal neurogenesis and neurotrophic factor expression. In stressed mice, hippocampal HSP105 expression decreased. However, administration of GGA increased HSP105 expression and improved depression-like behavior, induced hippocampal cell proliferation, and elevated brain-derived neurotrophic factor (BDNF) levels in mouse hippocampus. Co-treatment with GGA and the BDNF receptor inhibitor K252a suppressed the antidepressant effects of GGA. HSP105 knockdown decreased BDNF mRNA levels in HT22 hippocampal cell lines and hippocampal tissue and inhibited the GGA-mediated antidepressant effect. These observations suggest that GGA administration is a therapeutic candidate for depressive diseases by increasing hippocampal BDNF levels via HSP105 expression. PMID:28580422

  3. Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype.

    PubMed

    Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Herrera-Mundo, Nieves; Sykes, Catherine E; Francescutti, Dina M; Kuhn, Donald M

    2014-10-15

    Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2(-/-) mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2(-/-) mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2(-/-) mouse questions the role of 5HT in depression. Furthermore, the TPH2(-/-) mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

  4. Mice Genetically Depleted of Brain Serotonin do not Display a Depression-like Behavioral Phenotype

    PubMed Central

    Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Herrera-Mundo, Nieves; Sykes, Catherine E.; Francescutti, Dina M.; Kuhn, Donald M.

    2016-01-01

    Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2−/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2−/− mouse questions the role of 5HT in depression. Furthermore, the TPH2−/− mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. PMID:25089765

  5. Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice.

    PubMed

    Ahn, Na-Ri; Leem, Yea-Hyun; Kato, Morimasa; Chang, Hyuk-ki

    2016-09-01

    The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks' treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.

  6. Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice

    PubMed Central

    Ahn, Nari; Leem, Yea Hyun; Kato, Morimasa; Chang, Hyukki

    2016-01-01

    [Purpose] The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods] Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results] Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion] The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment. PMID:27757384

  7. Chronic stress-induced mechanical hyperalgesia is controlled by capsaicin-sensitive neurones in the mouse.

    PubMed

    Scheich, B; Vincze, P; Szőke, É; Borbély, É; Hunyady, Á; Szolcsányi, J; Dénes, Á; Környei, Zs; Gaszner, B; Helyes, Zs

    2017-09-01

    Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes. Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements. Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production. Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic

  8. Increased novelty-induced motor activity and reduced depression-like behavior in neuropeptide Y (NPY)-Y4 receptor knockout mice.

    PubMed

    Tasan, R O; Lin, S; Hetzenauer, A; Singewald, N; Herzog, H; Sperk, G

    2009-02-18

    There is growing evidence that neuropeptide Y (NPY) acting through Y1 and Y2 receptors has a prominent role in modulating anxiety- and depression-like behavior in rodents. However, a role of other Y-receptors like that of Y4 receptors in this process is poorly understood. We now investigated male Y2, Y4 single and Y2/Y4 double knockout mice in behavioral paradigms for changes in motor activity, anxiety and depression-like behavior. Motor activity was increased in Y2, Y4 and Y2/Y4 knockout mice under changing and stressful conditions, but not altered in a familiar environment. Y4 and Y2 knockout mice revealed an anxiolytic phenotype in the light/dark test, marble burying test and in stress-induced hyperthermia, and reduced depression-like behavior in the forced swim and tail suspension tests. In Y2/Y4 double knockout mice, the response in the light/dark test and in the forced swim test was further enhanced compared with Y4 and Y2 knockout mice, respectively. High levels of Y4 binding sites were observed in brain stem nuclei including nucleus of solitary tract and area postrema. Lower levels were found in the medial amygdala and hypothalamus. Peripheral administration of pancreatic polypeptide (PP) induced Y4 receptor-dependent c-Fos expression in brain stem, hypothalamus and amygdala. PP released peripherally from the pancreas in response to food intake, may act not only as a satiety signal but also modulate anxiety-related locomotion.

  9. 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.

  10. Resveratrol Ameliorates the Depressive-Like Behaviors and Metabolic Abnormalities Induced by Chronic Corticosterone Injection.

    PubMed

    Li, Yu-Cheng; Liu, Ya-Min; Shen, Ji-Duo; Chen, Jun-Jie; Pei, Yang-Yi; Fang, Xiao-Yan

    2016-10-13

    Chronic glucocorticoid exposure is known to cause depression and metabolic disorders. It is critical to improve abnormal metabolic status as well as depressive-like behaviors in patients with long-term glucocorticoid therapy. This study aimed to investigate the effects of resveratrol on the depressive-like behaviors and metabolic abnormalities induced by chronic corticosterone injection. Male ICR mice were administrated corticosterone (40 mg/kg) by subcutaneous injection for three weeks. Resveratrol (50 and 100 mg/kg), fluoxetine (20 mg/kg) and pioglitazone (10 mg/kg) were given by oral gavage 30 min prior to corticosterone administration. The behavioral tests showed that resveratrol significantly reversed the depressive-like behaviors induced by corticosterone, including the reduced sucrose preference and increased immobility time in the forced swimming test. Moreover, resveratrol also increased the secretion of insulin, reduced serum level of glucose and improved blood lipid profiles in corticosterone-treated mice without affecting normal mice. However, fluoxetine only reverse depressive-like behaviors, and pioglitazone only prevent the dyslipidemia induced by corticosterone. Furthermore, resveratrol and pioglitazone decreased serum level of glucagon and corticosterone. The present results indicated that resveratrol can ameliorate depressive-like behaviors and metabolic abnormalities induced by corticosterone, which suggested that the multiple effects of resveratrol could be beneficial for patients with depression and/or metabolic syndrome associated with long-term glucocorticoid therapy.

  11. Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency.

    PubMed

    Xu, Yongjun; Sheng, Hui; Tang, Zhiping; Lu, Jianqiang; Ni, Xin

    2015-07-15

    Estrogen deficiency is involved in the development of depression. However, the mechanism underlying estrogen modulates depression-like behavior remains largely unknown. Inflammation and indoleamine-2,3-dioxygenase (IDO) have been shown to play pivotal roles in various depression models. The objective of the present study was to investigate whether estrogen deficiency-induced depression-like behavior is associated with inflammation and IDO activation in brain. The results showed that ovariectomy resulted in depression-like behavior in female rats and caused a decrease in 5-HT content and an increase in levels of IDO, IFN-γ, IL-6, toll like receptor (TLR)-4 and phosphorylated NF-κB (p65 subunit) in hippocampus but not in prefrontal cortex (PFC). 17β-Estradiol (E2) treatment ameliorated depression-like behavior and restored above neurochemical alternations in hippocampus in ovariectomized rats. Partial correlation analysis showed that the levels of phosphorylated p65, IFN-γ and IL-6 in hippocampus correlated to serum E2 level. Our study suggests that estrogen inhibits inflammation and activates of IDO and maintains 5-HT level in hippocampus, thereby ameliorating depression-like behavior.

  12. 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

  13. Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site

    PubMed Central

    Le François, Brice; Soo, Jeremy; Millar, Anne M.; Daigle, Mireille; Le Guisquet, Anne-Marie; Leman, Samuel; Minier, Frédéric; Belzung, Catherine; Albert, Paul R.

    2015-01-01

    The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of the conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways. PMID:26188176

  14. Lithium Promotes Neuronal Repair and Ameliorates Depression-Like Behavior following Trimethyltin-Induced Neuronal Loss in the Dentate Gyrus

    PubMed Central

    Yoneyama, Masanori; Shiba, Tatsuo; Hasebe, Shigeru; Umeda, Kasumi; Yamaguchi, Taro; Ogita, Kiyokazu

    2014-01-01

    Lithium, a mood stabilizer, is known to ameliorate the stress-induced decrease in hippocampal neurogenesis seen in animal models of stress-related disorders. However, it is unclear whether lithium has beneficial effect on neuronal repair following neuronal damage in neuronal degenerative diseases. Here, we evaluated the effect of in vivo treatment with lithium on the hippocampal neuronal repair in a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampal dentate gyrus (such mice referred to as “impaired animals”) [Ogita et al. (2005) J Neurosci Res 82: 609–621]. The impaired animals had a dramatically increased number of 5-bromo-2′-deoxyuridine (BrdU)-incorporating cells in their dentate gyrus at the initial time window (days 3 to 5 post-TMT treatment) of the self-repair stage. A single treatment with lithium produced no significant change in the number of BrdU-incorporating cells in the dentate granule cell layer and subgranular zone on day 3 post-TMT treatment. On day 5 post-TMT treatment, however, BrdU-incorporating cells were significantly increased in number by lithium treatment for 3 days. Most interestingly, chronic treatment (15 days) with lithium increased the number of BrdU-incorporating cells positive for NeuN or doublecortin in the dentate granule cell layer of the impaired animals, but not in that of naïve animals. The results of a forced swimming test revealed that the chronic treatment with lithium improved the depression-like behavior seen in the impaired animals. Taken together, our data suggest that lithium had a beneficial effect on neuronal repair following neuronal loss in the dentate gyrus through promoted proliferation and survival/neuronal differentiation of neural stem/progenitor cells in the subgranular zone. PMID:24504050

  15. Hyperbaric Oxygen Effects on Depression-Like Behavior and Neuroinflammation in Traumatic Brain Injury Rats.

    PubMed

    Lim, Sher-Wei; Sung, Kuan-Chin; Shiue, Yow-Ling; Wang, Che-Chuan; Chio, Chung-Ching; Kuo, Jinn-Rung

    2017-04-01

    The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)-induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury. Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)-α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods. Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF-α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO. Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. 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.

  17. Stress-induced depressive behaviors are correlated with Par-4 and DRD2 expression in rat striatum.

    PubMed

    Zhu, Xiongzhao; Peng, Sufang; Zhang, Sheng; Zhang, Xiuwu

    2011-10-01

    Depression is a common mental disorder; however, its molecular mechanism has not been fully elucidated. In this study, we investigated the role of maternal deprivation (MD) and chronic mild stress (CMS) in the pathogenesis of depression in rat models. The mRNA levels of prostate apoptosis response-4 (Par-4) and dopamine receptor D2 (DRD2) genes in the striatum were measured by real-time PCR. Methylation level in the promoter of Par-4 gene was detected by bisulfite sequencing. Correlation between gene expression and depression-like behaviors were analyzed. Our results demonstrated that MD and CMS alone or their combination (dual stresses: DS) caused depression-like behaviors in rats. The mRNA levels of Par-4 and DRD2 genes in the striatum were significantly lower in MD-, CMS-, and DS-treated rats than in control rats. Importantly, Par-4 and DRD2 mRNA levels significantly correlated with depression-like behaviors. However, no significant differences in total methylation levels in the promoter of Par-4 gene were found between four groups. Our study suggested that either maternal deprivation or chronic mild stress plays a crucial role in the development of depression-like behaviors in rats. This process is associated with down-regulated Par-4 and DRD2 gene expression in the striatum through a non-methylation mechanism. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior.

    PubMed

    Sah, A; Schmuckermair, C; Sartori, S B; Gaburro, S; Kandasamy, M; Irschick, R; Klimaschewski, L; Landgraf, R; Aigner, L; Singewald, N

    2012-10-16

    Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety.

  19. Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

    PubMed Central

    Sah, A; Schmuckermair, C; Sartori, S B; Gaburro, S; Kandasamy, M; Irschick, R; Klimaschewski, L; Landgraf, R; Aigner, L; Singewald, N

    2012-01-01

    Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety. PMID:23047242

  20. 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.

  1. Depressive-Like Behavior in Adolescents after Maternal Separation: Sex Differences, Controllability, and GABA

    PubMed Central

    Leussis, Melanie P.; Freund, Nadja; Brenhouse, Heather C.; Thompson, Britta S.; Andersen, Susan L.

    2017-01-01

    Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments. PMID:22776911

  2. Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.

    PubMed

    Winther, Gudrun; Pyndt Jørgensen, Betina M; Elfving, Betina; Nielsen, Denis Sandris; Kihl, Pernille; Lund, Sten; Sørensen, Dorte Bratbo; Wegener, Gregers

    2015-06-01

    Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM. The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers. It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6. In conclusion, we hypothesise that imbalances of the microbiota-gut-brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour.

  3. Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin.

    PubMed

    Nasser, Arafat; Møller, Lisbeth B; Olesen, Jess H; Konradsen Refsgaard, Louise; Konradsen, Louise S; Andreasen, Jesper T

    2014-12-01

    Decreased tetrahydrobiopterin (BH4) biosynthesis has been implicated in the pathophysiology of anxiety and depression. The aim of this study was therefore to characterise the phenotype of homozygous hph-1 (hph) mice, a model of BH4 deficiency, in behavioural tests of anxiety and depression as well as determine hippocampal monoamine and plasma nitric oxide levels. In the elevated zero maze test, hph mice displayed increased anxiety-like responses compared to wild-type mice, while the marble burying test revealed decreased anxiety-like behaviour. This was particularly observed in male mice. In the tail suspension test, hph mice of both sexes displayed increased depression-like behaviours compared to wild-type counterparts, whereas the forced swim test showed a trend towards increased depression-like behaviours in male hph mice, but significant decrease in depression-like behaviours in female mice. This study provides the first evidence that congenital BH4 deficiency regulates anxiety- and depression-like behaviours. The altered responses observed possibly reflect decreased hippocampal serotonin and dopamine found in hph mice compared to wild-type mice, but also reduced nitric oxide formation. We propose that the hph-1 mouse may be a novel tool to investigate the role of BH4 deficiency in anxiety and depression.

  4. 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.

  5. Intracerebroventricular administration of neuronostatin induces depression-like effect in forced swim test of mice.

    PubMed

    Yang, Ai-min; Ji, Yue-ke; Su, Shu-fang; Yang, Shao-bin; Lu, Song-song; Mi, Ze-yun; Yang, Qing-zhen; Chen, Qiang

    2011-09-01

    Neuronostatin is a recently discovered endogenous bioactive peptide that is encoded by pro-mRNA of somatostatin. In the present study, we investigated the effect of neuronostatin on mood regulation in the forced swim test of mice. Our results showed intracerebroventricular (i.c.v.) administration of neuronostatin produced an increase in the immobility time, suggesting that neuronostatin induced depression-like effect. In order to rule out the possibility that neuronostatin had increased immobility time by a non-specific reduction in general activity, the effect of neuronostatin on locomotor activity was examined. Neuronostatin had no influence on locomotor activity in mice. In addition, the depression-like effect of neuronostatin was completely reversed by melanocortin 3/4 receptor antagonist SHU9119 or GABAA receptor antagonist bicuculline, but not by opioid receptor antagonist naloxone. These data suggested that the depression-like effect induced by i.c.v. administered neuronostatin was dependent upon the central melanocortin system and GABAA receptor. In conclusion, the results of this study report that neuronostatin induces depression-like effect. These findings reveal that neuronostatin is a new neuropeptide with an important role in regulating depressive behavior.

  6. Changes in brain protein expression are linked to magnesium restriction-induced depression-like behavior.

    PubMed

    Whittle, Nigel; Li, Lin; Chen, Wei-Qiang; Yang, Jae-Won; Sartori, Simone B; Lubec, Gert; Singewald, Nicolas

    2011-04-01

    There is evidence to suggest that low levels of magnesium (Mg) are associated with affective disorders, however, causality and central neurobiological mechanisms of this link are largely unproven. We have recently shown that mice fed a low Mg-containing diet (10% of daily requirement) display enhanced depression-like behavior sensitive to chronic antidepressant treatment. The aim of the present study was to utilize this model to gain insight into underlying mechanisms by quantifying amygdala/hypothalamus protein expression using gel-based proteomics and correlating changes in protein expression with changes in depression-like behavior. Mice fed Mg-restricted diet displayed reduced brain Mg tissue levels and altered expression of four proteins, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), manganese-superoxide dismutase (MnSOD), glutamate dehydrogenase 1 (GDH1) and voltage-dependent anion channel 1. The observed alterations in protein expression may indicate increased nitric oxide production, increased anti-oxidant response to increased oxidative stress and potential alteration in energy metabolism. Aberrant expressions of DDAH1, MnSOD and GDH1 were normalized by chronic paroxetine treatment which also normalized the enhanced depression-like behavior, strengthening the link between the changes in these proteins and depression-like behavior. Collectively, these findings provide first evidence of low magnesium-induced alteration in brain protein levels and biochemical pathways, contributing to central dysregulation in affective disorders.

  7. 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

  8. 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.

  9. Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing.

    PubMed

    Lamkin, Donald M; Lutgendorf, Susan K; Lubaroff, David; Sood, Anil K; Beltz, Terry G; Johnson, Alan Kim

    2011-03-01

    Considerable data demonstrate a high prevalence of depressive symptoms in cancer patients. This study introduces an experimental model to examine the effect of tumor on depressive-like behavior. Female C57BL/6 mice were injected i.p. with syngeneic ID8 ovarian carcinoma. Experiment 1 measured sucrose intake before and after tumor incubation to assess the effect of tumor on anhedonic depressive-like behavior. Experiment 2 examined effects of tumor and social housing on anhedonia and a second depressive-like behavior, tail suspension test (TST) immobility. Systemic proinflammatory and antiinflammatory cytokines were measured following each experiment. Additional behaviors assessed the specificity of tumor's effect on depressive-like behavior. Tumor caused a reduction in sucrose intake relative to baseline and control levels (P<.05). Moreover, individually-housed tumor-bearing mice exhibited a lower sucrose preference than group-housed tumor-bearing or control mice in either housing condition (P<.05). Although tumor-bearing mice exhibited less locomotion than controls (P<.001), there was no significant effect of tumor on TST immobility. Tumor caused higher levels of systemic proinflammatory and antiinflammatory cytokines and smaller body weight (P<.05), but appetite and motor capacity were not significantly affected. Statistical mediation analysis showed that circulating interleukin-6 partially mediated the effect between tumor and home cage locomotion (P<.01) but not between tumor and sucrose intake. It is concluded that tumor elicits anhedonic depressive-like behavior in a murine model of ovarian cancer. This may have important implications for etiology of depression in the clinical cancer setting.

  10. Cancer induces inflammation and depressive-like behavior in the mouse: Modulation by social housing

    PubMed Central

    Lamkin, Donald M.; Lutgendorf, Susan K.; Lubaroff, David; Sood, Anil K.; Beltz, Terry G.; Johnson, Alan Kim

    2011-01-01

    Considerable data demonstrate a high prevalence of depressive symptoms in cancer patients. This study introduces an experimental model to examine the effect of tumor on depressive-like behavior. Female C57BL/6 mice were injected i.p. with syngeneic ID8 ovarian carcinoma. Experiment 1 measured sucrose intake before and after tumor incubation to assess the effect of tumor on anhedonic depressive-like behavior. Experiment 2 examined effects of tumor and social housing on anhedonia and a second depressive-like behavior, tail suspension test (TST) immobility. Systemic proinflammatory and antiinflammatory cytokines were measured following each experiment. Additional behaviors assessed the specificity of tumor's effect on depressive-like behavior. Tumor caused a reduction in sucrose intake relative to baseline and control levels (P < .05). Moreover, individually-housed tumor-bearing mice exhibited a lower sucrose preference than group-housed tumor-bearing or control mice in either housing condition (P < .05). Although tumor-bearing mice exhibited less locomotion than controls (P < .001), there was no significant effect of tumor on TST immobility. Tumor caused higher levels of systemic proinflammatory and antiinflammatory cytokines and smaller body weight (P < .05), but appetite and motor capacity were not significantly affected. Statistical mediation analysis showed that circulating interleukin-6 partially mediated the effect between tumor and home cage locomotion (P < .01) but not between tumor and sucrose intake. It is concluded that tumor elicits anhedonic depressive-like behavior in a murine model of ovarian cancer. This may have important implications for etiology of depression in the clinical cancer setting. PMID:21182930

  11. Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

    PubMed

    Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram

    2014-07-15

    Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression.

  12. 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.

  13. A high-fat diet exacerbates depressive-like behavior in the Flinders Sensitive Line (FSL) rat, a genetic model of depression.

    PubMed

    Abildgaard, Anders; Solskov, Lasse; Volke, Vallo; Harvey, Brian H; Lund, Sten; Wegener, Gregers

    2011-06-01

    Major depressive disorder (MDD) and diabetes mellitus type II (T2DM) are two of the major health challenges of our time. It has been shown that MDD and T2DM are highly co-morbid, and recent work has proposed a bi-directional connection between the diseases. The aim of the current study was to investigate the effect of a high-fat diet (HFD) on behavior and metabolism in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Age and weight matched rats were fed a HFD or control diet for 10 weeks and subjected to behavioral testing and metabolic assessment. We found that HFD exacerbated the depressive-like behavior of the FSL rat in the Forced Swim Test (FST), a depression screening tool, although it did not affect the non-depressed FRL rat despite a higher caloric intake. Moreover, the depressive-like phenotype was associated with reduced anxiety and impairment in novel object recognition memory, while HFD consumption led to diminished object recognition memory as well. In both strains HFD increased insulin levels during an oral glucose tolerance test, although fasting blood glucose levels were only significantly increased by HFD in the FSL rat, suggesting a greater metabolic susceptibility in this rat strain. We conclude that compared with the FRL rat, the FSL rat is more susceptible to developing aberrant behaviors related to depression following metabolic stress induced by HFD. Further studies with a mechanistic focus could potentially lead to a better understanding of a possible pathophysiological link between T2DM and MDD.

  14. Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations.

    PubMed

    Bisaz, Reto; Sandi, Carmen

    2012-03-01

    Previous studies in rodents showed that chronic stress induces structural and functional alterations in several brain regions, including shrinkage of the hippocampus and the prefrontal cortex, which are accompanied by cognitive and emotional disturbances. Reduced expression of the neural cell adhesion molecule (NCAM) following chronic stress has been proposed to be crucially involved in neuronal retraction and behavioral alterations. Since NCAM gene polymorphisms and altered expression of alternatively spliced NCAM isoforms have been associated with bipolar depression and schizophrenia in humans, we hypothesized that reduced expression of NCAM renders individuals more vulnerable to the deleterious effects of stress on behavior. Here, we specifically questioned whether mice in which the NCAM gene is inactivated in the forebrain by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter (conditional NCAM-deficient mice), display increased vulnerability to stress. We assessed the evolving of depressive-like behaviors and spatial learning and memory impairments following a subchronic stress protocol (2 weeks) that does not result in behavioral dysfunction, nor in altered NCAM expression, in wild-type mice. Indeed, while no behavioral alterations were detected in wild-type littermates after subchronic stress, conditional NCAM-deficient mice showed increased immobility in the tail suspension test and deficits in reversal spatial learning in the water maze. These findings indicate that diminished NCAM expression might be a critical vulnerability factor for the development of behavioral alterations by stress and further support a functional involvement of NCAM in stress-induced cognitive and emotional disturbances.

  15. Long-Term Corticosterone Exposure Decreases Insulin Sensitivity and Induces Depressive-Like Behaviour in the C57BL/6NCrl Mouse

    PubMed Central

    van Donkelaar, Eva L.; Vaessen, Koen R. D.; Pawluski, Jodi L.; Sierksma, Annerieke S.; Blokland, Arjan; Cañete, Ramón; Steinbusch, Harry W. M.

    2014-01-01

    Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its

  16. Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse.

    PubMed

    van Donkelaar, Eva L; Vaessen, Koen R D; Pawluski, Jodi L; Sierksma, Annerieke S; Blokland, Arjan; Cañete, Ramón; Steinbusch, Harry W M

    2014-01-01

    Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its

  17. Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence.

    PubMed

    Zan, Gui-Ying; Wang, Qian; Wang, Yu-Jun; Liu, Yao; Hang, Ai; Shu, Xiao-Hong; Liu, Jing-Gen

    2015-09-15

    The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/κ opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of κ opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/κ opioid receptor system, and shed light on the κ opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal.

  18. Repeated Long Separations from Pups Produces Depression-like Behavior in Rat Mothers

    PubMed Central

    Boccia, Maria L.; Razzoli, Maria; Vadlamudi, Sivaram Prasad; Trumbull, Whit; Caleffie, Christopher; Pedersen, Cort A.

    2007-01-01

    Summary Long (LMS) versus brief (BMS) daily separations of rat pups from their mothers have contrasting effects on their adult stress responses and maternal behavior by respectively decreasing and increasing licking received from their mothers. We hypothesized that LMS decreases pup licking in mothers by inducing learned helplessness, creating a depression-like state. We subjected postpartum rats to LMS (3 h), BMS (15 min) or no separation (NMS) on postpartum days 2–14. After weaning, mothers were given a forced swim test (FST). LMS mothers exhibited more immobility and fewer escape attempts than BMS or NMS mothers. These results suggest that LMS induces a depression-like state, which may account for the reductions in maternal behavior seen in LMS mothers. Immobility in the FST is recognized as an animal model of depression. Therefore, LMS may be a model of maternal depression. PMID:17118566

  19. Pycnogenol ameliorates depression-like behavior in repeated corticosterone-induced depression mice model.

    PubMed

    Mei, Lin; Mochizuki, Miyako; Hasegawa, Noboru

    2014-01-01

    Oxidative stress is considered to be a mechanism of major depression. Pycnogenol (PYC) is a natural plant extract from the bark of Pinus pinaster Aiton and has potent antioxidant activities. We studied the ameliorative effect of PYC on depression-like behavior in chronic corticosterone- (CORT-) treated mice for 20 days. After the end of the CORT treatment period, PYC (0.2 mg/mL) was orally administered in normal drinking water. Depression-like behavior was investigated by the forced swimming test. Immobility time was significantly longer by CORT exposure. When the CORT-treated mice were supplemented with PYC, immobility time was significantly shortened. Our results indicate that orally administered PYC may serve to reduce CORT-induced stress by radical scavenging activity.

  20. 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.

  1. Light deprivation produces a sexual dimorphic effect on neural excitability and depression-like behavior in mice.

    PubMed

    Lu, Chanyi; Wang, Yun; Zhang, Yun-Feng

    2016-10-28

    Light sensory experience plays a crucial role in the regulation of mood, and light deficiency is considered as one important factor potentially leading to depression. Women are twice as likely as men to suffer from depression. However, the physiological mechanism underlying sex differences in the prevalence, incidence and morbidity risk of depression is still poorly understood. The potential causal relationship between sex dimorphic behavioral deficits and altered intrinsic electrophysiological properties of Layer V pyramidal cells (L5PCs) in the motor cortex was investigated using a mouse model with depression-like behavior that was induced by light deprivation. The depression-like behavior was characterized by increased immobility and decreased activity in the forced swimming test and tail suspension test. Compared with male depressive-like mice, light deprivation (LD) induced longer immobile behavior while shorter active behavior in female depressive-like mice, indicating that LD produces a sexual dimorphic effect on depression-like behavior with more severe depressive-like symptoms in females. LD induced lower locomotor activity in female depressive-like mice as evidenced by the significant decrease in pole-climbing and swimming during the anti-static fatigue test and exhaustive swimming test correspondingly. LD also significantly decreased the intrinsic excitability of L5PCs in female depressive-like mice, which may explain the reduced active behavior and locomotor activity of female mice. Collectively, it indicates that LD produces a sexual dimorphic effect on the depression-like behavior, locomotor activity and neural excitability in mice, and may suggest a causal relationship between the more severe depressive conditions and decreased neural excitability of L5PCs in female mice. These divergent findings from male and female depressive-like mice may provide one potential route to the physiological mechanism underlying sex differences in the prevalence of

  2. Emergence of anxiety-like behaviors in depressive-like Cpefat/fat mice

    PubMed Central

    Rodriguiz, Ramona M.; Wilkins, John J.; Creson, Thomas K.; Biswas, Reeta; Berezniuk, Iryna; Fricker, Arun D.; Fricker, Lloyd D.; Wetsel, William C.

    2013-01-01

    Cpefat/fat mice have a point mutation in carboxypeptidase E (CPE), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of CPE activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpefat/fat mice develop obesity, diabetes, and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviors are also present. Anxiety-like responses are not evident in young Cpefat/fat mice (~60 days), but appear in older animals (>90 days). These behaviors are reversed by acute treatment with diazepam or fluoxetine. By contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviors are reversed by acute administration of reboxetine. By comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wks of treatment. These data demonstrate that Cpefat/fat mice display depressive-like responses at ~60 days of age, whereas anxiety-like behaviors emerge ~1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpefat/fat mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviors are different. Since depressive-like responses in the Cpefat/fat mice are rescued by a 2 wk, but not acute, treatment with fluoxetine or buproprion, these mice may serve as a useful model that resembles human depression. PMID:23442571

  3. Emergence of anxiety-like behaviours in depressive-like Cpe(fat/fat) mice.

    PubMed

    Rodriguiz, Ramona M; Wilkins, John J; Creson, Thomas K; Biswas, Reeta; Berezniuk, Iryna; Fricker, Arun D; Fricker, Lloyd D; Wetsel, William C

    2013-08-01

    Cpe(fat/fat) mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpe(fat/fat) mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe(fat/fat) mice (∼60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpe(fat/fat) mice display depressive-like responses aged ∼60 d, whereas anxiety-like behaviours emerge ∼1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe(fat/fat) mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive-like responses in the Cpe(fat/fat) mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.

  4. Diphenyl diselenide supplemented diet reduces depressive-like behavior in hypothyroid female rats.

    PubMed

    Dias, Glaecir Roseni Mundstock; de Almeida, Tielle Moraes; Sudati, Jéssie Haigert; Dobrachinski, Fernando; Pavin, Sandra; Soares, Félix Alexandre Antunes; Nogueira, Cristina Wayne; Barbosa, Nilda Berenice Vargas

    2014-01-30

    Hypothyroidism has been associated to psychiatric disorder development and tissue oxidative damage. In this study, we evaluated the effect of diphenyl diselenide supplementation on depressive-like behavior triggered by methimazole exposure in female rats. Additionally, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and non-protein thiol (NP-SH) levels were analyzed in cerebral cortex, hippocampus and striatum structures of rats. Monoamine oxidase (MAO) activity was evaluated in total brain. Firstly, female rats received methimazole (MTZ) 20mg/100ml in the drinking water for 30days and were evaluated in open-field and forced swimming tests (FST). In this set of experiments, the rats exposed to MTZ presented a depressive-like behavior, which was evidenced by a significant increase in the immobility time when compared to control group. Thereafter, MTZ-induced hypothyroid rats received either a standard or a diet containing 5ppm of diphenyl diselenide, and then they were evaluated monthly in open-field and FST tests during 3months. No alteration on the locomotor performance was observed among the groups. The depressive-like behavior of hypothyroid rats was blunted by diphenyl diselenide supplementation during all experimental periods. The levels of thyroid hormones remained low in MTZ exposed groups until the end of experimental period. The MTZ group had an increase in TBARS and ROS levels that were restored by diphenyl diselenide supplementation. NP-SH content of cerebral structures was not modified by MTZ exposure and/or diphenyl diselenide supplementation. Diphenyl diselenide supplementation restored the MAO B activity that was decreased in MTZ group. In summary, our results show that hypothyroidism induced by MTZ methimazole triggers a depressive-like behavior in female rats and that dietary diphenyl diselenide was able to reduce this effect. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. The melanin-concentrating hormone (MCH) system in an animal model of depression-like behavior.

    PubMed

    García-Fuster, M J; Parks, G S; Clinton, S M; Watson, S J; Akil, H; Civelli, O

    2012-08-01

    Selective breeding for divergence in locomotion in a novel environment (bHR, bred High-Responder; bLR, bred Low-Responder) correlates with stress-reactivity, spontaneous anxiety-like behaviors and predicts vulnerability in a rodent model of depression. Identifying genetic factors that may account for such vulnerability are key determinants not only for the illness outcome but also for the development of better-tailored treatment options. Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits some of the hallmarks of a regulator of affective states. The aim of this study was to ascertain the role of the MCH system in depression-like behaviors in bHR vs. bLR rats. bLR rats showed a 44% increase in hypothalamic pMCH mRNA and a 14% decrease in hippocampal CA1 MCH1R mRNA when compared to bHR rats. Interestingly, the amount of time that rats spent immobile in the FST (depressive-like behavior) correlated positively with the amount of hypothalamic pMCH mRNA and negatively with that of hippocampal CA1 MCH1R. The results indicate that the bLR-bHR is a useful rat model to investigate individual basal genetic differences that participate in the monitoring of emotional responsiveness (i.e., depression- and anxiety-like behaviors). They also point to the MCH system (i.e., chronically higher pMCH expression and consequently receptor down-regulation) as a candidate biomarker for the severity of depressive-like behavior. The data indicate that MCH1R participates in the modulation of depression-like behavior through a process that involves the CA1 region of the hippocampus, supporting the possible use of MCH1R antagonists in the treatment of depression. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

  6. 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

  7. Pituitary Adenylate Cyclase-Activating Polypeptide induces a depressive-like phenotype in rats

    PubMed Central

    Seiglie, Mariel P.; Smith, Karen L.; Blasio, Angelo; Cottone, Pietro; Sabino, Valentina

    2015-01-01

    Major Depressive Disorder (MDD) is a chronic, life-threatening psychiatric condition characterized by depressed mood, psychomotor alterations, and a markedly diminished interest or pleasure in most activities, known as anhedonia. Available pharmacotherapies have limited success and the need for new strategies is clear. Recent studies attribute a major role to the pituitary adenylate cyclase-activating polypeptide (PACAP) system in mediating the response to stress. PACAP knockout mice display profound alterations in depressive-like behaviors and genetic association studies have demonstrated that genetic variants of the PACAP gene are associated with MDD. However, the effects of PACAP on depressive-like behaviors in rodents have not yet been systematically examined. The present study investigated the effects of central administration of PACAP in rats on depressive-like behaviors, using well-established animal models that represent some of the endophenotypes of depression. We used intracranial self-stimulation (ICSS) to assess the brain reward function, saccharin preference test to assess anhedonia, social interaction to assess social withdrawal, and forced swim test (FST) to assess behavioral despair. PACAP raised the current threshold for ICSS, elevation blocked by the PACAP antagonist PACAP(6-38). PACAP reduced the preference for a sweet saccharin solution, and reduced the time the rats spent interacting with a novel animal. Interestingly, PACAP administration did not affect immobility in the FST. Our results demonstrate a role for the central PACAP/PAC1R system in the regulation of depressive-like behaviors, and suggest that hyperactivity of the PACAP/PAC1R system may contribute to the pathophysiology of depression, particularly the associated anhedonic symptomatology and social dysfunction. PMID:26264905

  8. Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery.

    PubMed

    Pandey, Dilip Kumar; Rajkumar, Ramamoorthy; Mahesh, Radhakrishnan; Radha, Raghuraman

    2008-12-01

    The anti-serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5-2 mg kg(-1)) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg(-1)) that induced depressant-like effects were found to significantly reduce 5-hydroxytryptophan-induced head twitch response. Interaction studies revealed that the depressant-like effects of PTL (1 mg kg(-1)) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg(-1)) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.

  9. 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.

  10. Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression.

    PubMed

    Tang, Ming-Ming; Lin, Wen-Juan; Pan, Yu-Qin; Guan, Xi-Ting; Li, Ying-Cong

    2016-07-01

    Our previous work found that triple central lipopolysaccharide (LPS) administration could induce depressive-like behaviors and increased central pro-inflammatory cytokines mRNA, hippocampal cytokine mRNA in particular. Since several neuroinflammation-associated conditions have been reported to impair neurogenesis, in this study, we further investigated whether the neuroinflammation induced depression would be associated with hippocampal neurogenesis dysfunction. An animal model of depression induced by triple central lipopolysaccharide (LPS) administration was used. In the hippocampus, the neuroinflammatory state evoked by LPS was marked by an increased production of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-α. It was found that rats in the neuroinflammatory state exhibited depressive-like behaviors, including reduced saccharin preference and locomotor activity as well as increased immobility time in the tail suspension test and latency to feed in the novelty suppressed feeding test. Adult hippocampal neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. We also demonstrated that the decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes of decreased saccharine preference and distance travelled, the core and characteristic symptoms of depression, under neuro inflammation state. These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation.

  11. Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation.

    PubMed

    Ignácio, Zuleide M; Réus, Gislaine Z; Abelaira, Helena M; Maciel, Amanda L; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Gava, Fernanda F; Valvassori, Samira S; Carvalho, André F; Quevedo, João

    2017-03-01

    Stress in early life has been appointed as an important phenomenon in the onset of depression and poor response to treatment with classical antidepressants. Furthermore, childhood trauma triggers epigenetic changes, which are associated with the pathophysiology of major depressive disorder (MDD). Treatment with atypical antipsychotics such as quetiapine, exerts therapeutic effect for MDD patients and induces epigenetic changes. This study aimed to analyze the effect of chronic treatment with quetiapine (20mg/kg) on depressive-like behavior of rats submitted to maternal deprivation (MD), as well as the activity of histone acetylation by the enzymes histone acetyl transferases (HAT) and deacetylases (HDAC) and DNA methylation, through DNA methyltransferase enzyme (DNMT) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus. Maternally deprived rats had a depressive-like behavior in the forced swimming test and an increase in the HDAC and DNMT activities in the hippocampus and NAc. Treatment with quetiapine reversed depressive-like behavior and reduced the DNMT activity in the hippocampus. This is the first study to show the antidepressant-like effect of quetiapine in animals subjected to MD and a protective effect by quetiapine in reducing epigenetic changes induced by stress in early life. These results reinforce an important role of quetiapine as therapy for MDD. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. 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.

  13. 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.

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

    PubMed Central

    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. PMID:25559957

  15. 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.

  16. Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors

    PubMed Central

    2013-01-01

    Background Activation of the tryptophan degrading enzyme indoleamine-2,3-dioxygenase 1 (IDO1) is associated with the development of behavioral signs of depression. Systemic immune challenge induces IDO1 in both the periphery and the brain, leading to increased circulating and brain concentrations of kynurenines. However, whether IDO1 activity within the brain is necessary for the manifestation of depression-like behavior of mice following a central immune challenge remains to be elucidated. Methods We investigated the role of brain IDO1 in mediating depression-like behavior of mice in response to intracerebroventricular injection of saline or lipopolysaccharide (LPS, 10 ng). Results LPS increased the duration of immobility in the tail suspension test and decreased preference for a sucrose solution. These effects were associated with an activation of central but not peripheral IDO1, as LPS increased brain kynurenine but had no effect on plasma concentrations of kynurenine. Interestingly, genetic deletion or pharmacological inhibition of IDO1, using 1-methyl-tryptophan, abrogated the reduction in sucrose preference induced by intracerebroventricular LPS. 1-Methyl-tryptophan also blocked the LPS-induced increase in duration of immobility during the tail suspension test. Conclusions These data indicate that activation of brain IDO1 is sufficient to induce depression-like behaviors of mice in response to central LPS. PMID:23866724

  17. Preventive effect of estrogen on depression-like behavior induced by chronic restraint stress.

    PubMed

    Li, Wei; Li, Qing-Jiao; An, Shu-Cheng

    2010-04-01

    To investigate the roles of estrogen and kalirin-7 in chronic restraint stress (CRS)-induced depression and the pathophysiological mechanism of depression. Healthy female mice from Institute of Cancer Research (ICR) were randomly divided into 3 groups: control group, CRS group, and estrogen + CRS group. CRS was used to establish the animal model of depression. Forced swimming test and immunohistochemistry method were utilized to investigate the animal behavior and kalirin-7 expression in the hippocampus, respectively. Compared with the control group, the CRS mice displayed depression-like behaviors, including a significant reduction in body weight, a significant increase in immobility time in forced swimming test, and a dramatic decrease in kalirin-7 expression in the hippocampus. However, administration of estrogen attenuated the CRS-induced negative behaviors, and simultaneously increased kalirin-7 expression. Estrogen replacement therapy (ERT) could prevent CRS-induced depression-like behaviors in female ICR mice. Besides, kalirin-7 also plays a role in preventing CRS-induced depression-like behaviors.

  18. Depressive-like symptoms in a reserpine-induced model of fibromyalgia in rats.

    PubMed

    Blasco-Serra, Arantxa; Escrihuela-Vidal, Francesc; González-Soler, Eva M; Martínez-Expósito, Fernando; Blasco-Ausina, M Carmen; Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Teruel-Martí, Vicent; Valverde-Navarro, Alfonso A

    2015-11-01

    Since the pathogenesis of fibromyalgia is unknown, treatment options are limited, ineffective and in fact based on symptom relief. A recently proposed rat model of fibromyalgia is based on central depletion of monamines caused by reserpine administration. This model showed widespread musculoskeletal pain and depressive-like symptoms, but the methodology used to measure such symptoms has been criticized. Evidence relates the high prevalence of pain and depression in fibromyalgia to common pathogenic pathways, most probably focused on the monoaminergic system. The present study aims at a validation of the reserpine model of fibromyalgia. For this purpose, rats undergoing this model have been tested for depressive-like symptoms with a Novelty-Suppressed Feeding Test adaptation. Animals administered with reserpine and subjected to forced food deprivation performed a smaller number of incursions to the center of the open field, evidenced by a decrease in the per-minute rate of the rats' approaching, smelling or touching the food. They also took more time to eat from the central food than control rats. These NSFT findings suggest the presence of depressive-like disorders in this animal model of fibromyalgia.

  19. GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology.

    PubMed

    Müller, Iris; Obata, Kunihiko; Richter-Levin, Gal; Stork, Oliver

    2014-01-01

    GABAergic mechanisms are critically involved in the control of fear and anxiety, but their role in the development of stress-induced psychopathologies, including post-traumatic stress disorder (PTSD) and mood disorders is not sufficiently understood. We studied these functions in two established mouse models of risk factors for stress-induced psychopathologies employing variable juvenile stress and/or social isolation. A battery of emotional tests in adulthood revealed the induction of contextually generalized fear, anxiety, hyperarousal and depression-like symptoms in these paradigms. These reflect the multitude and complexity of stress effects in human PTSD patients. With factor analysis we were able to identify parameters that reflect these different behavioral domains in stressed animals and thus provide a basis for an integrated scoring of affectedness more closely resembling the clinical situation than isolated parameters. To test the applicability of these models to genetic approaches we further tested the role of GABA using heterozygous mice with targeted mutation of the GABA synthesizing enzyme GAD65 [GAD65(+/-) mice], which show a delayed postnatal increase in tissue GABA content in limbic and cortical brain areas. Unexpectedly, GAD65(+/-) mice did not show changes in exploratory activity regardless of the stressor type and were after the variable juvenile stress procedure protected from the development of contextual generalization in an auditory fear conditioning experiment. Our data demonstrate the complex nature of behavioral alterations in rodent models of stress-related psychopathologies and suggest that GAD65 haplodeficiency, likely through its effect on the postnatal maturation of GABAergic transmission, conveys resilience to some of these stress-induced effects.

  20. [Stress-induced cellular adaptive mutagenesis].

    PubMed

    Zhu, Linjiang; Li, Qi

    2014-04-01

    The adaptive mutations exist widely in the evolution of cells, such as antibiotic resistance mutations of pathogenic bacteria, adaptive evolution of industrial strains, and cancerization of human somatic cells. However, how these adaptive mutations are generated is still controversial. Based on the mutational analysis models under the nonlethal selection conditions, stress-induced cellular adaptive mutagenesis is proposed as a new evolutionary viewpoint. The hypothetic pathway of stress-induced mutagenesis involves several intracellular physiological responses, including DNA damages caused by accumulation of intracellular toxic chemicals, limitation of DNA MMR (mismatch repair) activity, upregulation of general stress response and activation of SOS response. These responses directly affect the accuracy of DNA replication from a high-fidelity manner to an error-prone one. The state changes of cell physiology significantly increase intracellular mutation rate and recombination activity. In addition, gene transcription under stress condition increases the instability of genome in response to DNA damage, resulting in transcription-associated DNA mutagenesis. In this review, we summarize these two molecular mechanisms of stress-induced mutagenesis and transcription-associated DNA mutagenesis to help better understand the mechanisms of adaptive mutagenesis.

  1. Increased depression-like behaviors with dysfunctions in the stress axis and the reward center by free access to highly palatable food.

    PubMed

    Park, E; Kim, J Y; Lee, J-H; Jahng, J W

    2014-03-14

    This study was conducted to examine the behavioral consequences of unlimited consumption of highly palatable food (HPF) and investigate its underlying neural mechanisms. Male Sprague-Dawley rats had free access to chocolate cookie rich in fat (HPF) in addition to ad libitum chow and the control group received chow only. Rats were subjected to behavioral tests during the 2nd week of food condition; i.e. ambulatory activity test on the 8th, elevated plus maze test (EPM) on the 10th and forced swim test (FST) on the 14th day of food condition. After 8 days of food condition, another group of rats were placed in a restraint box and tail bloods were collected at 0, 20, 60, and 120 time points during 2h of restraint period, used for the plasma corticosterone assay. At the end of restraint session, rats were sacrificed and the tissue sections of the nucleus accumbens (NAc) were processed for c-Fos immunohistochemistry. Ambulatory activities and the scores of EPM were not significantly affected by unlimited cookie consumption. However, immobility duration during FST was increased, and swim decreased, in the rats received free cookie access compared with control rats. Stress-induced corticosterone increase was exaggerated in cookie-fed rats, while the stress-induced c-Fos expression in the NAc was blunted, compared to control rats. Results suggest that free access to HPF may lead to the development of depression-like behaviors in rats, likely in relation with dysfunctions in the hypothalamic-pituitary-adrenal axis and the reward center.

  2. Functional implications of decreases in neurogenesis following chronic mild stress in mice.

    PubMed

    Mineur, Y S; Belzung, C; Crusio, W E

    2007-12-05

    Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.

  3. The acute social defeat stress and nest-building test paradigm: A potential new method to screen drugs for depressive-like symptoms.

    PubMed

    Otabi, Hikari; Goto, Tatsuhiko; Okayama, Tsuyoshi; Kohari, Daisuke; Toyoda, Atsushi

    2017-02-01

    Psychosocial stress can cause mental conditions such as depression in humans. To develop drug therapies for the treatment of depression, it is necessary to use animal models of depression to screen drug candidates that exhibit anti-depressive effects. Unfortunately, the present methods of drug screening for antidepressants, the forced-swim test and tail-suspension test, are limiting factors in drug discovery because they are not based on the constructive validity of objective phenotypes in depression. Previously, we discovered that the onset of nest building is severely delayed in mice exposed to subchronic mild social defeat stress (sCSDS). Therefore, a novel paradigm combining acute social defeat stress (ASDS) and the nest-building test (SNB) were established for the efficient screening of drugs for depressive-like symptoms. Since ASDS severely delayed the nest-building process as shown in chronically social defeated mice, we sought to rescue the delayed nest-building behavior in ASDS mice. Injecting a specific serotonin 2a receptor antagonist (SR-46349B), the nest-building deficit exhibited by ASDS mice was partially rescued. On the other hand, a selective serotonin reuptake inhibitor (fluoxetine) did not rescue the nest-building deficit in ASDS mice. Therefore, we conclude that the SNB paradigm is an another potential behavioral method for screening drugs for depressive-like symptoms including attention deficit, anxiety, low locomotion, and decreased motivation. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Stress and vitamin D: altered vitamin D metabolism in both the hippocampus and myocardium of chronic unpredictable mild stress exposed rats.

    PubMed

    Jiang, Pei; Zhang, Wen-Yuan; Li, Huan-De; Cai, Hua-Lin; Liu, Yi-Ping; Chen, Lin-Yao

    2013-10-01

    Exposure to stressful life events is associated with the onset of major depression and increases the risk of cardiac morbidity and mortality. While recent evidence has indicated the existence of an interrelationship between local vitamin D (VD) metabolism and many aspects of human physiology including brain and heart function, much is still unknown concerning the biological link between VD signaling and stress-induced depressive behavior and cardiac dysfunction. In the present study, we observed the VD intracrine system in the hippocampus and myocardium of chronic unpredictable mild stress (CUMS) exposed rats. After 4 weeks of CUMS procedure, rats were induced to a depressive-like state and the cytochromes P450 enzymes involved in VD activating and catabolizing (CYP27B1 and CYP24A1 respectively) and VD receptor (VDR) were assessed by real time RT-PCR and western blot in the hippocampus, myocardium and kidney. In the hippocampus of depressed rats, CYP27B1, CYP24A1 and VDR expression were significantly increased and the local status of 1,25-dihydroxyvitamin D (1,25(OH)2D) was higher compared with controls. Furthermore, hippocampal mRNA levels of VD target genes (calbindin-d28k, neurotrophin-3) and RXRα (heterodimeric partner of VDR) were upregulated in response to chronic stress. Similar to the hippocampus, CUMS also induced CYP27B1/CYP24A1/VDR expression in the myocardium. However, renal metabolism of VD and serum1,25(OH)2D status were unchanged. Meanwhile, sertraline treatment could partly normalize the stress-induced alterations of VD metabolism. In conclusion, this study firstly showed a co-elevated expression of CYP27B1/CYP24A1/VDR in both the hippocampus and myocardium of CUMS rats, which suggests VD signaling may be involved in the compensatory mechanism that protect from stress-induced deteriorating effects on the brain and heart.

  5. Chronic ω-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol.

    PubMed

    Ferraz, Anete Curte; Delattre, Ana Marcia; Almendra, Rhiana G; Sonagli, Marina; Borges, Conrado; Araujo, Paula; Andersen, Monica L; Tufik, Sergio; Lima, Marcelo M S

    2011-05-16

    Recent evidence has demonstrated dietary influence on the manifestation of different types of behaviors induced by stressor tasks. The present study examined the impact of ω-3 polyunsaturated fatty acids (PUFAs) supplementation in an early phase of the brain development with the goal of preventing or even attenuating the occurrence of stress-related behaviors such as depressive-like behaviors, anxiety and cognitive dysfunctions in male rats subjected to restraint stress. Our results indicated that the supplementation regimen successfully counteracted the anxiogenic effects of stress as evidenced by the rats' increased exploration time in the aversive arms of the elevated plus maze. The forced swimming test indicated that immobility and swimming were more deeply influenced by PUFAs supplementation, thereby demonstrating an antidepressant effect. Furthermore, cognitive function was shown to be intensely affected by restraint stress, but the effects were surprisingly counteracted by the PUFAs supplementation. Lastly, plasmatic corticosterone levels were demonstrated to be drastically increased by the restraint stress; however, PUFAs supplementation promoted a reduction of this stress-related hormone to levels that were comparable to those observed in the control group. Our results suggested that the mechanisms underlying these effects are possibly associated with the reduction of corticosterone levels promoted by the PUFAs supplementation in the stress-induced animals. Further studies to examine the participation of PUFAs in mediating different behaviors in rats subjected to restraint stress are warranted.

  6. Unpredictable Chronic Mild Stress Paradigm Established Effects of Pro- and Anti-inflammatory Cytokine on Neurodegeneration-Linked Depressive States in Hamsters with Brain Endothelial Damages.

    PubMed

    Avolio, Ennio; Fazzari, Gilda; Mele, Maria; Alò, Raffaella; Zizza, Merylin; Jiao, Wei; Di Vito, Anna; Barni, Tullio; Mandalà, Maurizio; Canonaco, Marcello

    2016-10-11

    The mechanisms by which inflammation affects the different emotional moods are only partially known. Previous works have pointed to stress hormones like glucocorticoids plus the vascular factor endothelin-1 as key factors evoking stressful states especially in relation to endothelial dysfunctions. With this work, it was our intention to establish the role of pro- and anti-inflammatory cytokine expression variations towards depression-like behaviors and consequently the development of neurodegeneration events caused by endothelial damages in the hamster (Mesocricetus auratus). Such a rodent, which is considered a valuable animal model to test depression and anxiety states, exhibited a variety of depression-like behaviors including reduction in sucrose consumption, locomotion, and exploration (p < 0.01) following exposure to unpredictable chronic mild stress. Contextually, a tight correlation between unpredictable chronic mild stress-induced depressive states and expression of the pro-inflammatory cytokines was detected as shown by marked expression levels (p < 0.01) of IL-1β and NF-kB in the hippocampus, amygdala, and prefrontal cortex. Even the anti-inflammatory cytokine IL-10 supplied notably significant (p < 0.001) expression levels in the same areas of resilient hamsters. Application of hemodynamic and endothelial functional studies pointed to altered arterial endothelial activities in depressed with respect to resilient animals. Moreover, evident damaged neuronal fields in the above areas of depressed hamsters allowed us to correlate such a behavioral phenomenon to the upregulation of IL-1β and NF-κB. Overall, the differing roles of pro- and anti-inflammatory cytokines on depressive states, especially in view of brain endothelial damages, may provide novel therapeutic measures against mood disorders linked to neurodegenerative diseases.

  7. Effects of the chronic restraint stress induced depression on reward-related learning in rats.

    PubMed

    Xu, Pan; Wang, Kezhu; Lu, Cong; Dong, Liming; Chen, Yixi; Wang, Qiong; Shi, Zhe; Yang, Yanyan; Chen, Shanguang; Liu, Xinmin

    2017-03-15

    Chronic mild or unpredictability stress produces a persistent depressive-like state. The main symptoms of depression include weight loss, despair, anhedonia, diminished motivation and mild cognition impairment, which could influence the ability of reward-related learning. In the present study, we aimed to evaluate the effects of chronic restraint stress on the performance of reward-related learning of rats. We used the exposure of repeated restraint stress (6h/day, for 28days) to induce depression-like behavior in rats. Then designed tasks including Pavlovian conditioning (magazine head entries), acquisition and maintenance of instrumental conditioning (lever pressing) and goal directed learning (higher fixed ratio schedule of reinforcement) to study the effects of chronic restraint stress. The results indicated that chronic restraint stress influenced rats in those aspects including the acquisition of a Pavlovian stimulus-outcome (S-O) association, the formation and maintenance of action-outcome (A-O) causal relation and the ability of learning in higher fixed ratio schedule. In conclusion, depression could influence the performances in reward-related learning obviously and the series of instrumental learning tasks may have potential as a method to evaluate cognitive changes in depression.

  8. Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior.

    PubMed

    Wu, Ting-Ching; Chen, Han-Ting; Chang, Han-Ying; Yang, Ching-Yao; Hsiao, Mei-Chun; Cheng, Mei-Ling; Chen, Jin-Chung

    2013-06-01

    High level of serum corticosteroid is frequently associated with depression, in which a notable HPA (hypothalamus-pituitary-adrenal) axis hyperactivity is often observed. There are two types of corticosteroid receptors expressed in the hippocampus that provide potent negative feedback regulation on the HPA axis but dysfunction during depression, i.e. the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The balance between hippocampal MR and GR during chronic stress plays an important role in the occurrence of depression. The aim of this study is to explore if chronic corticosterone administration would induce depression-like behavior and affect the expression and function of hippocampal MR and GR, in addition to assess whether manipulation of corticosteroid receptors would modulate depressive behaviors. Hence, mice were treated with corticosterone (40 mg/kg) for 21 days followed by assessment in a battery of depression-like behaviors. The results show that chronic corticosterone-treated animals displayed an increased immobility time in a forced-swimming test, decreased preference to sucrose solution and novel object recognition performance, and enhanced hippocampal serotonin but decreased MR expression in both hippocampus and hypothalamus. On the other hand, co-administration of MR antagonist, spironolactone (25mg/kg, i.p. × 7 days) in corticosteroid-treated animals reduced immobility time in a forced-swimming test and improved performance in a novel object recognition test. In conclusion, we demonstrate that chronic corticosterone treatment triggers several depression-like behaviors, and in parallel, down-regulates MR expression in the hippocampus and hypothalamus. Administration of an MR antagonist confers an anti-depressant effect in chronic corticosterone-treated animals.

  9. 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

  10. Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice.

    PubMed

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

    2015-12-15

    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 is 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. 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. 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. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. 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

  12. Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice.

    PubMed

    Moriguchi, Shigeki; Sakagami, Hiroyuki; Yabuki, Yasushi; Sasaki, Yuzuru; Izumi, Hisanao; Zhang, Chen; Han, Feng; Fukunaga, Kohji

    2015-12-01

    Sigma-1 receptor (Sig-1R) is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to the mitochondria. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice exhibit depressive-like behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Here, we demonstrate that chronic stimulation of Sig-1R by treatment with the agonist SA4503 or the SSRI fluvoxamine for 14 days improves depressive-like behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors. Reduced numbers of BrdU-positive cells and decreased brain-derived neurotrophic factor (BDNF) mRNA expression and protein kinase B (Akt; Ser-473) phosphorylation seen in the DG of CaMKIV null mice were significantly rescued by chronic Sig-1R stimulation. Interestingly, reduced ATP production observed in the DG of CaMKIV null mice was improved by chronic Sig-1R stimulation. Such stimulation also improved hippocampal long-term potentiation (LTP) induction and maintenance, which are impaired in the DG of CaMKIV null mice. LTP rescue was closely associated with both increases in calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and GluA1 (Ser-831) phosphorylation. Taken together, Sig-1R stimulation by SA4503 or fluvoxamine treatment increased hippocampal neurogenesis, which is closely associated with amelioration of depressive-like behaviors in CaMKIV null mice.

  13. Chronic dim light at night provokes reversible depression-like phenotype: possible role for TNF.

    PubMed

    Bedrosian, T A; Weil, Z M; Nelson, R J

    2013-08-01

    The prevalence of major depression has increased in recent decades and women are twice as likely as men to develop the disorder. Recent environmental changes almost certainly have a role in this phenomenon, but a complete set of contributors remains unspecified. Exposure to artificial light at night (LAN) has surged in prevalence during the past 50 years, coinciding with rising rates of depression. Chronic exposure to LAN is linked to increased risk of breast cancer, obesity and mood disorders, although the relationship to mood is not well characterized. In this study, we investigated the effects of chronic exposure to 5 lux LAN on depression-like behaviors in female hamsters. Using this model, we also characterized hippocampal brain-derived neurotrophic factor expression and hippocampal dendritic morphology, and investigated the reversibility of these changes 1, 2 or 4 weeks following elimination of LAN. Furthermore, we explored the mechanism of action, focusing on hippocampal proinflammatory cytokines given their dual role in synaptic plasticity and the pathogenesis of depression. Using reverse transcription-quantitative PCR, we identified a reversible increase in hippocampal tumor necrosis factor (TNF), but not interleukin-1β, mRNA expression in hamsters exposed to LAN. Direct intracerebroventricular infusion of a dominant-negative inhibitor of soluble TNF, XPro1595, prevented the development of depression-like behavior under LAN, but had no effect on dendritic spine density in the hippocampus. These results indicate a partial role for TNF in the reversible depression-like phenotype observed under chronic dim LAN. Recent environmental changes, such as LAN exposure, may warrant more attention as possible contributors to rising rates of mood disorders.

  14. The Effect of Congenital and Postnatal Hypothyroidism on Depression-Like Behaviors in Juvenile Rats

    PubMed Central

    Özgür, Erdoğan; Gürbüz Özgür, Börte; Aksu, Hatice; Cesur, Gökhan

    2016-01-01

    Objective: The aim of this study was to investigate depression-like behaviors of juvenile rats with congenital and postnatal hypothyroidism. Methods: 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. Results: 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. Conclusion: 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. PMID:27611926

  15. Intravenous injection of neural progenitor cells improved depression-like behavior after cerebral ischemia

    PubMed Central

    Moriyama, Y; Takagi, N; Tanonaka, K

    2011-01-01

    Poststroke depression (PSD) occurs in approximately one-third of stroke survivors and is one of the serious sequelae of stroke. The onset of PSD causes delayed functional recovery by rehabilitation and also increases cognitive impairment. However, appropriate strategies for the therapy against ischemia-induced depression-like behaviors still remain to be developed. Such behaviors have been associated with a reduced level of brain-derived neurotrophic factor (BDNF). In addition, accumulating evidence indicates the ability of stem cells to improve cerebral ischemia-induced brain injuries. However, it remains to be clarified as to the effect of neural progenitor cells (NPCs) on PSD and the association between BDNF level and PSD. Using NPCs, we investigated the effect of intravenous injection of NPCs on PSD. We showed that injection of NPCs improved ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test without having any effect on the viable area between vehicle- and NPC-injected ischemic rats. The injection of NPCs prevented the decrease in the level of BDNF in the ipsilateral hemisphere. The levels of phosphorylated CREB, ERK and Akt, which have been implicated in events downstream of BDNF signaling, were also decreased after cerebral ischemia. NPC injection inhibited these decreases in the phosphorylation of CREB and ERK, but not that of Akt. Our findings provide evidence that injection of NPCs may have therapeutic potential for the improvement of depression-like behaviors after cerebral ischemia and that these effects might be associated with restoring BDNF-ERK-CREB signaling. PMID:22832603

  16. Estradiol reduces anxiety- and depression-like behavior of aged female mice.

    PubMed

    Walf, Alicia A; Frye, Cheryl A

    2010-02-09

    Beneficial effects of the ovarian steroid, 17beta-estradiol (E(2)), for affective behavior have been reported in young individuals, but less is known about the effects of E(2) among older individuals, and the capacity of older individuals to respond to E(2) following its decline. In the present study, the effects of acute E(2) administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N=18) that were approximately 24 months old were administered vehicle (sesame oil, n=9) or E(2) (10 microg, n=9) subcutaneously 1h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light-dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light-dark transition task) were determined. Mice administered E(2), compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light-dark transition task, and anti-depressive-like behavior in the forced swim task. E(2) also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E(2) did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E(2) regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice.

  17. Offspring-exposure reduces depressive-like behaviour in the parturient female rat.

    PubMed

    Pawluski, Jodi L; Lieblich, Stephanie E; Galea, Liisa A M

    2009-01-30

    In women, breastfeeding generally results in reductions in anxiety and increased positive mood. However, approximately 10-15% of women experience depressed mood and increased anxiety during the first year postpartum. Recent research has demonstrated that offspring-exposure is important for the reduction in behaviours related to depression and anxiety in the mother. It remains to be determined whether these effects are due to factors related to pregnancy and/or pup-exposure, are associated with the degree of maternal behaviour by the mother towards offspring, or persist after weaning. To address these questions the present study used four groups of female rats; primiparous, nulliparous, primip-no-pups (primiparous females with pups permanently removed), and sensitized females. Depressive- and anxiety-like behaviours were assessed 1 week after weaning/pup-exposure (4 weeks after birth for primip-no-pups animals) using the forced swim test for measures of depressive-like behaviour, and the open field test and elevated plus maze for measure of anxiety-like behaviour. Results demonstrate that primiparous females without pup-exposure have increased depressive-like, but not anxiety-like, behaviour compared to primiparous and sensitized females. In addition, kyphotic nursing by primiparous mothers was negatively related to behavioural measures of depression and anxiety. From this work it is clear that pup-exposure is important for reductions in depressive-like behaviour in parturient females. Further research is needed to determine the extent of these changes and the neural and hormonal correlates of these events.

  18. Estradiol reduces anxiety- and depression-like behavior of aged female mice

    PubMed Central

    Walf, Alicia A.; Frye, Cheryl A.

    2013-01-01

    Beneficial effects of the ovarian steroid, 17β-estradiol (E2), for affective behavior have been reported in young individuals, but less is known about the effects of E2 among older individuals, and the capacity of older individuals to respond to E2 following its decline. In the present study, the effects of acute E2 administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N=18) that were approximately 24 months old were administered vehicle (sesame oil, n=9) or E2 (10 μg, n=9) subcutaneously 1h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light–dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light–dark transition task) were determined. Mice administered E2, compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light–dark transition task, and anti-depressive-like behavior in the forced swim task. E2 also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E2 did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E2 regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice. PMID:19804793

  19. SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens

    PubMed Central

    Kim, Hee-Dae; Hesterman, Jennifer; Call, Tanessa; Magazu, Samantha; Keeley, Elizabeth; Armenta, Kristyna; Kronman, Hope; Neve, Rachael L.; Nestler, Eric J.

    2016-01-01

    Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression- and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive- and anxiety-like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression- and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood-related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders. SIGNIFICANCE STATEMENT In this study, we demonstrate a pivotal role for SIRT1 in anxiety- and depression-like behaviors in the nucleus accumbens (NAc), a key brain reward region. We show that stress stably induces SIRT1 expression in this brain region and that altering

  20. Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats.

    PubMed

    Abildgaard, Anders; Elfving, Betina; Hokland, Marianne; Lund, Sten; Wegener, Gregers

    2017-10-01

    Major depressive disorder (MDD) is highly associated with dysmetabolic conditions, such as obesity and diabetes mellitus type 2, and the gut microbiota may interact with both disease entities. We have previously shown that a high-fat diet (HFD) exacerbated depressive-like behaviour uniquely in Flinders Sensitive Line (FSL) rats that inherently present with an increased level of depressive-like behaviour compared with Flinders Resistant Line (FRL) rats. We therefore investigated whether multispecies probiotics possessed anti-depressant-like effect in FSL rats or protected against the pro-depressant-like effect of HFD. We also examined blood and cerebral T cell subsets as well as plasma cytokines. Lastly, we investigated the effect of HFD in outbred Sprague-Dawley (SD) rats to substantiate the association between depressive-like behaviour and any immunological measures affected by HFD. HFD exacerbated the depressive-like behaviour in FSL rats in the forced swim test, whereas SD rats remained unaffected. Probiotic treatment completely precluded the pro-depressant-like effect of HFD, but it did not affect FSL rats on control diet. Cerebral T lymphocyte CD4/8 ratios closely mirrored the behavioural changes, whereas the proportions of Treg and Th17 subsets were unaltered. No association between blood and brain CD4/8 ratios were evident; nor did plasma cytokine levels change as a consequence of HFD of probiotic treatment. Our findings suggest that MDD may hold a dysmetabolic component that responds to probiotic treatment. This finding has wide implications owing to the high metabolic comorbidity in MDD. Furthermore, the close association between depressive-like behaviour and cerebral T cell populations demonstrate lymphocyte-brain interactions as a promising future research area in the field of psychoneuroimmunology. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Venlafaxine ameliorates the depression-like behaviors and hippocampal S100B expression in a rat depression model.

    PubMed

    Wang, Chang-Hong; Gu, Jing-Yang; Zhang, Xiao-Li; Dong, Jiao; Yang, Jun; Zhang, Ying-Li; Ning, Qiu-Fen; Shan, Xiao-Wen; Li, Yan

    2016-12-08

    Accumulating evidence has indicated that S100B may be involved in the pathophysiology of depression. No published study has examined the effect of the antidepressant drug venlafaxine on S100B in animal models of depression. This study investigated S100B expression in the hippocampus and assessed the effect of venlafaxine on S100B mRNA level and protein expression in rats exposed to chronic unpredictable mild stress (CUMS). Forty Sprague-Dawley rats were randomly divided into four groups as control, 0, 5 and 10 mg venlafaxine groups. The venlafaxine groups were exposed to CUMS from day 2 to day 43. Venlafaxine 0, 5 and 10 mg/kg were then administered from day 23 to day 43. We performed behavioral assessments with weight change, open-field and sucrose preference, and analyzed S100B protein expression and mRNA level in the hippocampus. The CUMS led to a decrease in body weight, locomotor activity and sucrose consumption, but venlafaxine treatment (10 mg) reversed these CUMS-induced decreases Also, CUMS increased S100B protein expression and mRNA level in the hippocampus, but venlafaxine treatment (10 mg) significantly decreased S100B protein expression and mRNA level, which were significantly lower than the other treatment groups, without significant difference between the 10 mg venlafaxine and the control groups. Our findings showed that venlafaxine treatment (10 mg) may improve the depression-like behaviors and decrease over-expression of S100B protein and mRNA in the hippocampus in a rat model of depression.

  2. GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

    PubMed Central

    Ramirez, Karol; Niraula, Anzela; Sheridan, John F.

    2015-01-01

    Objective Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+ /Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9%NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and

  3. GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations.

    PubMed

    Ramirez, Karol; Niraula, Anzela; Sheridan, John F

    2016-01-01

    Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b(+)/Ly6C(hi)) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD. C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b(+)/CD45(high)) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior

  4. Effects of depressive-like behavior of rats on brain glutamate uptake.

    PubMed

    Almeida, Roberto Farina; Thomazi, Ana Paula; Godinho, Graça Fabiana; Saute, Jonas Alex Morales; Wofchuk, Susana Tchernin; Souza, Diogo Onofre; Ganzella, Marcelo

    2010-08-01

    Learned helplessness paradigm is a widely accepted animal model of depressive-like behavior based on stress. Glutamatergic system is closely involved with the stress-neurotoxicity in the brain and recently it is pointed to have a relevant role in the pathophysiology of depression disorder. Glutamate uptake is the main mechanism to terminate the glutamatergic physiological activity and to neuroprotection against excitotoxicity. We investigated the profile of glutamate uptake in female rats submitted to the learned helplessness paradigm and to different classes of stress related to the paradigm, in slices of brain cortex, striatum and hippocampus. Glutamate uptake in slices of hippocampus differ between learned helplessness (LH) and non-learned helplessness (NLH) animals immediately persisting up to 21 days after the paradigm. In addition, there were a decrease of glutamate uptake in the three brain structures analyzed at 21 days after the paradigm for LH animals. These results may contribute to better understand the role of the glutamatergic system on the depressive-like behavior.

  5. Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles

    PubMed Central

    Zhang, Xin; Xu, Yan; Zhou, Lian; Zhang, Chengcheng; Meng, Qingtao; Wu, Shenshen; Wang, Shizhi; Ding, Zhen; Chen, Xiaodong; Li, Xiaobo; Chen, Rui

    2015-01-01

    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. PMID:26690197

  6. Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice.

    PubMed

    Onishchenko, Natalia; Tamm, Christoffer; Vahter, Marie; Hökfelt, Tomas; Johnson, Jeffrey A; Johnson, Delinda A; Ceccatelli, Sandra

    2007-06-01

    To investigate the long-term effects of developmental exposure to methylmercury (MeHg), pregnant mice were exposed to at 0.5 mg MeHg/kg/day via drinking water from gestational day 7 until day 7 after delivery. The behavior of offspring was monitored at 5-15 and 26-36 weeks of age using an automated system (IntelliCage) designed for continuous long-term recording of the home cage behavior in social groups and complex analysis of basic activities and learning. In addition, spontaneous locomotion, motor coordination on the accelerating rotarod, spatial learning in Morris water maze, and depression-like behavior in forced swimming test were also studied. The analysis of behavior performed in the IntelliCage without social deprivation occurred to be more sensitive in detecting alterations in activity and learning paradigms. We found normal motor function but decreased exploratory activity in MeHg-exposed male mice, especially at young age. Learning disturbances observed in MeHg-exposed male animals suggest reference memory impairment. Interestingly, the forced swimming test revealed a predisposition to depressive-like behavior in the MeHg-exposed male offspring. This study provides novel evidence that the developmental exposure to MeHg can affect not only cognitive functions but also motivation-driven behaviors.

  7. 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.

  8. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors.

    PubMed

    Scott, Michael M; Marcus, Jacob N; Pettersen, Ami; Birnbaum, Shari G; Mochizuki, Takatoshi; Scammell, Thomas E; Nestler, Eric J; Elmquist, Joel K; Lutter, Michael

    2011-09-23

    The orexin/hypocretin system has the potential to significantly modulate affect, based on both the neuroanatomical projection patterns of these neurons and on the sites of orexin receptor expression. However, there is little data supporting the role of specific orexin receptors in the modulation of depression-like behavior. Here we report behavioral profiling of mice after genetic or pharmacologic inhibition of hcrtr1 and 2 receptor signaling. Hcrtr1 null mice displayed a significant reduction in behavioral despair in the forced swim test and tail suspension test. Wild-type mice treated with the hcrtr1 antagonist SB-334867 also displayed a similar reduction in behavioral despair. No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety. These studies suggest that the balance of orexin action at either the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated.

  9. Xiaochaihutang prevents depressive-like behaviour in rodents by enhancing the serotonergic system.

    PubMed

    Su, Guang Yue; Yang, Jing Yu; Wang, Fang; Xiong, Zhi Li; Hou, Yue; Zhang, Kuo; Song, Cui; Ma, Jie; Song, Shao Jiang; Teng, Huai Feng; Wu, Chun Fu

    2014-06-01

    Xiaochaihutang (XCHT) has been used in China for thousands of years to treat 'Shaoyang syndrome', which involves depressive-like symptoms. However, no studies were conducted to demonstrate its antidepressant effect and mechanism. This study was designed to confirm the antidepressant effect of XCHT and explore its mechanism using the pharmacological methods. Ultra-HPLC and mass spectrometry was used to identify the chemical constituents of XCHT. Forced swimming test (FST) and tail suspension test (TST) were used to determine the antidepressant-like activity of XCHT in mice and rats. The possible mechanism of XCHT was elucidated by the reserpine-induced hypothermia and 5-hydroxytryptophan (5-HTP)-induced head-twitch in mice. The levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in prefrontal cortex and hippocampus tissue of both mice and rats. Moreover, the extracellular 5-HT in rat hippocampus was assessed by using microdialysis coupled to HPLC with electrochemical detection. Forty-four components were detected in XCHT. XCHT significantly reduced immobility time in the TST and the FST, antagonized reserpine-induced depressive-like behaviours, increased 5-HTP-induced head-twitches, elevated 5-HT and 5-HIAA levels, and increased 5-HT turnover at doses that did not affect general activity. These data demonstrate that XCHT has therapeutic effects in animal models of depression by enhancing the serotoninergic system in the prefrontal cortex and hippocampus. © 2013 Royal Pharmaceutical Society.

  10. [Neurochemical mechanisms of depression-like behavior in WAG/Rij rats].

    PubMed

    Sarkisova, K Iu; Kulikov, M A; Kudrin, V S; Narkevich, V B; Midzianovskaia, I S; Biriukova, L M; Folomkina, A A; Basian, A S

    2013-01-01

    Behavior in the light-dark choice, open-field, sucrose consumption/preference and forced swimming tests, monoamines and their metabolites level in 6 brain structures (prefrontal cortex, nucleus accumbens, striatum, hypothalamus, hippocampus, amygdala), and density of D2-like dopamine receptors in 21 brain regions were studied in WAG/Rij and Wistar rats. WAG/Rij rats exhibited symptoms of depression-like behavior such as increased immobility in the forced swim test and decreased sucrose consumption/preference (anhedonia). Substantial changes in behavior indicating increased anxiety in WAG/Rij rats were not revealed. Neurochemical abnormalities suggesting hypofunction of the mesolimbic dopaminergic brain system were found in "depressive" WAG/Rij rats compared with "normal" Wistar rats: decreased levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine in the nucleus accumbens, and increased density of D2-like dopamine receptors in the nucleus accumbens and ventral tegmental area. Reduced levels of dopamine were also observed in the prefrontal cortex and striatum. No substantial changes in the content of monoamines and their metabolites have been revealed in the hypothalamus, hippocampus and amygdala as well as in the content ofserotonin and its metabolite 5-hydroxyindolacetic acid in all studied brain structures with the exception of increased level ofserotonin in the amygdala. Results suggest that hypofunction of the mesolimbic dopaminergic brain system (nucleus accumbens) is a neurochemical mechanism of depression-like behavior in WAG/Rij rats.

  11. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors

    PubMed Central

    Scott, Michael M.; Marcus, Jacob N.; Pettersen, Ami; Birnbaum, Shari G.; Mochizuki, Takatoshi; Scammell, Thomas E.; Nestler, Eric J.; Elmquist, Joel K.; Lutter, Michael

    2012-01-01

    The orexin/hypocretin system has the potential to significantly modulate affect, based on both the neuroanatomical projection patterns of these neurons and on the sites of orexin receptor expression. However, there is little data supporting the role of specific orexin receptors in the modulation of depression-like behavior. Here we report behavioral profiling of mice after genetic or pharmacologic inhibition of hcrtr1 and 2 receptor signaling. Hcrtr1 null mice displayed a significant reduction in behavioral despair in the forced swim test and tail suspension test. Wild-type mice treated with the hcrtr1 antagonist SB-334867 also displayed a similar reduction in behavioral despair. No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety. These studies suggest that the balance of orexin action at either the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated. PMID:21377495

  12. MAPK Signaling Determines Anxiety in the Juvenile Mouse Brain but Depression-Like Behavior in Adults

    PubMed Central

    Wefers, Benedikt; Hitz, Christiane; Hölter, Sabine M.; Trümbach, Dietrich; Hansen, Jens; Weber, Peter; Pütz, Benno; Deussing, Jan M.; de Angelis, Martin Hrabé; Roenneberg, Till; Zheng, Fang; Alzheimer, Christian; Silva, Alcino; Wurst, Wolfgang; Kühn, Ralf

    2012-01-01

    MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice, which exhibit protein depletion in principle forebrain neurons, enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inducible or constitutive inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In juvenile, constitutive mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype. Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as a new valuable approach, allowing it to discriminate between gene function in the adult and the developing postnatal brain. PMID:22529971

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

    PubMed Central

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

    2010-01-01

    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 GABAA 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. PMID:21163582

  14. 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.

  15. The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-like Behavior.

    PubMed

    Commons, Kathryn G; Cholanians, Aram B; Babb, Jessica A; Ehlinger, Daniel G

    2017-03-22

    The forced swim test (FST) measures coping strategy to an acute inescapable stress and thus provides unique insight into the neural limb of the stress response. Stress, particularly chronic stress, is a contributing factor to depression in humans and depression is associated with altered response to stress. In addition, drugs that are effective antidepressants in humans typically promote active coping strategy in the FST. As a consequence, passive coping in the FST has become loosely equated with depression and is often referred to as "depression-like" behavior. This terminology oversimplifies complex biology and misrepresents both the utility and limitations of the FST. The FST provides little construct- or face-validity to support an interpretation as "depression-like" behavior. While stress coping and the FST are arguably relevant to depression, there are likely many factors that can influence stress coping strategy. Importantly, there are other neuropsychiatric disorders characterized by altered responses to stress and difficulty in adapting to change. One of these is autism spectrum disorder (ASD), and several mouse genetic models of ASD exhibit altered stress-coping strategies in the FST. Here we review evidence that argues a more thoughtful consideration of the FST, and more precise terminology, would benefit the study of stress and disorders characterized by altered response to stress, which include but are not limited to depression.

  16. ER stress-induced cell death mechanisms

    PubMed Central

    Sano, Renata; Reed, John C.

    2013-01-01

    The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. PMID:23850759

  17. Cold stress induces lower urinary tract symptoms.

    PubMed

    Imamura, Tetsuya; Ishizuka, Osamu; Nishizawa, Osamu

    2013-07-01

    Cold stress as a result of whole-body cooling at low environmental temperatures exacerbates lower urinary tract symptoms, such as urinary urgency, nocturia and residual urine. We established a model system using healthy conscious rats to explore the mechanisms of cold stress-induced detrusor overactivity. In this review, we summarize the basic findings shown by this model. Rats that were quickly transferred from room temperature (27 ± 2°C) to low temperature (4 ± 2°C) showed detrusor overactivity including increased basal pressure and decreased voiding interval, micturition volume, and bladder capacity. The cold stress-induced detrusor overactivity is mediated through a resiniferatoxin-sensitve C-fiber sensory nerve pathway involving α1-adrenergic receptors. Transient receptor potential melastatin 8 channels, which are sensitive to thermal changes below 25-28°C, also play an important role in mediating the cold stress responses. Additionally, the sympathetic nervous system is associated with transient hypertension and decreases of skin surface temperature that are closely correlated with the detrusor overactivity. With this cold stress model, we showed that α1-adrenergic receptor antagonists have the potential to treat cold stress-exacerbated lower urinary tract symptoms. In addition, we showed that traditional Japanese herbal mixtures composed of Hachimijiogan act, in part, by increasing skin temperature and reducing the number of cold sensitive transient receptor potential melastatin channels in the skin. The effects of herbal mixtures have the potential to treat and/or prevent the exacerbation of lower urinary tract symptoms by providing resistance to the cold stress responses. Our model provides new opportunities for utilizing animal disease models with altered lower urinary tract functions to explore the effects of novel therapeutic drugs.

  18. Fish Oil Prevents Lipopolysaccharide-Induced Depressive-Like Behavior by Inhibiting Neuroinflammation.

    PubMed

    Shi, Zhe; Ren, Huixia; Huang, Zhijian; Peng, Yu; He, Baixuan; Yao, Xiaoli; Yuan, Ti-Fei; Su, Huanxing

    2016-11-04

    Depression is associated with somatic immune changes, and neuroinflammation is now recognized as hallmark for depressive disorders. N-3 (or omega-3) polyunsaturated fatty acids (PUFAs) are well known to suppress neuroinflammation, reduce oxidative stress, and protect neuron from injury. We pretreated animals with fish oil and induced acute depression-like behaviors with systemic lipopolysaccharide (LPS) injection. The levels of cytokines and stress hormones were determined from plasma and different brain areas. The results showed that fish oil treatment prevent LPS-induce depressive behavior by suppression of neuroinflammation. LPS induced acute neuroinflammation in different brain regions, which were prevented in fish oil fed mice. However, neither LPS administration nor fish oil treatment has strong effect on stress hormone secretion in the hypothalamus and adrenal. Fish oil might provide a useful therapy against inflammation-associated depression.

  19. Anxiety- and depressive-like behaviors in olfactory deficient Cnga2 knockout mice.

    PubMed

    Chen, Yanmei; Liu, Xiaofen; Jia, Xianglei; Zong, Wei; Ma, Yuanye; Xu, Fuqiang; Wang, Jianhong

    2014-12-15

    There is a close neuroanatomical connection between odor and emotional processing. Olfactory dysfunction is found in various neurodegenerative and neuropsychiatric disorders. Here, mice take the cyclic nucleotide gated channel 2 mutant gene (Cnga2), which is critical for olfactory sensory neurons to generate odor induced action potentials were used. The Cnga2 mice were congenitally anosmic. Adult mice were tested in a series behavioral paradigm such as open field, light/dark box, forced swim test and Y-maze. Our study found that Cnga2 mice showed increased anxiety- and depressive-like behaviors than their wide type siblings. However, Cnga2 mice showed no difference from the wide types when tested in the two-trial recognition Y-maze. The results indicate that innate olfactory deficiency might modulate emotional behaviors in mice.

  20. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice.

    PubMed

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-08-04

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell-cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.

  1. Attenuated orexinergic signaling underlies depression-like responses induced by daytime light deficiency.

    PubMed

    Deats, S P; Adidharma, W; Lonstein, J S; Yan, L

    2014-07-11

    Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a,b). By utilizing a 12:12-h dim light:dark (DLD) paradigm that simulates the lower light intensity of winter, we showed that the animals housed in DLD exhibited increased depression-like behaviors in the forced swim test (FST) and sweet solution preference (SSP) compared to animals housed in bright light during the day (BLD). The objective of the present study was to test the hypothesis that light affects mood by acting on the brain orexinergic system in the diurnal grass rat model of SAD. First, orexin A immunoreactivity (OXA-ir) was examined in DLD and BLD grass rats. Results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. Results suggest that attenuated orexinergic signaling is associated with increased depression-like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood.

  2. IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations.

    PubMed

    Park, Hyun-Jung; Shim, Hyun-Soo; An, Kyungeh; Starkweather, Angela; Kim, Kyung Soo; Shim, Insop

    2015-01-01

    It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study.

  3. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms.

    PubMed

    Lim, L W; Prickaerts, J; Huguet, G; Kadar, E; Hartung, H; Sharp, T; Temel, Y

    2015-03-31

    Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.

  4. IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations

    PubMed Central

    Park, Hyun-Jung; Shim, Hyun-Soo; An, Kyungeh; Starkweather, Angela; Kim, Kyung Soo; Shim, Insop

    2015-01-01

    It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study. PMID:26417153

  5. Optogenetics to study the circuits of fear- and depression-like behaviors: a critical analysis.

    PubMed

    Belzung, Catherine; Turiault, Marc; Griebel, Guy

    2014-07-01

    In recent years, the development and extensive use of optogenetics resulted in impressive findings on the neurobiology of anxiety and depression in animals. Indeed, it permitted to depict precisely the role of specific cell populations in various brain areas, including the amygdala nuclei, the auditory cortex, the anterior cingulate, the hypothalamus, the hippocampus and the bed nucleus of stria terminalis in specific aspects of fear and anxiety behaviors. Moreover, these findings emphasized the involvement of projections from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex in eliciting depressive-like behaviors in stress-resilient mice or in inhibiting the expression of such behaviors in stress-vulnerable mice. Here we describe the optogenetic toolbox, including recent developments, and then review how the use of this technique contributed to dissect further the circuit underlying anxiety- and depression-like behaviors. We then point to some drawbacks of the current studies, particularly a) the sharp contrast between the sophistication of the optogenetic tools and the rudimentary aspect of the behavioral assays used, b) the fact that the studies were generally undertaken using normal rodents, that is animals that have not been subjected to experimental manipulations shifting them to a state relevant for pathologies and c) that the opportunity to explore the potential of these techniques to develop innovative therapeutics has been fully ignored yet. Finally, we discuss the point that these findings frequently ignore the complexity of the circuitry, as they focus only on a particular subpart of it. We conclude that users of this cutting edge technology could benefit from dialog between behavioral neuroscientists, psychiatrists and pharmacologists to further improve the impact of the findings. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. 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).

  7. Treating Depression and Depression-Like Behavior with Physical Activity: An Immune Perspective

    PubMed Central

    Eyre, Harris A.; Papps, Evan; Baune, Bernhard T.

    2012-01-01

    The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field. PMID:23382717

  8. Attenuated orexinergic signaling underlies depression-like responses induced by daytime light deficiency

    PubMed Central

    Deats, Sean P.; Adidharma, Widya; Lonstein, Joseph S.; Yan, Lily

    2014-01-01

    Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a, Leach et al., 2013b). By utilizing a 12:12hr Dim Light:Dark (DLD) paradigm that simulates the lower light intensity of winter, we showed that the animals housed in DLD exhibited increased depression-like behaviors in the forced swim test (FST) and sweet solution preference (SSP) compared to animals housed in bright light during the day (BLD). The objective of the present study was to test the hypothesis that light affects mood by acting on the brain orexinergic system in the diurnal grass rat model of SAD. First, orexinA immunoreactivity (OXA-ir) was examined in DLD and BLD grass rats. The results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. The results suggest that attenuated orexinergic signaling is associated with increased depression-like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood. PMID:24813431

  9. Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice.

    PubMed

    Desai, S J; Borkar, C D; Nakhate, K T; Subhedar, N K; Kokare, D M

    2014-09-26

    We investigated the involvement of neuropeptide Y (NPY) in the modulation of cholecystokinin-4 (CCK-4)-evoked anxiety and depression. Adult male mice were injected with vehicle, CCK-4, NPY, NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY or antagonist BIBP3226, via intracerebroventricular route, and subjected to social interaction or forced swim test (FST) for the evaluation of anxiety- and depression-like phenotypes, respectively. To assess the interactions between the two systems, if any, NPYergic agents were administered prior to CCK-4 and the animals were subjected to these behavioral tests. Treatment with CCK-4 or BIBP3226 dose-dependently reduced social interaction time, while NPY or [Leu(31), Pro(34)]-NPY produced opposite effect. CCK-4 treatment increased immobility time in FST. This effect was reversed by NPY and [Leu(31), Pro(34)]-NPY, although BIBP3226 per se did not alter the immobility time. In a combination study, the anxiogenic or depressive effects of CCK-4 were attenuated by NPY or [Leu(31), Pro(34)]-NPY and potentiated by BIBP3226. The brains of CCK-4 treated rats were processed for NPY immunohistochemistry. Following CCK-4 treatment, the nucleus accumbens shell (AcbSh), ventral part of lateral division of the bed nucleus of stria terminalis (BSTLV), hypothalamic paraventricular nucleus and locus coeruleus showed a reduction in NPY-immunoreactive fibers. Population of NPY-immunopositive cells was also decreased in the AcbSh, BSTLV, prefrontal cortex and hypothalamic arcuate nucleus (ARC). However, NPY-immunoreaction in the fibers of the ARC and cells of the central nucleus of amygdala was unchanged. We conclude that, inhibition of NPY signaling in the brain by CCK-4 might be causal to anxiety- and depression-like behaviors. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice

    PubMed Central

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-01-01

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell–cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors. PMID:26195764

  11. Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism.

    PubMed

    Wang, Sisi; Pan, Jiyang

    2016-05-20

    Depression is a common psychiatric disorder that affects millions of people around the world, however, little is known about the pathophysiology of depression and the therapeutic strategy for anti-depression. In this study, we investigated the role of irisin, a regulator of energy metabolism, in the modulation of depressive-like behaviors in chronic unpredictable stress (CUS) exposed rats. ELISA showed that irisin was aberrantly regulated by CUS in the prefrontal cortex tissues and cerebrospinal fluid (CSF) of rats. CUS-induced behavioral deficits in rats were reversed by injection treatment with recombinant irisin in a dose dependent manner. Treatment with irisin at concentrations of 100 ng/ml or higher significantly increased the sucrose preference and reduced the immobility time in CUS rats. Additionally, irisin treatment also increased the activities of mitochondrial complexes I, II and IV as well as creatine kinase, which were inhibited by CUS in the prefrontal cortex of rats. We then confirmed that irisin significantly increased the levels of glucose transport and phosphorylation, as reflected by the increased type I and type II hexokinase (Hx-1 and Hx-2) and GLUT-4 as well as the ATP level in vivo and vitro. Further studies indicated that AMPK pathway was involved in the regulation of irisin on depressive-like behaviors in CUS rats. In conclusion, we demonstrated that irisin has a crucial role in inducing antidepressant-like effects in CUS rats by regulating energy metabolism in the prefrontal cortex of brain, which may provide a new insight into the biological mechanism of depression. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

    PubMed Central

    Sun, Jian-Dong; Liu, Yan; Yuan, Yu-He; Li, Jing; Chen, Nai-Hong

    2012-01-01

    Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression. PMID:22189291

  13. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms

    PubMed Central

    Lim, L W; Prickaerts, J; Huguet, G; Kadar, E; Hartung, H; Sharp, T; Temel, Y

    2015-01-01

    Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN. PMID:25826110

  14. Stress and IL-1β contribute to the development of depressive-like behavior following peripheral nerve injury

    PubMed Central

    Norman, GJ; Karelina, K; Zhang, N; Walton, JC; Morris, JS; DeVries, AC

    2016-01-01

    The physiological link between neuropathic pain and depression remains unknown despite a high comorbidity between these two disorders. A mouse model of spared nerve injury (SNI) was used to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that prior exposure to stress exacerbates the behavioral and neuroinflammatory consequences of nerve injury. As compared with sham surgery, SNI induced mechanical allodynia, and significantly increased depressive-like behavior. Moreover, SNI animals displayed increased interleukin-1β (IL-1β) gene expression within the frontal cortex and concurrent increases in the expression of glial fibrillary acidic protein (GFAP) within the periaqueductal grey (PAG). Additionally, exposure to chronic restraint stress for 2 weeks before SNI exacerbated mechanical allodynia and depressive-like behavior, and resulted in an increase in IL-1β gene expression in the frontal cortex and brain-derived neurotrophic factor (BDNF) gene expression in PAG. Treatment with metyrapone (MET), a corticosteroid synthesis inhibitor, before stress eliminated deleterious effects of chronic stress on SNI. Finally, this study showed that interference with IL-1β signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that peripheral nerve injury leads to increased cytokine expression in the brain, which in turn, contributes to the development of depressive-like behavior. Furthermore, stress can facilitate the development of depressive-like behavior after nerve injury by promoting IL-1β expression. PMID:19773812

  15. 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.

  16. Blockade of nociceptin/orphanin FQ receptor signaling reverses LPS-induced depressive-like behavior in mice.

    PubMed

    Medeiros, Iris U; Ruzza, Chiara; Asth, Laila; Guerrini, Remo; Romão, Pedro R T; Gavioli, Elaine C; Calo, Girolamo

    2015-10-01

    Nociceptin/orphanin FQ is the natural ligand of a Gi-protein coupled receptor named NOP. This peptidergic system is involved in the regulation of mood states and inflammatory responses. The present study aimed to investigate the consequences of blocking NOP signaling in lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors in mice. LPS 0.8mg/kg, ip, significantly induced sickness signs such as weight loss, decrease of water and food intake and depressive-like behavior in the tail suspension test. Nortriptyline (ip, 60min prior the test) reversed the LPS-induced depressive states. The NOP receptor antagonist SB-612111, 30min prior LPS, did not modify LPS-induced sickness signs and depressive-like behavior. However, when injected 24h after LPS, NOP antagonists (UFP-101, icv, and SB-612111, ip) significantly reversed the mood effects of LPS. LPS evoked similar sickness signs and significantly increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) plasma levels 6h post-injection in wild-type ((NOP(+/+)) and NOP knockout ((NOP(-/-)) mice. However, LPS treatment elicited depressive-like effects in NOP(+/+) but not in NOP(-/-) mice. In conclusion, the pharmacological and genetic blockade of NOP signaling does not affect LPS evoked sickness signs while reversing depressive-like behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Stress induces transient auditory hypersensitivity in rats.

    PubMed

    Mazurek, Birgit; Haupt, Heidemarie; Joachim, Ricarda; Klapp, Burghard F; Stöver, Timo; Szczepek, Agnieszka J

    2010-01-01

    Exposure to harsh environment induces stress reactions that increase probability of survival. Stress influences the endocrine, nervous and immune systems and affects the functioning of a variety of organs. Numerous researchers demonstrated that a 24-h exposure to an acoustic rodent repellent provokes stress reaction in exposed animals. In addition to the activated hypothalamic-pituitary-adrenal (HPA) axis, exposed animals had pathological reactions in the reproductive organs, bronchia and skin. Here, we examined the effect of above stress model on the auditory system of Wistar rats. We found that 24-h stress decreases the thresholds and increases the amplitudes of auditory brainstem responses and distortion product otoacoustic emissions. Resultant auditory hypersensitivity was transient and most pronounced between 3 and 6h post-stress, returning to control levels one week later. The concentration of corticosterone and tumor necrosis factor alpha was systemically elevated in stressed animals between 3 and 6h post-stress, confirming the activation of the HPA axis. In addition, expression of the HPA-axis-associated genes: glucocorticoid receptor (GR) and hypoxia-inducible factor 1 alpha (Hif1a) was modulated in the auditory tissues. In detail, in the inferior colliculus, we found an up-regulation of GR mRNA 3h post-stress and continuous up-regulation of Hif1a up to 24h post-stress. In the spiral ganglion, we found no differences in gene expression between stressed and control animals. In the organ of Corti, expression of GR mRNA remained stable, whereas that of Hif1a was significantly down-regulated one week after stress. In addition, the expression of an outer hair cell marker prestin was significantly up-regulated 6h post-stress. We conclude that 24-h stress induces transient hypersensitivity of the auditory system and modulates gene expression in a tissue-specific manner. Stress-induced auditory hypersensitivity could have evolutionary consequence by giving animals

  18. Effects of acute treadmill running at different intensities on activities of serotonin and corticotropin-releasing factor neurons, and anxiety- and depressive-like behaviors in rats.

    PubMed

    Otsuka, Tomomi; Nishii, Ayu; Amemiya, Seiichiro; Kubota, Natsuko; Nishijima, Takeshi; Kita, Ichiro

    2016-02-01

    Accumulating evidence suggests that physical exercise can reduce and prevent the incidence of stress-related psychiatric disorders, including depression and anxiety. Activation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is implicated in antidepressant/anxiolytic properties. In addition, the incidence and symptoms of these disorders may involve dysregulation of the hypothalamic-pituitary-adrenal axis that is initiated by corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN). Thus, it is possible that physical exercise produces its antidepressant/anxiolytic effects by affecting these neuronal activities. However, the effects of acute physical exercise at different intensities on these neuronal activation and behavioral changes are still unclear. Here, we examined the activities of 5-HT neurons in the DRN and CRF neurons in the PVN during 30 min of treadmill running at different speeds (high speed, 25 m/min; low speed, 15m/min; control, only sitting on the treadmill) in male Wistar rats, using c-Fos/5-HT or CRF immunohistochemistry. We also performed the elevated plus maze test and the forced swim test to assess anxiety- and depressive-like behaviors, respectively. Acute treadmill running at low speed, but not high speed, significantly increased c-Fos expression in 5-HT neurons in the DRN compared to the control, whereas high-speed running significantly enhanced c-Fos expression in CRF neurons in the PVN compared with the control and low-speed running. Furthermore, low-speed running resulted in decreased anxiety- and depressive-like behaviors compared with high-speed running. These results suggest that acute physical exercise with mild and low stress can efficiently induce optimal neuronal activation that is involved in the antidepressant/anxiolytic effects.

  19. Stress induced changes in testis function.

    PubMed

    López-Calderón, A; Ariznavarreta, C; González-Quijano, M I; Tresguerres, J A; Calderón, M D

    1991-01-01

    The mechanism through which chronic stress inhibits the hypothalamic-pituitary-testicular axis has been investigated. Chronic restraint stress decreases testosterone secretion, an effect that is associated with a decrease in plasma gonadotropin levels. In chronically stressed rats there was a decrease in hypothalamic luteinizing hormone-releasing hormone (LHRH) content and the response on plasma gonadotropins to LHRH administration was enhanced. Thus the inhibitory effect of chronic stress on plasma LH and FSH levels seems not to be due to a reduction in pituitary responsiveness to LHRH, but rather to a modification in LHRH secretion. It has been suggested that beta-endorphin might interfere with hypothalamic LHRH secretion during stress. Chronic immobilization did not modify hypothalamic beta-endorphin, while an increase in pituitary beta-endorphin secretion was observed. Since we cannot exclude that changes in beta-endorphin secreted by the pituitary or other opioids may play some role in the stress-induced decrease in LHRH secretion, the effect of naltrexone administration on plasma gonadotropin was studied in chronically stressed rats. Naltrexone treatment did not modify the decrease in plasma concentrations of LH or FSH. These findings suggest that the inhibitory effect of restraint on the testicular axis is exerted at hypothalamic level by some mechanism other than opioids.

  20. Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior.

    PubMed

    Chen, Wen-Jin; Du, Jian-Kui; Hu, Xing; Yu, Qing; Li, Dong-Xia; Wang, Chang-Nan; Zhu, Xiao-Yan; Liu, Yu-Jian

    2017-09-27

    Growing evidence suggests that inflammatory processes may be involved in depressive disorders. Inflammation is known to induce mitochondrial dysfunction in the nervous system. However, whether mitochondrial dysfunction is involved in the occurrence of inflammation-induced depressive-like behavior remains to be investigated. The present study aims to firstly, clarify whether mitochondrial dysfunction contributes to lipopolysaccharide (LPS)-induced depression-like behavior in mice and secondly, determine whether the anti-oxidant resveratrol alleviates inflammation-induced depressive-like behavior through the prevention of mitochondrial dysfunction in the hippocampus. We found that the administration of LPS led to mitochondrial oxidative stress and dysfunction as evidenced by increased mitochondrial superoxide production and decreased mitochondrial membrane potential and ATP production in the hippocampus. These effects were attenuated by intracerebroventricular (ICV) Injection of the mitochondria-targeted antioxidant Mito-TEMPO. LPS-treated mice displayed depressive-like behaviors as evidenced by reduced sucrose preference, increased immobility time and decreased struggling time in the forced swimming test. Both Mito-TEMPO and resveratrol could significantly improve the LPS-induced depressive-like behaviors. In contrast, ICV Injection of rotenone, the mitochondrial respiratory chain inhibitor, induced mitochondrial oxidative stress and dysfunction in the hippocampus, and resulted in depressive-like behaviors. Moreover, resveratrol alleviated the LPS-induced apoptosis of hippocampal cells. The antidepressant action of resveratrol was accomplished through the interruption of mitochondrial oxidative stress and the prevention of cell apoptosis in the hippocampus. These findings support the potential for resveratrol as a possible pharmacological agent for depression treatment in the future. Copyright © 2017. Published by Elsevier Inc.

  1. 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

  2. Blockade of glucocorticoid receptors with ORG 34116 does not normalize stress-induced symptoms in male tree shrews.

    PubMed

    Van Kampen, Marja; De Kloet, E Ronald; Flügge, Gabriele; Fuchs, Eberhard

    2002-12-20

    Glucocorticoid receptors play an important role in the regulation of the activity of the hypothalamo-pituitary-adrenal axis, and are thought to be involved in the pathophysiology of depressive disorders. The present study investigated the effect of the specific glucocorticoid receptor antagonist ORG 34116 (a substituted 11,21 bisarylsteroid compound) in the tree shrew (Tupaia belangeri) chronic psychosocial stress model, an established animal model for depressive disorders. Animals were stressed for 10 days before treatment with ORG 34116 started (25 mg/kg p.o. for 28 days). Stress induced a decrease in body weight, which just failed significance, whereas ORG 34116 did not affect body weight in stress and control animals. ORG 34116 enhanced the stress-induced increase in the concentration of urinary-free cortisol, although no differences between the different experimental groups existed during the last week of treatment. In stressed animals, ORG 34116 did not affect marking behavior, but decreased locomotor activity. Post mortem analysis of 5-HT(1A) receptors revealed a decreased affinity of 3[H]-8-OH-DPAT (3[H]-8-hydroxy-2-[di-n-propylamino]tetralin) binding sites in the hippocampus of animals treated with the glucocorticoid receptor antagonist. In conclusion, under our experimental conditions, the glucocorticoid receptor antagonist ORG 34116 did not normalize the depressive-like symptoms in the psychosocial stress model of male tree shrews. This finding, however, does not exclude that specific central, neuroendocrine and behavioral features are affected by the compound.

  3. Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal.

    PubMed

    Zaniewska, Magdalena; McCreary, Andrew C; Wydra, Karolina; Filip, Małgorzata

    2010-06-01

    A pronounced withdrawal syndrome including depressed mood prevents cigarette smoking cessation. We tested if blockade or activation of serotonin (5-HT)(2) receptors affected the time of immobility (as an indirect measure of depression-like behavior) in naïve animals and in those withdrawn from chronic nicotine in the forced swim test (FST). The antidepressant imipramine was used as a control. In the FST, the selective 5-HT(2A) receptor antagonist M100,907 (1-2 mg/kg, but not 0.5 mg/kg), the selective 5-HT(2C) receptor antagonist SB 242,084 (0.3-1 mg/kg, but not 0.1 mg/kg), the 5-HT(2C) receptor agonists Ro 60-0175 (10 mg/kg, but not 3 mg/kg) and WAY 163,909 (1.5-10 mg/kg, but not 0.75 mg/kg) as well as imipramine (30 mg/kg, but not 15 mg/kg) decreased the immobility time while the non-selective 5-HT(2) receptor agonist DOI (0.1-1 mg/kg) was inactive in naïve rats. We found an increase in immobility time in rats that were withdrawn from nicotine exposure after 5 days of chronic nicotine treatment. This effect increased from day 1 until day 10 following withdrawal of nicotine, with maximal withdrawal effects on day 3. M100,907 (1 mg/kg), SB 242,084 (0.3 mg/kg), Ro 60-0175 (3 mg/kg), WAY 163,909 (0.75-1.5 mg/kg) and imipramine (15-30 mg/kg) shortened the immobility time in rats that had been removed from nicotine exposure for 3 days. Locomotor activity studies indicated that the effects of SB 242,084 might have been non-specific, as we noticed enhanced basal locomotion in naïve rats. This data set demonstrates that 5-HT(2A) receptor antagonist and 5-HT(2C) receptor agonists exhibited effects similar to antidepressant drugs and abolished the depression-like effects in nicotine-withdrawn rats. These drugs should be considered as adjuncts to smoking cessation therapy, to ameliorate abstinence-induced depressive symptoms.

  4. Desipramine blocks alcohol-induced anxiety- and depressive-like behaviors in two rat strains.

    PubMed

    Getachew, Bruk; Hauser, Sheketha R; Taylor, Robert E; Tizabi, Yousef

    2008-11-01

    Epidemiological studies indicate significant co-morbid expression of alcoholism, anxiety, and depression. These symptoms are often under-diagnosed and under-treated and can worsen prognostic and treatment outcome for alcoholism. Nonetheless, a causal relationship between alcoholism and these conditions is yet to be established. In this study we sought to determine the effects of daily alcohol administration on the indices of anxiety and depression in two rat strains, one of which exhibits inherent depressive-like characteristics. Moreover, it was of relevance to examine the effects of a clinically useful antidepressant on alcohol-induced behavioral changes. Wistar-Kyoto (WKY) rats derived from Wistar stock show low levels of locomotor activity in an open field and high levels of immobility in the forced swim test (FST) which is considered a measure of their helplessness and hence are considered a putative animal model of depression. Adult female WKY and Wistar rats were exposed for 3 hrs daily to 95% ethanol vapor to achieve a mean blood alcohol level (BAL) of approximately 150 mg/dL. Controls were exposed to air in similar inhalation chambers. Sixteen to 18 hrs following 7 or 14 days of exposure to alcohol, locomotor activity (LCA) in open field, duration of time spent in the open arm of the elevated plus-maze (EPM), reflective of anxiety-like behavior and immobility in FST were evaluated. Alcohol exposure for 7 or 14 days reduced LCA only in Wistar rats but enhanced FST immobility in both strains at both time points. Only 14 day alcohol exposure reduced EPM open arm time in both WKY and Wistar rats. Daily treatment with desipramine (8 mg/kg) blocked all the changes induced by alcohol in both strains. Thus, subchronic (7 day) exposure to alcohol induces depressive-like characteristics in Wistar rats and exacerbates that of WKY rats. Chronic (14 day) exposure, however, also induces an anxiety-like effect in both strains. The depressive- and anxiety-like behaviors

  5. 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.

  6. Effect of dietary fat type on anxiety-like and depression-like behavior in mice.

    PubMed

    Mizunoya, Wataru; Ohnuki, Koichiro; Baba, Kento; Miyahara, Hideo; Shimizu, Naomi; Tabata, Kuniko; Kino, Takako; Sato, Yusuke; Tatsumi, Ryuichi; Ikeuchi, Yoshihide

    2013-12-01

    Dietary fat plays an important role in higher brain functions. We aimed to assess the short and long term intake of three different types of dietary fat (soybean oil, lard, and fish oil) on anxiety-like and depression-like behavior in mice. For the short term intake assessment, a behavioral test battery for anxiety and depression was carried out for a 3-day feeding period. For the long term intake assessment, a behavioral test battery began after the 4-week feeding period. During the short term intake, the time spent in the open arms of the elevated plus-maze was the longest in the fish oil fed group, followed by the soybean oil and lard-fed groups. The elevated plus-maze is a common animal model to assess anxiety, in which an increased time spent in the open arms indicates an anxiolytic effect. The difference between the fish oil-fed group and lard-fed group was statistically significant (p < 0.01), but there was no significant difference between the soybean oil-fed group and the other two groups. Similar results were observed after a 4-week feeding period. On the other hand, there was no significant difference among the three groups in behavior tests to evaluate depression. Thus, the dietary fat types appeared to influence anxiety but not depression in mice, both in short term (3 days) and long term (4 weeks) feeding.

  7. Endogenous ciliary neurotrophic factor modulates anxiety and depressive-like behavior.

    PubMed

    Peruga, Isabella; Hartwig, Silvia; Merkler, Doron; Thöne, Jan; Hovemann, Bernhard; Juckel, Georg; Gold, Ralf; Linker, Ralf A

    2012-04-15

    On a molecular level, depression is characterized by an altered monoaminergic neurotransmission as well as a modulation of cytokines and other mediators in the central nervous system. In particular, neurotrophic factors may influence affective behavior including depression and anxiety. Ciliary neurotrophic factor (CNTF) plays an important role in the regulation of neuronal development, neuroprotection and may also influence cognitive processes. Here we investigate the affective behavior in mice deficient for CNTF (CNTF -/- mice) at young age of 10-20 weeks. CNTF -/- mice displayed an increased anxiety-like behavior with a 30% reduction of the time spent in the bright compartment of the light/dark box as well as a significantly increased startle response. In the learned helplessness paradigm, CNTF -/- mice are more prone to depressive-like behavior. In the hippocampus of 20 weeks old, but not 10 weeks old, CNTF -/- mice, these changes correlated with a loss of parvalbumin immunoreactive GABAergic interneurons and a reduction of serotonin levels as well as 5-HT receptor 1A expression. Modulation of monoaminergic neurotransmitter levels via chronic application of the antidepressants amitriptyline and citalopram did not exert beneficial effects. These data imply that endogenous CNTF plays a pivotal role for the structural maintenance of hippocampal functions and thus has an important impact on the modulation of affective behavior in rodent models of anxiety and depression.

  8. Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology.

    PubMed

    Fonken, L K; Xu, X; Weil, Z M; Chen, G; Sun, Q; Rajagopalan, S; Nelson, R J

    2011-10-01

    Particulate matter air pollution is a pervasive global risk factor implicated in the genesis of pulmonary and cardiovascular disease. Although the effects of prolonged exposure to air pollution are well characterized with respect to pulmonary and cardiovascular function, comparatively little is known about the impact of particulate matter on affective and cognitive processes. The central nervous system may be adversely affected by activation of reactive oxygen species and pro-inflammatory pathways that accompany particulate matter pollution. Thus, we investigated whether long-term exposure to ambient fine airborne particulate matter (<2.5 μm (PM(2.5))) affects cognition, affective responses, hippocampal inflammatory cytokines and neuronal morphology. Male mice were exposed to either PM(2.5) or filtered air (FA) for 10 months. PM(2.5) mice displayed more depressive-like responses and impairments in spatial learning and memory as compared with mice exposed to FA. Hippocampal pro-inflammatory cytokine expression was elevated among PM(2.5) mice. Apical dendritic spine density and dendritic branching were decreased in the hippocampal CA1 and CA3 regions, respectively, of PM(2.5) mice. Taken together, these data suggest that long-term exposure to particulate air pollution levels typical of exposure in major cities around the globe can alter affective responses and impair cognition.

  9. Low dose dexamethasone reverses depressive-like parameters and memory impairment in rats submitted to sepsis.

    PubMed

    Cassol-Jr, Omar J; Comim, Clarissa M; Petronilho, Fabricia; Constantino, Larissa S; Streck, Emilio L; Quevedo, João; Dal-Pizzol, Felipe

    2010-04-05

    Sepsis is characterized by a systemic inflammatory response of the immune system against an infection, presenting with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, behavior alterations, and high mortality. In this study, we aimed to evaluate the effects of dexamethasone on mortality, anhedonia, circulating corticosterone and adrenocorticotropin hormone (ACTH) levels, body and adrenal gland weight, and aversive memory in sepsis survivor rats. Male Wistar rats underwent sham operation or cecal ligation and perforation (CLP) procedure. Rats subjected to CLP were treated with "basic support" and dexamethasone (at 0.2 and 2mg/kg daily for 7 days after CLP, intraperitonially) or saline. After 10 days of sepsis procedure, it was evaluated aversive memory, sweet food consumption, and body and adrenal gland weight. Serum and plasma were also obtained. It was observed that low dose dexamethasone reverted anhedonia, normalized adrenal gland and body weight, corticosterone and ACTH levels, and decreased mortality and avoidance memory impairment, demonstrating that low doses of dexamethasone for moderate periods may be beneficial for sepsis treatment and its sequelae-depressive-like parameters and memory impairment.

  10. Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice*

    PubMed Central

    Beckman, Danielle; Santos, Luis E.; Americo, Tatiana A.; Ledo, Jose H.; de Mello, Fernando G.; Linden, Rafael

    2015-01-01

    We sought to examine interactions of the prion protein (PrPC) with monoaminergic systems due to: the role of PrPC in both Prion and Alzheimer diseases, which include clinical depression among their symptoms, the implication of monoamines in depression, and the hypothesis that PrPC serves as a scaffold for signaling systems. To that effect we compared both behavior and monoaminergic markers in wild type (WT) and PrPC-null (PrP−/−) mice. PrP−/− mice performed poorly when compared with WT in forced swimming, tail suspension, and novelty suppressed feeding tests, typical of depressive-like behavior, but not in the control open field nor rotarod motor tests; cyclic AMP responses to stimulation of D1 receptors by dopamine was selectively impaired in PrP−/− mice, and responses to serotonin, but not to norepinephrine, also differed between genotypes. Contents of dopamine, tyrosine hydroxylase, and the 5-HT5A serotonin receptor were increased in the cerebral cortex of PrP−/−, as compared with WT mice. Microscopic colocalization, as well as binding in overlay assays were found of PrPC with both the 5HT5A and D1, but not D4 receptors. The data are consistent with the scaffolding of monoaminergic signaling modules by PrPC, and may help understand the pathogenesis of clinical depression and neurodegenerative disorders. PMID:26152722

  11. Investigating attentional processes in depressive-like domestic horses (Equus caballus).

    PubMed

    Rochais, C; Henry, S; Fureix, C; Hausberger, M

    2016-03-01

    Some captive/domestic animals respond to confinement by becoming inactive and unresponsive to external stimuli. Human inactivity is one of the behavioural markers of clinical depression, a mental disorder diagnosed by the co-occurrence of symptoms including deficit in selective attention. Some riding horses display 'withdrawn' states of inactivity and low responsiveness to stimuli that resemble the reduced engagement with their environment of some depressed patients. We hypothesized that 'withdrawn' horses experience a depressive-like state and evaluated their level of attention by confronting them with auditory stimuli. Five novel auditory stimuli were broadcasted to 27 horses, including 12 'withdrawn' horses, for 5 days. The horses' reactions and durations of attention were recorded. Non-withdrawn horses reacted more and their attention lasted longer than that of withdrawn horses on the first day, but their durations of attention decreased over days, but those of withdrawn horses remained stable. These results suggest that the withdrawn horses' selective attention is altered, adding to already evidenced common features between this horses' state and human depression. Copyright © 2016. Published by Elsevier B.V.

  12. Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus.

    PubMed

    Kasahara, T; Takata, A; Kato, T M; Kubota-Sakashita, M; Sawada, T; Kakita, A; Mizukami, H; Kaneda, D; Ozawa, K; Kato, T

    2016-01-01

    Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.

  13. Gender differences in genetic mouse models evaluated for depressive-like and antidepressant behavior.

    PubMed

    Kreiner, Grzegorz; Chmielarz, Piotr; Roman, Adam; Nalepa, Irena

    2013-01-01

    Depression is a mental disease that affects complex cognitive and emotional functions. It is believed that depression is twice as prevalent in women as in men. This phenomenon may influence the response to various antidepressant therapies, and these differences are still underestimated in clinical treatment. Nevertheless, most of the current findings are based on studies on male animal models, and relatively few of these studies take possible gender differences into consideration. Advancements in genetic engineering over the last two decades have introduced many transgenic lines that have been screened to study the pathomechanisms of depression. In this mini-review, we provide a compendious list of genetically altered mice that underwent tests for depressive-like or antidepressant behavior and determine if and how the gender factor was analyzed in their evaluation. Furthermore, we compile the gender differences in response to antidepressant treatment. On the basis of these analyses, we conclude that in many cases, gender variability is neglected or not taken into consideration in the presented results. We note the necessity of discussing this issue in the phenotypic characterization of transgenic mice, which seems to be particularly important while modeling mental diseases.

  14. Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice.

    PubMed

    Weng, Lianjin; Guo, Xiaohua; Li, Yang; Yang, Xin; Han, Yuanyuan

    2016-03-05

    Previous researches found that apigenin exerted antidepressant-like effects in rodents. However, it is unclear whether the neurotrophic system is involved in the antidepressant-like effects of apigenin. Our present study aimed to explore the neurotrophic related mechanism of apigenin in depressive-like mice induced by chronic corticosterone treatment. Mice were repeatedly injected with corticosterone (40 mg/kg) subcutaneously (s.c) once daily for consecutive 21 days. Apigenin (20 and 40 mg/kg) and fluoxetine (20 mg/kg) were administered 30 min prior to the corticosterone injection. The behavioral tests indicated that apigenin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by chronic corticosterone treatment. In addition, the increase in serum corticosterone levels and the decrease in hippocampal brain-derived neurotrophic factor (BDNF) levels in corticosterone-treated mice were also ameliorated by apigenin administration. Taken together, our findings intensively confirmed the antidepressant-like effects of apigenin and indicated that the antidepressant-like mechanism of apigenin was mediated, at least partly by up-regulation of BDNF levels in the hippocampus.

  15. Zinc and imipramine reverse the depression-like behavior in mice induced by chronic restraint stress.

    PubMed

    Ding, Qin; Li, Hongxia; Tian, Xue; Shen, Zhilei; Wang, Xiaoli; Mo, Fengfeng; Huang, Junlong; Shen, Hui

    2016-06-01

    Depression is a common psychopathological disorders. Studies of depression have indicated that zinc play a role in the depression pathophysiology and treatment. In present study, we examined the effects of zinc and imipramine supplement alone or combination of zinc and imipramine in mice induced by chronic restraint stress (CRS). Moreover, the possible roles of zinc receptor (G protein-coupled receptor 39, GPR39)-related pathway was investigated. Decreased weight and increased corticosterone (CORT) were observed after 3 weeks CRS exposure. It was shown that CRS induced lower serum zinc, higher hippocampal zinc, increased immobility time in tail suspension test and decreased movement distance in spontaneous activity test, which could be normalized by zinc (30 mg/kg) and imipramine (20 mg/kg) supplement alone and combination of zinc (15 mg/kg) and imipramine (5 mg/kg) for 3 weeks after CRS exposure. Moreover, the changes in mRNA expressions of GPR39, cAMP-response element binding protein (CREB), brain-derived neurotropic factor (BDNF) and n-methytl-d-aspartate receptors (NMDAR) could be reversed by the same treatment mentioned above. These results suggested that zinc dyshomeostasis in serum and hippocampus and depression-like behavior in CRS exposure animals observed in present study could be normalized by zinc and imipramine. The combination of zinc and imipramine in low dose has synergetic effects. The possible mechanism might be correlated to GPR39 receptor-related pathway.

  16. Social isolation after stroke leads to depressive-like behavior and decreased BDNF levels in mice.

    PubMed

    O'Keefe, Lena M; Doran, Sarah J; Mwilambwe-Tshilobo, Laetitia; Conti, Lisa H; Venna, Venugopal R; McCullough, Louise D

    2014-03-01

    Social isolation prior to stroke leads to poorer outcomes after an ischemic injury in both animal and human studies. However, the impact of social isolation following stroke, which may be more clinically relevant as a target for therapeutic intervention, has yet to be examined. In this study, we investigated both the sub-acute (2 weeks) and chronic (7 weeks) effects of social isolation on post-stroke functional and histological outcome. Worsened histological damage from ischemic injury and an increase in depressive-like behavior was observed in isolated mice as compared to pair-housed mice. Mice isolated immediately after stroke showed a decrease in the levels of brain-derived neurotrophic factor (BDNF). These changes, both histological and behavioral, suggest an overall negative effect of social isolation on stroke outcome, potentially contributing to post-stroke depression and anxiety. Therefore, it is important to identify patients who have perceived isolation post-stroke to hopefully prevent this exacerbation of histological damage and subsequent depression.

  17. Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats

    PubMed Central

    Sun, Min; Wang, Ke; Yu, Yan; Su, Wen-Ting; Jiang, Xin-Xin

    2016-01-01

    Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD. PMID:27525025

  18. Prenatal Exposure to Silver Nanoparticles Causes Depression Like Responses in Mice

    PubMed Central

    Tabatabaei, S. R. F.; Moshrefi, M.; Askaripour, M.

    2015-01-01

    Despite increasing studies on silver nanoparticles, their mechanism of action is not so clear, especially their probable toxicity on reproduction procedure, developmental process and offspring behavior. Therefore in the present study the effect of silver nanoparticles exposure during gestational period on offspring's depression behavior was assessed. Thirty virgin female mice were divided into three groups (n=10 for each group) including: one control and two experimental groups, which received an equal volume (0.2 ml) of suspension containing 0, 0.2 and 2 mg/kg of silver nanoparticles, respectively. After mating, the suspension was injected and repeated every 3 days till accouchement. Depression behaviors were assessed by tail suspension test and forced swimming test, in 45-day-old male and female progenies (6 groups, n=10). In males, both dose of silver nanoparticles (0.2 and 2 mg/kg) decreased mobility and increased immobility time in forced swimming test (P<0.05), but in female no effects were observed in mobility and immobility time. In tail suspension test, 2 mg/kg of silver nanoparticles lead to decrease of mobility time (P<0.05) and increase of immobility time (P<0.05) in female offspring but in males no significant effect was observed on mobility and immobility time. We may concluded that the prenatal exposure to silver nanoparticles probably cause gender-specific depression like behaviors in offspring, possibly through neurotoxic effect during neuronal development. PMID:26997695

  19. Resveratrol counteracts lipopolysaccharide-induced depressive-like behaviors via enhanced hippocampal neurogenesis

    PubMed Central

    Liu, Liang; Zhang, Qin; Cai, Yulong; Sun, Dayu; He, Xie; Wang, Lian; Yu, Dan; Li, Xin; Xiong, Xiaoyi; Xu, Haiwei; Yang, Qingwu; Fan, Xiaotang

    2016-01-01

    Radial glial-like cells (RGLs) in the adult dentate gyrus (DG) function as progenitor cells for adult hippocampal neurogenesis, a process involved in the stress-related pathophysiology and treatment efficiency of depression. Resveratrol (RSV) has been demonstrated to be a potent activator of neurogenesis. The present study investigated whether chronic RSV treatment has antidepressant potential in relation to hippocampal neurogenesis. Mice received two weeks of RSV (20 mg/kg) or dimethylsulfoxide (DMSO) treatment, followed by lipopolysaccharide (LPS; 1 mg/kg) or saline injections for 5 days. We found that RSV treatment abrogated the increased immobility in the forced swimming test and tail suspension test induced by LPS. Immunohistochemical staining revealed that RSV treatment reversed the increase in microglial activation and the inhibition in DG neurogenesis. RSV treatment also attenuated LPS-induced defects in the expanding of RGLs through promoting symmetric division. In addition, RSV ameliorated LPS-induced NF-κB activation in the hippocampus coincides with the up-regulation levels of Sirt1 and Hes1. Taken together, these data indicated that RSV-induced Sirt1 activation counteracts LPS-induced depression-like behaviors via a neurogenic mechanism. A new model to understand the role of RSV in treating depression may result from these findings. PMID:27517628

  20. Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus

    PubMed Central

    Kasahara, T; Takata, A; Kato, T M; Kubota-Sakashita, M; Sawada, T; Kakita, A; Mizukami, H; Kaneda, D; Ozawa, K; Kato, T

    2016-01-01

    Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism. PMID:26481320

  1. Ziziphi spinosae lily powder suspension in the treatment of depression-like behaviors in rats.

    PubMed

    Wang, Yifang; Huang, Mei; Lu, Xinyi; Wei, Runze; Xu, Jinyong

    2017-04-28

    Depression is a chronic, recurring and potentially life-threatening illness. Current treatments for depression are characterized by a low success rate and associated with a wide variety of side effects. The aim of the present study was to evaluate the behavioral anti-depressant effect of a novel herbal compounds named ziziphi spinosae lily powder suspension, as well as to investigate its potential mechanisms. Except for body weight, depressive-like behaviors were also evaluated using forced swimming test, sucrose consumption test and open field test. In order to investigate the underlying potential mechanisms, serum 5-HT and brain 5-HIAA were measured using ultrahigh-performance liquid chromatography and high-performance liquid chromatography, respectively. Results showed that the herbal compounds ziziphi spinosae lily suspension could alleviate depressive symptoms in rat model of chronic depression. Biochemical analysis revealed that the herbal compounds elevated serum 5-HT and brain 5-HIAA. Ziziphi spinosae lily powder suspension could alleviate depressive behaviors in depression model animals. The underlying mechanisms may be related to the increase of serum 5-HT in peripheral blood and 5-HIAA in brain. The study provides important mechanistic insights into the protective effect of the herbal compounds against chronic depressive disorder and suggests that the herbal compounds may be a potential pharmacological agent for treatment of major depressive disorder.

  2. Social isolation after stroke leads to depressive-like behavior and decreased BDNF levels in mice

    PubMed Central

    O’Keefe, Lena M.; Doran, Sarah J.; Mwilambwe-Tshilobo, Laetitia; Conti, Lisa H.; Venna, Venugopal R.; McCullough, Louise D.

    2014-01-01

    Social isolation in the pre-stroke environment leads to poorer outcomes after an ischemic injury in both animal and human studies. However, the impact of social isolation following stroke, which may be more clinically relevant as a target for therapeutic intervention, has yet to be examined. In this study, we investigated both the sub-acute (2 weeks) and chronic (7 weeks) effects of social isolation on post-stroke functional and histological outcome. Worsened histological damage from ischemic injury and an increase in depressive-like behavior was observed in isolated mice as compared to pair-housed mice. Mice isolated immediately after stroke showed a decrease in the levels of brain-derived neurotrophic factor (BDNF). These changes, both histological and behavioral, suggest an overall negative effect of social isolation on stroke outcome, potentially contributing to post-stroke depression and anxiety. Therefore, it is important to identify patients who have perceived isolation post-stroke to hopefully prevent this exacerbation of histological damage and subsequent depression. PMID:24211537

  3. Palatable cafeteria diet ameliorates anxiety and depression-like symptoms following an adverse early environment.

    PubMed

    Maniam, Jayanthi; Morris, Margaret J

    2010-06-01

    Early trauma contributes to psychosocial disorders later in life. An adverse early environment induced by maternal separation (MS) is known to alter behavioural and stress responses in rats. Palatable food dampens stress responses. We investigated the influence of palatable cafeteria high-fat diet (HFD) on behavioural responses following MS or non-handling (NH), versus 15min brief separation. After littering, Sprague-Dawley rats were exposed to short separation, S15 (15min), prolonged separation, S180 (180min) daily from postnatal days 2 to 14 or were non-handled. Pups were assigned to HFD or chow at weaning. We assessed depression and anxiety-like behaviour with sucrose preference test (SPT) and elevated plus maze (EPM) respectively, and measured hypothalamic CRH and hippocampal glucocorticoid receptor (GR) expression. S180 rats showed increased anxiety-and depression-like behaviours, with increased plasma corticosterone, hypothalamic CRH, and reduced hippocampal GR expression versus S15 rats. Similar effects were observed across gender. These were normalized by provision of HFD, with greater beneficial effects in males. S15 showed no benefit of HFD. NH female rats had less adverse impacts; HFD had beneficial impact on behaviour in NH males. Thus behavioural deficits and gene expression changes induced by early life stress were ameliorated by HFD. These results highlight the important place of palatable food in reducing central stress responses supporting the therapeutic value of 'comfort food'. Crown Copyright 2009. Published by Elsevier Ltd. All rights reserved.

  4. Depression-like behaviors in tree shrews and comparison of the effects of treatment with fluoxetine and carbetocin.

    PubMed

    Meng, Xiaolu; Shen, Fang; Li, Chunlu; Li, Yonghui; Wang, Xuewei

    2016-06-01

    Tree shrews, a species phylogenetically close to primates, are regarded as a suitable and naturalistic animal model for depression studies. However, psychological symptoms that are essential for depression diagnosis and treatment, such as helplessness and social withdrawal, have not been studied in this model. Therefore, in this study, we first investigated learned helplessness, social interaction and sucrose preference induced by two chronic stress paradigms: uncontrollable foot shocks (1-week foot shocks) and multiple unpredictable stimuli (1-week foot shocks and 3-week unpredictable stressors) in tree shrews. Our results showed that uncontrollable foot shocks could only induce learned helplessness in animals; whereas animals treated with multiple unpredictable stimuli exhibited more depression-like behaviors including social withdrawal, anhedonia and learned helplessness. These findings suggested that multiple unpredictable stimuli could effectively induce various depression-like behaviors in tree shrews. More importantly, we compared the antidepressant effects of fluoxetine and carbetocin, a long-acting oxytocin analog, on specific depression-like behaviors. Our present data displayed that, compared with fluoxetine, carbetocin was also effective in reversing learned helplessness, elevating sucrose preference and improving social interaction behaviors in depression-like animals. Therefore, carbetocin might be a potential antidepressant with applications in humans.

  5. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

    PubMed Central

    O’Connor, J.C.; Lawson, M.A.; André, C.; Moreau, M.; Lestage, J.; Castanon, N.; Kelley, K.W.; Dantzer, R.

    2009-01-01

    Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase(IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naïve mice dose-dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway. PMID:18195714

  6. Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling.

    PubMed

    Dellarole, Anna; Morton, Paul; Brambilla, Roberta; Walters, Winston; Summers, Spencer; Bernardes, Danielle; Grilli, Mariagrazia; Bethea, John R

    2014-10-01

    Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1(-/-) mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.

  7. Propentofylline Prevents Sickness Behavior and Depressive-Like Behavior Induced by Lipopolysaccharide in Rats via Neuroinflammatory Pathway

    PubMed Central

    Cabral, Danilo; Coelho, Cideli P.; Queiroz-Hazarbassanov, Nicolle; Martins, Maria F. M.; Bondan, Eduardo F.; Bernardi, Maria M.; Kirsten, Thiago Berti

    2017-01-01

    Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases. PMID:28056040

  8. Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.

    PubMed

    Moretti, Morgana; Colla, André; de Oliveira Balen, Grasiela; dos Santos, Danúbia Bonfanti; Budni, Josiane; de Freitas, Andiara Espíndola; Farina, Marcelo; Severo Rodrigues, Ana Lúcia

    2012-03-01

    Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.

  9. Chronic curcumin treatment normalizes depression-like behaviors in mice with mononeuropathy: involvement of supraspinal serotonergic system and GABAA receptor.

    PubMed

    Zhao, Xin; Wang, Chuang; Zhang, Jun-Fang; Liu, Li; Liu, Ai-Ming; Ma, Qing; Zhou, Wen-Hua; Xu, Ying

    2014-05-01

    Comorbid depression is commonly observed in individuals who suffer from neuropathic pain, which necessitates improved treatment. Curcumin, a phenolic compound derived from Curcuma longa, possesses both antinociceptive and antidepressant-like activities in animal studies, suggesting its possible usefulness in treating this comorbidity. We investigated the effect of curcumin on depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Chronic constriction injury (CCI) was produced by loosely ligating the sciatic nerves in mice. The nociceptive behaviors were examined using Hargreaves test, and the depressive-like behaviors were determined by forced swim test (FST) and tail suspension test (TST). After CCI injury, the neuropathic mice developed nociceptive and depressive-like behaviors, as shown by thermal hyperalgesia in Hargreaves test and protracted immobility time in FST and TST. Chronic treatment of neuropathic mice with curcumin (45 mg/kg, p.o., twice per day for 3 weeks) corrected their exacerbated nociceptive and depressive-like behaviors, which was abolished by chemical depletion of brain serotonin rather than noradrenaline. The paralleled antinociceptive and antidepressant-like actions of curcumin seem to be pharmacologically segregated, since intrathecal and intracerebroventricular injection of methysergide, a nonselective 5-HT receptor antagonist, separately counteracted the two actions of curcumin. Further, this antidepression was abrogated by repeated co-treatment with 5-HT1A receptor antagonist WAY-100635 and greatly attenuated by acute co-treatment with GABAA receptor antagonist bicuculline. Curcumin can normalize the depressive-like behaviors of neuropathic mice, which may be independent of the concurrent analgesic action and possibly mediated via the supraspinal serotonergic system and downstream GABAA receptor.

  10. Sodium butyrate functions as an antidepressant and improves cognition with enhanced neurotrophic expression in models of maternal deprivation and chronic mild stress.

    PubMed

    Valvassori, Samira Silva; Varela, Roger Bitencourt; Arent, Camila Orlandi; Dal-Pont, Gustavo Colombo; Bobsin, Tamara Sarate; Budni, Josiane; Reus, Gislaine Zilli; Quevedo, Joao

    2014-01-01

    It is known that cognitive processes, such as learning and memory, are affected in depression. Several authors have described histone deacetylase (HDAC) inhibitors as a class of drugs that improves long-term memory formation. The current study examined the effects of maternal deprivation (MD) and chronic mild stress (CMS), which have been shown as animal models of depression, and the effects of sodium butyrate (SB), a HDAC inhibitor, on recognition memory. Considering that neurotrophic factors has been pointed as a key event involved with cognition and depressive disorder, levels of neurotrophic factors (BDNF, NGF and GDNF) were also investigated. MD and CMS induced depressive-like behavior in the forced swimming test (FST) and memory impairment in the object recognition (OR) test, without altering locomotor activity of rats. In addition, SB was able to reverse the stress-induced neurotrophic factors decrease and reversed memory impairment. The results indicate that the stress both at early and later stage of life may induce cognitive impairment in animals and neurotrofic factors (BDNF, NGF and GDNF) levels decrease. SB treatment improved the recognition memory and reversed the neurotrophins levels decreased in the hippocampus of rats submitted to the MD and CMS models. Together, our results reinforce the notion that SB displays a specific antidepressant profile and improve cognition in MD and CMS rats that may be, at least in part, due to its upregulation of neurotrophic factors.

  11. Antidepressant like effects of hydrolysable tannins of Terminalia catappa leaf extract via modulation of hippocampal plasticity and regulation of monoamine neurotransmitters subjected to chronic mild stress (CMS).

    PubMed

    Chandrasekhar, Y; Ramya, E M; Navya, K; Phani Kumar, G; Anilakumar, K R

    2017-02-01

    Terminalia catappa L. belonging to Combretaceae family is a folk medicine, known for its multiple pharmacological properties, but the neuro-modulatory effect of TC against chronic mild stress was seldom explored. The present study was designed to elucidate potential antidepressant-like effect of Terminalia cattapa (leaf) hydro-alcoholic extract (TC) by using CMS model for a period of 7 weeks. Identification of hydrolysable tannins was done by using LC-MS. After the CMS exposure, mice groups were administered with imipramine (IMP, 10mg/kg, i.p.) and TC (25, 50 and 100mg/kg of TC, p.o.). Behavioural paradigms used for the study included forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT). After behavioural tests, monoamine neurotransmitter, cortisol, AchE, oxidative stress levels and mRNA expression studies relevant to depression were assessed. TC supplementation significantly reversed CMS induced immobility time in FST and other behavioural paradigms. Moreover, TC administration significantly restored CMS induced changes in concentrations of hippocampal neurotransmitters (5-HT, DA and NE) as well as levels of acetyl cholinesterase, cortisol, monoamine oxidases (MAO-A, MAO-B), BDNF, CREB, and p-CREB. It suggests that TC supplementation could supress stress induced depression by regulating monoamine neurotransmitters, CREB, BDNF, cortisol, AchE level as well as by amelioration of oxidative stress. Hence TC can be used as a complementary medicine against depression-like disorder. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.

    PubMed

    Renoir, Thibault; Pang, Terence Y C; Zajac, Michelle S; Chan, Grace; Du, Xin; Leang, Leah; Chevarin, Caroline; Lanfumey, Laurence; Hannan, Anthony J

    2012-03-01

    Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT(1A) and 5-HT(2A) receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT(1A) autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT(1A) and 5-HT(2) heteroceptor function observed in HD animals. We report for the first time a crucial role for 5-HT(1A) autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  13. Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise

    PubMed Central

    Renoir, Thibault; Pang, Terence YC; Zajac, Michelle S; Chan, Grace; Du, Xin; Leang, Leah; Chevarin, Caroline; Lanfumey, Laurence; Hannan, Anthony J

    2012-01-01

    BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT1A and 5-HT2A receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTS Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT1A autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT1A and 5-HT2 heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONS We report for the first time a crucial role for 5-HT1A autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits. PMID:21718306

  14. Probiotic treatment reduces depressive-like behaviour in rats independently of diet.

    PubMed

    Abildgaard, Anders; Elfving, Betina; Hokland, Marianne; Wegener, Gregers; Lund, Sten

    2017-05-01

    The gut microbiota has recently emerged as an important regulator of brain physiology and behaviour in animals, and ingestion of certain bacteria (probiotics) therefore appear to be a potential treatment for major depressive disorder (MDD). However, some conceptual and mechanistical aspects need further elucidation. We therefore aimed at investigating whether the habitual diet may interact with the effect of probiotics on depression-related behaviour and further examined some potentially involved mechanisms underlying the microbe-mediated behavioural effects. Forty male Sprague-Dawley rats were fed a control (CON) or high-fat diet (HFD) for ten weeks and treated with either a multi-species probiotic formulation or vehicle for the last five weeks. Independently of diet, probiotic treatment markedly reduced depressive-like behaviour in the forced swim test by 34% (95% CI: 22-44%). Furthermore, probiotic treatment skewed the cytokine production by stimulated blood mononuclear cells towards IFNγ, IL2 and IL4 at the expense of TNFα and IL6. In addition, probiotics lowered hippocampal transcript levels of factors involved in HPA axis regulation (Crh-r1, Crh-r2 and Mr), whereas HFD increased these levels. A non-targeted plasma metabolomics analysis revealed that probiotics raised the level of indole-3-propionic acid, a potential neuroprotective agent. Our findings clearly support probiotics as a potential treatment strategy in MDD. Importantly, the efficacy was not attenuated by intake of a "Western pattern" diet associated with MDD. Mechanistically, the HPA axis, immune system and microbial tryptophan metabolism could be important in this context. Importantly, our study lend inspiration to clinical trials on probiotics in depressed patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Antidepressants reduce extinction-induced withdrawal and biting behaviors: a model for depressive-like behavior.

    PubMed

    Huston, J P; van den Brink, J; Komorowski, M; Huq, Y; Topic, B

    2012-05-17

    The withholding of expected rewards results in extinction of behavior and, hypothetically, to depression-like symptoms. In a test of this hypothesis, we examined the effects of extinction of food-reinforced lever-pressing on collateral behaviors that might be indices of depression. Operant extinction is known to be aversive to the organism and results in avoidance behavior. We hypothesized that avoidance of, or withdrawal from, the former source of reward may serve as a marker for "despair." Adult male Wistar rats (n=6-7 animals per group) were exposed to a Skinner box attached to a second compartment of the same size, providing opportunity for the animals to leave the operant chamber and to enter the "withdrawal" compartment. The animals spent a portion of the time during the extinction trials in this second chamber. To assess the predictive validity of this behavior as a potential marker of "despair," we tested the effects of chronic administration of two common antidepressant drugs on this measure. The tricyclic antidepressant imipramine (20 mg/kg) as well as the selective serotonin reuptake inhibitor citalopram (20 mg/kg) reduced the number of entries and time spent in the withdrawal compartment. We propose that entries into and time spent in the withdrawal compartment may operationalize "avoidance," a core symptom of major depression. Rearing as well as biting behaviors during the extinction trials were also attenuated by the antidepressant treatment. These results lend support to the hypothesis that extinction of positively reinforced operants evokes behaviors that reflect elements of "despair/depression" because these behaviors are modulated by antidepressant treatment. The avoidance of the operant chamber as a consequence of extinction, together with rearing and biting behaviors, may serve as useful measures for the testing of antidepressant treatments.

  16. MicroRNA-155 deletion reduces anxiety- and depressive-like behaviors in mice.

    PubMed

    Fonken, Laura K; Gaudet, Andrew D; Gaier, Kristopher R; Nelson, Randy J; Popovich, Phillip G

    2016-01-01

    Depressive disorders have complex and multi-faceted underlying mechanisms, rendering these disorders difficult to treat consistently and effectively. One under-explored therapeutic strategy for alleviating mood disorders is the targeting of microRNAs (miRs). miRs are small non-coding RNAs that cause sequestration/degradation of specific mRNAs, thereby preventing protein translation and downstream functions. miR-155 has validated and predicted neurotrophic factor and inflammatory mRNA targets, which led to our hypothesis that miR-155 deletion would modulate affective behaviors. To evaluate anxiety-like behavior, wildtype (wt) and miR-155 knockout (ko) mice (littermates; both male and female) were assessed in the open field and on an elevated plus maze. In both tests, miR-155 ko mice spent more time in open areas, suggesting they had reduced anxiety-like behavior. Depressive-like behaviors were assessed using the forced swim test. Compared to wt mice, miR-155 ko mice exhibited reduced float duration and increased latency to float. Further, although all mice exhibited a strong preference for a sucrose solution over water, this preference was enhanced in miR-155 ko mice. miR-155 ko mice had no deficiencies in learning and memory (Barnes maze) or social preference/novelty suggesting that changes in mood were specific. Finally, compared to wt hippocampi, miR-155 ko hippocampi had a reduced inflammatory signature (e.g., decreased IL-6, TNF-a) and female miR-155 ko mice increased ciliary neurotrophic factor expression. Together, these data highlight the importance of studying microRNAs in the context of anxiety and depression and identify miR-155 as a novel potential therapeutic target for improving mood disorders.

  17. Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters.

    PubMed

    Kim, Kyoung-Shim; Han, Pyung-Lim

    2006-02-15

    Chronic stress is a risk factor for psychiatric illnesses, such as anxiety and depression disorders. To understand the underlying mechanism regarding how chronic stress triggers such psychiatric dysfunctions, restraint-based chronic stress models have been attempted in the past. However, total durations of repeated restraint stress and the evaluation time points used after the last restraint application vary from experiment to experiment. One reason for these methodological heterogeneities is related to considerable ambiguity concerning the definition of chronic stress, particularly in animal models. In the present study, we used behavioral traits, anxiety and depression, as stress-assessment parameters that meet operationally useful requirements for the definition of the chronic stress state. We demonstrate that restraint treatment for 2 or 8 hr daily for 14 days is enough to produce anxiety- and depression-like behaviors, whereas a 2 hr-10 days restraint was marginally effective. cDNA microarray analysis identified 34 genes in the hippocampus and 72 genes in the amygdala with expression levels that were up- or down-regulated by >2.0-fold. Among the wide range of genes identified in this analysis, genes required for energy metabolism, signal transduction, transcription, synaptic plasticity, and remodeling of the brain architecture were notable. Our results suggest that the psychiatric criteria of anxiety and depression can be used as chronic stress-assessment parameters and that a restraint stress paradigm consisting of restraint treatment for 2 or 8 hr daily for 14 days could be used as a prototype paradigm for chronic stress studies.

  18. Chronic Creatine Supplementation Alters Depression-like Behavior in Rodents in a Sex-Dependent Manner

    PubMed Central

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

    2010-01-01

    Impairments in bioenergetic function, cellular resiliency, and structural plasticity are associated with the pathogenesis of mood disorders. Preliminary evidence suggests that creatine, an ergogenic compound known to promote cell survival and influence the production and usage of energy in the brain, can improve mood in treatment-resistant patients. This study examined the effects of chronic creatine supplementation using the forced swim test (FST), an animal model selectively sensitive to antidepressants with clinical efficacy in human beings. Thirty male (experiment 1) and 36 female (experiment 2) Sprague–Dawley rats were maintained on either chow alone or chow blended with either 2% w/w creatine monohydrate or 4% w/w creatine monohydrate for 5 weeks before the FST. Open field exploration and wire suspension tests were used to rule out general psychostimulant effects. Male rats maintained on 4% creatine displayed increased immobility in the FST as compared with controls with no differences by diet in the open field test, whereas female rats maintained on 4% creatine displayed decreased immobility in the FST and less anxiety in the open field test compared with controls. Open field and wire suspension tests confirmed that creatine supplementation did not produce differences in physical ability or motor function. The present findings suggest that creatine supplementation alters depression-like behavior in the FST in a sex-dependent manner in rodents, with female rats displaying an antidepressant-like response. Although the mechanisms of action are unclear, sex differences in creatine metabolism and the hormonal milieu are likely involved. PMID:19829292

  19. Neuroprotective effect of nebivolol against cisplatin-associated depressive-like behavior in rats.

    PubMed

    Abdelkader, Noha F; Saad, Muhammed A; Abdelsalam, Rania M

    2017-05-01

    One-third of cancer patients undergoing chemotherapy treatment often display symptoms of depression leading to poor adherence and decreased quality of life. Thus, this study aimed to investigate the possible protective effect of nebivolol against cisplatin-associated depressive symptoms in adult male rats. Nebivolol is a highly cardioselective β-adrenergic receptor blocker that possesses endothelium-dependent vasodilator properties and antioxidant capacities. Animals were allocated into four groups. Group one was given aqueous solution of carboxymethyl cellulose and served as control, group two was given nebivolol (10 mg/kg p.o., daily), group three was given cisplatin (2 mg/kg i.p. once per week) for 10 consecutive weeks and group four was treated with cisplatin concomitantly with nebivolol as per above schedule. Cisplatin-treated rats showed an increase in both depressive-like behaviors in open-field and forced swimming tests. In addition, histopathological examination revealed cortical encephalomalacia along with hippocampal neuronal degeneration and kidney dysfunction. In parallel, cisplatin administration prominently reduced GABA and elevated glutamate levels in the cortical and hippocampal tissues. Furthermore, it resulted in a significant decline in cortical and hippocampal brain-derived neurotrophic factor and nitric oxide contents concomitantly with a marked decrease in endothelial- and an increase in inducible-nitric oxide synthase genes expression. On the other hand, treatment with nebivolol effectively mitigated the aforementioned cisplatin-associated behavioral, biochemical, and histopathological alterations without changing its antitumor activity as evidenced by sulforhodamine B cell survival assay. Taken together, our results suggest that nebivolol may offer a promising approach for alleviating depressive symptoms associated with the use of cisplatin. © 2017 International Society for Neurochemistry.

  20. Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior.

    PubMed

    Ronovsky, Marianne; Berger, Stefanie; Zambon, Alice; Reisinger, Sonali N; Horvath, Orsolya; Pollak, Arnold; Lindtner, Claudia; Berger, Angelika; Pollak, Daniela D

    2017-07-01

    Gestational infection is increasingly being recognized for its involvement as causative mechanism in severe developmental brain abnormalities and its contribution to the pathogenesis of psychopathologies later in life. First observations in the widely accepted maternal immune activation (MIA) model based upon the systemic administration of the viral mimetic Polyinosinic:polycytidylic acid (poly(I:C)) have recently suggested a transmission of behavioral and transcriptional traits across generations. Although maternal care behavior (MCB) is known as essential mediator of the transgenerational effects of environmental challenges on offspring brain function and behavior, the possible propagation of alterations of MCB resulting from MIA to following generations has not yet been examined. Here we show that poly(I:C) stimulation at embryonic day 12.5 (E12.5) leads to aberrant MCB and that this effect is transmitted to the female F1 offspring. The transgenerational effects on MCB are paralleled by enhanced depression-like behavior in the second generation F2 offspring with contributions of both maternal and paternal heritages. Examination of offspring hippocampal expression of genes known as targets of MCB and relevant for ensuing non-genetic transmission of altered brain function and behavior revealed transgenerationally conserved and modified expressional patterns in the F1 and F2 generation. Collectively these data firstly demonstrate the transgenerational transmission of the impact of gestational immune activation on the reproductive care behavior of the mother. Behavioral and molecular characteristics of first and second generation offspring suggest transgenerationally imprinted consequences of gestational infection on psychopathological traits related to mood disorders which remain to be examined in future cross-fostering experiments. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Environmental manipulation affects depressive-like behaviours in female Wistar-Kyoto rats.

    PubMed

    Mileva, Guergana R; Bielajew, Catherine

    2015-10-15

    While the efficacy of pharmacological interventions to treat depression has been well-studied in animal models, much less work has been done to shed light on how changes in the immediate environment can impact behaviour. Furthermore, most studies have focused on male rodents despite the prevalence of mood disorders in women. In this study, 36 Wistar Kyoto (validated animal model of depression) and 36 Wistar (control) female rats were used to examine the effects of environmental manipulation on depressive- and anxiety-like behaviours. Animals were assigned to one of three groups: standard (3 rats/cage), enriched (6 rats/cage plus physical enrichment), and isolation (1 rat/cage) housing. The elevated plus maze (EPM) and forced swim test (FST) were conducted prior to, and four weeks after environmental assignment to measure anxiety-like and depressive-like behaviours, respectively. Sucrose preference assessed anhedonia both before and after environmental assignment. Weight was measured every week to monitor weight-gain over time. Post-environment sucrose preference was significantly increased in animals in enriched housing as compared to those in isolated housing in both strains. While there were significant differences between strains in measures of open arm duration in the EPM and immobility in the FST, there appeared to be no differences between environmental groups. The results of this study highlight the importance of environmental factors in the expression of anhedonia. Enrichment appears to reduce anhedonia while isolation increases anhedonia. These effects should be studied further to assess whether longer periods of social and physical enrichment alleviate other symptoms of depression.

  2. Adoptive transfer of macrophage from mice with depression-like behavior enhances susceptibility to colitis.

    PubMed

    Ghia, Jean-Eric; Park, Amber J; Blennerhassett, Patricia; Khan, Waliul I; Collins, Stephen M

    2011-07-01

    Depression is common in patients with inflammatory bowel disease (IBD) but the pathway is not well understood. We examined whether the locus of susceptibility to colitis in mice with depression-like behavior (DLB) resides with the macrophage and implicates the vagus nerve. Chronic colitis mimicking ulcerative colitis (UC) was induced by dextran sulfate sodium administered to C57BL/6-mice. Depression was induced by intracerebroventricular infusion of reserpine in healthy or vagotomized mice treated with antidepressant desmethylimipramine (DMI). Colitis was assessed macroscopically, histologically, and by C-reactive protein measurement in serum and by cytokines in colonic samples. Cytokine release was measured on macrophages isolated from these models. Naive macrophage colony-stimulating factor-deficient mice (op/op) were injected with peritoneal macrophages obtained from the different groups and acute colitis was induced. Vagotomy reactivated inflammation in mice with chronic colitis. DLB reactivated colitis and this was prevented by DMI only in mice with intact vagi. Macrophages isolated from vagotomized or DLB-mice showed a selective increase of proinflammatory cytokine release and this was not seen in macrophages isolated from DLB-DMI-treated mice; moreover, vagotomy abolished this beneficial effect. In op/op, adoptive transfer of macrophages from non-DLB mice significantly increased the inflammatory markers. These parameters were significantly increased when transferred with macrophages isolated from DLB or VXP mice. Op/op mice that received macrophages from DLB-DMI-treated mice showed a significant decrease of all parameters and vagotomy abolished this effect. These data identify the critical role of macrophage in linking depression and susceptibility to intestinal inflammation via the vagus nerve. The results provide a basis for developing new approaches to the management of UC patients with coexisting depression by rebalancing cytokine production by the cell

  3. Depressive-like behavior in adrenocorticotropic hormone-treated rats blocked by memantine.

    PubMed

    Tokita, Kenichi; Fujita, Yuko; Yamaji, Takayuki; Hashimoto, Kenji

    2012-08-01

    Hyperactivity of the hypothalamic pituitary-adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-D-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and D-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100 μg/rat/day, sc, for 14 days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, L-serine, and D-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, L-serine, and D-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10 mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15 mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.

  4. The forced swim test as a model of depressive-like behavior.

    PubMed

    Yankelevitch-Yahav, Roni; Franko, Motty; Huly, Avrham; Doron, Ravid

    2015-03-02

    The goal of the present protocol is to describe the forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. The FST is based on the assumption that when placing an animal in a container filled with water, it will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair. This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors that are influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia. The main advantages of this procedure are that it is relatively easy to perform and that its results are easily and quickly analyzed. Moreover, its sensitivity to a broad range of antidepressant drugs that makes it a suitable screening test is one of the most important features leading to its high predictive validity. Despite its appeal, this model has a number of disadvantages. First, the issue of chronic augmentation is problematic in this test because in real life patients need to be treated for at least several weeks before they experience any relief from their symptoms. Last, due to the aversiveness of the FST, it is important to take into account possible influences it might have on brain structure/function if brain analyses are to be carried out following this procedure.

  5. The Forced Swim Test as a Model of Depressive-like Behavior

    PubMed Central

    Yankelevitch-Yahav, Roni; Franko, Motty; Huly, Avrham; Doron, Ravid

    2015-01-01

    The goal of the present protocol is to describe the forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. The FST is based on the assumption that when placing an animal in a container filled with water, it will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair. This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors that are influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia. The main advantages of this procedure are that it is relatively easy to perform and that its results are easily and quickly analyzed. Moreover, its sensitivity to a broad range of antidepressant drugs that makes it a suitable screening test is one of the most important features leading to its high predictive validity. Despite its appeal, this model has a number of disadvantages. First, the issue of chronic augmentation is problematic in this test because in real life patients need to be treated for at least several weeks before they experience any relief from their symptoms. Last, due to the aversiveness of the FST, it is important to take into account possible influences it might have on brain structure/function if brain analyses are to be carried out following this procedure. PMID:25867960

  6. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice.

    PubMed

    Walker, Adam K; Budac, David P; Bisulco, Stephanie; Lee, Anna W; Smith, Robin A; Beenders, Brent; Kelley, Keith W; Dantzer, Robert

    2013-08-01

    We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA

  7. 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.

  8. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats

    PubMed Central

    Li, Jiali; Luo, Yixiao; Zhang, Ruoxi; Shi, Haishui; Zhu, Weili; Shi, Jie

    2015-01-01

    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. PMID:26633367

  9. Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A

    PubMed Central

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2015-01-01

    Abstract Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 μg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression. PMID:26060449

  10. Female rats exposed to stress and alcohol show impaired memory and increased depressive-like behaviors.

    PubMed

    Gomez, J L; Luine, V N

    2014-01-17

    Exposure to daily life stressors is associated with increases in anxiety, depression, and overall negative affect. Alcohol or other psychoactive drugs are often used to alleviate stress effects. While females are more than twice as likely to develop mood disorders and are more susceptible to dependency than males, they are infrequently examined. In this study, female rats received no stress/no alcohol control (CON), alcohol alone (ALC), stress alone (STR), or stress plus alcohol (STR+ALC). Stress consisted of restraint for 6h/day/7days, and alcohol was administered immediately following restraint via gastric gavage at a dose of 2.0g/kg. Dependent measures included tests utilizing object recognition (OR), Y-maze, elevated plus maze (EPM), forced swim (FST), blood alcohol content, corticosterone levels, and body weights. ALC, STR+ALC, but not stress alone, impaired memory on OR. All treatments impaired spatial memory on the Y-maze. Anxiety was not affected on the EPM, but rats treated with alcohol or in combination with stress showed increased immobility on the FST, suggestive of alcohol-induced depression. Previously, we found alcohol reversed deleterious effects of stress on memory and mood in males, but current results show that females reacted negatively when the two treatments were combined. Thus, responses to alcohol, stress and their combination suggest that sex specific treatments are needed for stress-induced behavioral changes and that self-medicating with alcohol to cope with stress maybe deleterious in females.

  11. 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 Me

  12. Berberine up-regulates the BDNF expression in hippocampus and attenuates corticosterone-induced depressive-like behavior in mice.

    PubMed

    Shen, Ji-Duo; Ma, Li-Gang; Hu, Chun-Yue; Pei, Yang-Yi; Jin, Shuang-Li; Fang, Xiao-Yan; Li, Yu-Cheng

    2016-02-12

    Depression is increasingly become a global public healthy problem. This study was to investigate whether berberine could attenuate the depressive-like behavior induced by repeated corticosterone injection and explore the possible mechanisms. The present results showed that exogenous corticosterone injection caused depressive-like behaviors in mice, such as decreased sucrose intake in sucrose preference test (SPT) and increased immobility time in forced swimming test (FST). These behavioral alterations were accompanying with the decreased BDNF mRNA and protein levels in hippocampus and the elevated serum corticosterone levels. Treatment with berberine prevented these changes above. Our findings confirmed the antidepressant-like effect of berberine and suggested its mechanisms might be partially mediated by up-regulation of BDNF in hippocampus.

  13. Effect of Electroconvulsive Therapy on Cognitive Functions of Rats with Depression-Like Disorders Induced by Ultrasound Exposure.

    PubMed

    Ushakova, V M; Zubkov, E A; Morozova, A Y; Gorlova, A V; Pavlov, D A; Inozemtsev, A N; Chekhonin, V P

    2017-09-01

    We studied the effect of electroconvulsive therapy on cognitive functions in rats with depression-like disorder caused by exposure to ultrasound of varying frequency (20-45 kHz). Object recognition and Morris water-maze tests revealed no negative effects of the therapy on memory. Moreover, positive effect of therapy was demonstrated that manifested in amelioration of memory disturbances in depression-like disorders in these behavioral tests. The results of this study do not support the idea about side effects of electroconvulsive therapy, in particular, development of transient amnesia, and are a prerequisite for a more thorough study of internal mechanisms of the effect of the therapy on cognitive sphere.

  14. Alterations in splenic function and gene expression in mice with depressive-like behavior induced by exposure to corticosterone

    PubMed Central

    Zhan, Heqin; Huang, Feng; Yan, Fulin; Zhao, Zhenghang; Zhang, Jixia; Cui, Taizhen; Yang, Fan; Hai, Guangfan; Jia, Xiaoman; Shi, Yongji

    2017-01-01

    Depressed patients present with increased cortisol levels and attenuated immune responses. However, little is known about the association between depression and the spleen, as this is the largest peripheral immune organ. In this study, we examined alterations in splenic function and gene expression in mice with depressive-like behavior, well as the expression of certain proteins in related pathways. A mouse model of depression was established with the use of corticosterone. Splenic function and histopathology were assessed using Wright and H&E staining. The Agilent Whole Mouse Genome Oligo Microarray containing >41,174 transcript probes was used to measure the levels of gene-expression in the spleens from control and model mice, and the levels of certain proteins associated with depression were measured by western blot analysis in the brain and spleen separately. We found that splenic function and immunity in the mice with depressive-like behavior were markedly impaired. A total of 53 genes exhibited a differential response in the mice with depressive-like behavior, 11 of which were more notable, including collagen, type VI, α5 (Col6a5), immunoglobulin superfamily, member 11 (Igsf11), D site albumin promoter binding protein (Dbp), tachykinin 2 (Tac2) and γ-aminobutyric acid B receptor 2 (Gabbr2). Pathway analysis revealed that the amino acid biosynthesis and the clock gene pathways were more meaningful among these genes. The levels of GABBR2, DBP and substance P (SP; encoded by the Tac2 gene) related proteins in the brain were markedly downregulated, and similar results were observed in the spleen. The anti-depressant, fluoxetine, reversed the changes in the levels of these proteins. The findings of our study regarding changes occurring in the spleen during depression may indirectly elucidate and shed light into the pathogenesis of depression and depressive-like behavior. PMID:28075471

  15. Constant darkness induces IL-6-dependent depression-like behavior through the NF-κB signaling pathway.

    PubMed

    Monje, Francisco J; Cabatic, Maureen; Divisch, Isabella; Kim, Eun-Jung; Herkner, Kurt R; Binder, Bernd R; Pollak, Daniela D

    2011-06-22

    Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression.

  16. Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model.

    PubMed

    Zhang, Guang-Fen; Wang, Jing; Han, Jin-Feng; Guo, Jie; Xie, Ze-Min; Pan, Wei; Yang, Jian-Jun; Sun, Kang-Jian

    2016-09-19

    Both chronic pain and depression are debilitating diseases, which often coexist in clinic. However, current analgesics and antidepressants exhibit limited efficacy for this comorbidity. The present study aimed to investigate the effect of ketamine on the comorbidity of inflammatory pain and consequent depression-like behaviors in a rat model established by intraplantar administration of complete Freunds adjuvant (CFA). The mechanical withdrawal threshold, thermal withdrawal latency, open field test, forced swimming test, and sucrose preference test were evaluated after the CFA injection and ketamine treatment. The hippocampus was harvested to determine the levels of interleukin (IL)-6, IL-1β, indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), 5-hydroxytryptamine (5-HT), and tryptophan (TRP). The inflammatory pain-induced depression-like behaviors presented on 7days and lasted to at least 14days after the CFA injection. Single dose of ketamine at 20mg/kg relieved both the mechanical allodynia and the associated depression-like behaviors as demonstrated by the attenuated mechanical withdrawal threshold, reduced immobility time in the forced swim test, and increased sucrose preference after ketamine treatment. The total distance had no significant change after the CFA injection or ketamine treatment in the open field test. Simultaneously, ketamine reduced the levels of IL-6, IL-1β, IDO, and KYN/TRP ratio and increased the 5-HT/TRP ratio in the hippocampus. In conclusion, acute single dose of ketamine can rapidly attenuate mechanical allodynia and consequent depression-like behaviors and down-regulate hippocampal proinflammatory responses and IDO/KYN signal pathway in rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

    PubMed

    Posillico, Caitlin K; Schwarz, Jaclyn M

    2016-02-01

    Postpartum depression is a specific type of depression that affects approximately 10-15% of mothers [28]. 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.

  18. 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

  19. Age-dependent regulation of depression-like behaviors through modulation of adrenergic receptor α₁A subtype expression revealed by the analysis of interleukin-1 receptor antagonist knockout mice.

    PubMed

    Wakabayashi, C; Kiyama, Y; Kunugi, H; Manabe, T; Iwakura, Y

    2011-09-29

    Interleukin-1 (IL-1) plays a crucial role in stress responses and its mRNA is induced in the brain by stress load; however, the precise role of IL-1 in higher brain functions and their abnormalities is largely unknown. Here, we report that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lack IL-1Ra molecules that antagonize the IL-1 receptor, displayed anti-depression-like phenotypes in the tail suspension test (TST) and forced-swim test (FST) only at a young stage (8 weeks), whereas the phenotypes disappeared at later stages (20 and 32 weeks). These anti-depression-like phenotypes were reversed by administration of adrenergic receptor (AR) antagonists against the ARα(1), ARα(2), and ARβ subtypes. Although the contents of 5-HT, norepinephrine (NE), and dopamine (DA), which are known to be associated with major symptoms of psychiatric disorders, were not significantly different in the hippocampus or cerebral cortex between IL-1Ra KO and their wild-type (WT) littermate mice, the mRNA expression level of the ARα(1A) subtype was significantly changed in the cerebral cortex. Interestingly, the change in expression of the ARα(1A) subtype was correlated with an age-dependent alteration in the TST and FST in IL-1Ra KO mice. Furthermore, mild immobilization stress loaded on C57BL/6J male mice caused similar anti-depression-like phenotypes in the TST and FST to those observed in mutant mice. These results suggest that sustained activation of IL-1 signaling induced by gene manipulation in mutant mice affects the expression of the ARα(1A) subtype and that modification of adrenergic signaling by the IL-1 system may ultimately cause significant psychiatric abnormalities such as depression, and this mutant mouse could be regarded as a model animal of depression that specifically appears in children and adolescents.

  20. Rapid Amygdala Kindling Causes Motor Seizure and Comorbidity of Anxiety- and Depression-Like Behaviors in Rats

    PubMed Central

    Chen, Shang-Der; Wang, Yu-Lin; Liang, Sheng-Fu; Shaw, Fu-Zen

    2016-01-01

    Amygdala kindling is a model of temporal lobe epilepsy (TLE) with convulsion. The rapid amygdala kindling has an advantage on quick development of motor seizures and for antiepileptic drugs screening. The rapid amygdala kindling causes epileptogenesis accompanied by an anxiolytic response in early isolation of rat pups or depressive behavior in immature rats. However, the effect of rapid amygdala kindling on comorbidity of anxiety- and depression-like behaviors is unexplored in adult rats with normal breeding. In the present study, 40 amygdala stimulations given within 2 days were applied in adult Wistar rats. Afterdischarge (AD) and seizure stage were recorded throughout the amygdala kindling. Anxiety-like behaviors were evaluated by the elevated plus maze (EPM) test and open field (OF) test, whereas depression-like behaviors were assessed by the forced swim (FS) and sucrose consumption (SC) tests. A tonic-clonic convulsion was provoked in the kindle group. Rapid amygdala kindling resulted in a significantly lower frequency entering an open area of either open arms of the EPM or the central zone of an OF, lower sucrose intake, and longer immobility of the FS test in the kindle group. Our results suggest that rapid amygdala kindling elicited severe motor seizures comorbid with anxiety- and depression-like behaviors. PMID:27445726

  1. Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey.

    PubMed

    Landgraf, Dominic; Long, Jaimie E; Welsh, David K

    2016-05-01

    An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined.

  2. A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice.

    PubMed

    Silva, Carlos D; Neves, Ana F; Dias, Ana I; Freitas, Hugo J; Mendes, Sheena M; Pita, Inês; Viana, Sofia D; de Oliveira, Paulo A; Cunha, Rodrigo A; Fontes Ribeiro, Carlos A; Prediger, Rui D; Pereira, Frederico C

    2014-04-01

    Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.

  3. Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats.

    PubMed

    Fischer, Christina Weide; Eskelund, Amanda; Budac, David P; Tillmann, Sandra; Liebenberg, Nico; Elfving, Betina; Wegener, Gregers

    2015-10-15

    Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain. The following treatment groups were used: Control (saline), IFN-α (6×10(4)IU/kg s.c.), IFN-α+imipramine or IFN-α+celecoxib. Drugs were administered daily for 1 week. IFN-α treatment induced depression-like behaviour by increasing immobility in the forced swim test (FST), and decreased tryptophan levels in the brain. There was a trend for an increased kynurenine/tryptophan ratio, indicative of indoleamine 2,3-dioxygenase (IDO) activation, and increased quinolinic acid in the hippocampus. Imipramine decreased immobility in the FST, but did not reverse the IFN-α-induced changes in the tryptophan-kynurenine pathway. There was a trend for celecoxib to decrease immobility and to reverse the IFN-α-induced increase in the kynurenine/tryptophan ratio. Thus, our study provides further evidence for IFN-α-induced depression-like behaviour through central changes of the tryptophan-kynurenine pathway.

  4. [Rapid eye-movement sleep for five days deprivation causes delayed depressive-like behavior in mice].

    PubMed

    Chen, Lu; Wang, Zhen; Wang, Xue-Min

    2016-05-01

    To observe the effect of rapid eye movement sleep deprivation (REMSD) for 5 days on depressive-like behavior and monoamine oxidase A (MAOA) expression in the amygdale of mice. Adult male C57BL/6J mice were divided into blank control group, control group and REMSD group. REMSD models were established by a modified multiple small platform method. The mice were examined for locomotive activity in open field test (OFT) and for depressive-like behavior in forced swimming test (FST) and sucrose preference test (SPT) after treatment. After all the tests, the protein and mRNA expressions of MAOA in the amygdala were detected with Western blotting and real-time PCR, respectively. REMSD for 5 days significantly impaired the locomotive activity of the mice, which was obvious in 1 to 3 days after REMSD. The locomotive activity became normal on day 4 after the 5-day REMSD. The immobility time of the mice was lengthened in days 7 to 14 (P<0.01), and sucrose preference rate was reduced significantly in days 8 and 9 (P<0.01). The expression level of MAOA in the amygdala was increased significantly after the 5-day REMSD (P<0.01). REMSD for 5 days causes delayed depressive-like behavior in mice possible in relation with the increased expression of MAOA in the amygdale.

  5. 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.

  6. 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

  7. bi-3-azaoxoisoaporphine derivatives have antidepressive properties in a murine model of post stroke-depressive like behavior.

    PubMed

    Nabavi, Seyed Fazel; Sobarzo-Sánchez, Eduardo; Nabavi, Seyed Mohammad; Sureda, Antoni; Moghaddam, Akbar Hajizadeh

    2013-05-01

    In the present study, three bi-3-azaoxoisoaporphine derivatives were synthesized and intracerebroventricularly administrated to BALB/c mice. The antidepressant actions in stroke-induced depressive like behavior in mice were examined using despair swimming test and tail suspension test. The results reported that bilateral common carotid arteries occlusion caused a significant abnormality of the normal behaviors. Behavioral models demonstrated that synthesized compounds showed antidepressant action. The most antidepressant active compound was DIME2 (4,4'-dimethyl-7H,7'H- [6,6'-bibenzo[e]perimidine]-7,7'-dione), which decreased the immobility time and increased the swimming and climbing times in despair swimming model. DIME2 also showed similar results in decreasing the immobility time in the tail suspension model. In open field tests, DIME2 at 0.1 μg/μl showed a significant activity in the modification of the distance movement and the number and duration of rearing versus bilateral common carotid arteries occlusion (P<0.001). Furthermore, bilateral common carotid arteries occlusion caused a significant increase in the water consumption and significant decreasing in the sucrose consumption which are indicated as a state of anhedonia, a well known common symptom of transient ischemic stroke-induced depressive like behavior, versus normal group (P<0.001). In conclusion, bi- 3-azaoxoisoaporphine derivatives can be considered as antidepressant agents for post stroke-induced depressive like behavior therapy.

  8. Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat.

    PubMed

    Amorim, Diana; Puga, Sónia; Bragança, Rui; Braga, António; Pertovaara, Antti; Almeida, Armando; Pinto-Ribeiro, Filipa

    2017-03-08

    A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.

  9. Imipramine protects against the deleterious effects of chronic corticosterone on depression-like behavior, hippocampal reelin expression, and neuronal maturation.

    PubMed

    Fenton, Erin Y; Fournier, Neil M; Lussier, April L; Romay-Tallon, Raquel; Caruncho, Hector J; Kalynchuk, Lisa E

    2015-07-03

    We have hypothesized that a downregulation of reelin and deficient maturation of adult-born hippocampal neurons are important factors in the pathogenesis of depression. This hypothesis is based on previous work showing that depression-like behavior in rats treated with protracted corticosterone develops in concert with decreased dendritic complexity in newborn hippocampal granule neurons and decreased reelin expression in the proliferative subgranular zone of the dentate gyrus. In addition, heterozygous reeler mice with approximately 50% of normal brain levels of reelin are more vulnerable to the depressogenic effects of corticosterone than wild-type mice. The purpose of this experiment was to provide pharmacological validation for the link between reelin, neuronal maturation, and depression by examining whether the deleterious effects of corticosterone on these measures could be prevented by co-administration of the antidepressant imipramine. Rats received corticosterone injections, corticosterone injections plus either 10 or 15mg/kg imipramine injections, or vehicle injections for 21 consecutive days. They were then subjected to the forced swim test to assess depression-like behavior and sacrificed for immunohistochemical examination of immature neuron number and dendritic complexity and the presence of reelin+cells. We found that corticosterone increases depression-like behavior, decreases the number of reelin+cells in the subgranular zone, and decreases the number and complexity of immature neurons in the granule cell layer. All of these behavioral and cellular phenotypes were prevented by imipramine, providing further support for the idea that reelin is involved in the pathogenesis of depression.

  10. Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice.

    PubMed

    Ge, Li; Liu, Liwei; Liu, Hansen; Liu, Song; Xue, Hao; Wang, Xueer; Yuan, Lin; Wang, Zhen; Liu, Dexiang

    2015-12-05

    Current evidence supports that depression is accompanied by the activation of the inflammatory-response system, and overproduction of pro-inflammatory cytokines may play a role in the pathophysiology of depressive disorders. Resveratrol has anti-inflammatory, antioxidant and anti-depressant-like properties. Using an animal model of depression induced by a single administration of lipopolysaccharide (LPS), the present study investigated the effects of resveratrol on LPS-induced depressive-like behavior and inflammatory-response in adult mice. Our results showed that pretreatment with resveratrol (80mg/kg, i.p.) for 7 consecutive days reversed LPS-increased the immobility time in the forced swimming test and tail suspension test, and LPS-reduced sucrose preference test. Moreover, the antidepressant action of resveratrol was paralleled by significantly reducing the expression levels of pro-inflammatory cytokines, and up-regulating phosphorylated cAMP response-element-binding protein (pCREB)/brain-derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC) and hippocampus. In addition, resveratrol ameliorated LPS-induced NF-κB activation in the PFC and hippocampus. The results demonstrate that resveratrol may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude and by modulating pCREB and BDNF expression in the brain region of mice.

  11. Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats

    PubMed Central

    Li, Xiao-Li; Yuan, Yong-Gui; Xu, Hua; Wu, Di; Gong, Wei-Gang; Geng, Lei-Yu; Wu, Fang-Fang; Tang, Hao; Xu, Lin

    2015-01-01

    Background: Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment. Methods: Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests. Results: The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats. Conclusion: These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration. PMID:25899067

  12. DHEA administration modulates stress-induced analgesia in rats.

    PubMed

    Cecconello, Ana Lúcia; Torres, Iraci L S; Oliveira, Carla; Zanini, Priscila; Niches, Gabriela; Ribeiro, Maria Flávia Marques

    2016-04-01

    An important aspect of adaptive stress response is the pain response suppression that occurs during or following stress exposure, which is often referred to as acute stress-induced analgesia. Dehydroepiandrosterone (DHEA) participates in the modulation of adaptive stress response, changing the HPA axis activity. The effect of DHEA on the HPA axis activity is dependent on the state and uses the same systems that participate in the regulation of acute stress-induced analgesia. The impact of DHEA on nociception has been studied; however, the effect of DHEA on stress-induced analgesia is not known. Thus, the aim of the present study was to evaluate the effect of DHEA on stress-induced analgesia and determine the best time for hormone administration in relation to exposure to stressor stimulus. The animals were stressed by restraint for 1h in a single exposure and received treatment with DHEA by a single injection before the stress or a single injection after the stress. Nociception was assessed with a tail-flick apparatus. Serum corticosterone levels were measured. DHEA administered before exposure to stress prolonged the acute stress-induced analgesia. This effect was not observed when the DHEA was administered after the stress. DHEA treatment in non-stressed rats did not alter the nociceptive threshold, suggesting that the DHEA effect on nociception is state-dependent. The injection of DHEA had the same effect as exposure to acute stress, with both increasing the levels of corticosterone. In conclusion, acute treatment with DHEA mimics the response to acute stress indexed by an increase in activity of the HPA axis. The treatment with DHEA before stress exposure may facilitate adaptive stress response, prolonging acute stress-induced analgesia, which may be a therapeutic strategy of interest to clinics.

  13. SCO2 Mediates Oxidative Stress-Induced Glycolysis to Oxidative Phosphorylation Switch in Hematopoietic Stem Cells.

    PubMed

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F; Pang, Qishen

    2016-04-01

    Fanconi anemia (FA) is an inherited bone marrow (BM) failure syndrome, presumably resulting from defects in hematopoietic stem cells (HSCs). Normal HSCs depend more on glycolysis than on oxidative phosphorylation (OXPHOS) for energy production. Here, we show that FA HSCs are more sensitive to the respiration inhibitor NaN3 treatment than to glycolytic inhibitor 2-deoxy-d-glucose (2-DG), indicating more dependence on OXPHOS. FA HSCs undergo glycolysis-to-OXPHOS switch in response to oxidative stress through a p53-dependent mechanism. Metabolic stresses induce upregulation of p53 metabolic targets in FA HSCs. Inactivation of p53 in FA HSCs prevents glycolysis-to-OXPHOS switch. Furthermore, p53-deficient FA HSCs are more sensitive to 2-DG-mediated metabolic stress. Finally, oxidative stress-induced glycolysis-to-OXPHOS switch is mediated by synthesis of cytochrome c oxidase 2 (SCO2). These findings demonstrate p53-mediated OXPHOS function as a compensatory alteration in FA HSCs to ensure a functional but mildly impaired energy metabolism and suggest a cautious approach to manipulating p53 signaling in FA. © 2015 AlphaMed Press.

  14. Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

    PubMed

    Mehta, Vineet; Parashar, Arun; Udayabanu, Malairaman

    2017-03-15

    It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Increased thermal and mechanical nociceptive thresholds in rats with depressive-like behaviors

    PubMed Central

    Shi, Miao; Qi, Wei-Jing; Gao, Ge; Wang, Jin-Yan; Luo, Fei

    2010-01-01

    Clinical observations suggest that depressed patients were less sensitive to experimental pain than healthy subjects. However, few animal studies are reported concerning the association of depression and pain. The purpose of this study was to investigate the effects of unpredictable chronic mild stress (UCMS) induced depression on the perceived intensity of painful stimulation in rats. We measured the thermal and mechanical paw withdrawal thresholds (PWT) of normal and spinal nerve ligated (SNL) rats using hot plate test and von Frey test, respectively. The results showed that rats exposed to UCMS exhibited significantly higher thermal and mechanical pain thresholds in comparison to the non-depressed controls. In particular, the PWT of the SNL group was restored to nearly normal level after three weeks of UCMS, and even comparable to that of the control group. These results strongly suggest that the depressed subjects have decreased sensitivity to externally applied noxious stimulation, which is consistent with our previous findings. Research Highlight ▶ Unpredictable chronic mild stress (UCMS) induces depressive behaviors in rats ▶ UCMS elevates contact heat paw withdrawal threshold in normal rats ▶ UCMS elevates mechanical paw withdrawal threshold in normal rats ▶ UCMS elevates mechanical paw withdrawal threshold in SNL rats PMID:20637742

  16. Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine

    PubMed Central

    Szot, Patricia; Franklin, Allyn; Miguelez, Cristina; Wang, Yangqing; Vidaurrazaga, Igor; Ugedo, Luisa; Sikkema, Carl; Wilkinson, Charles W.; Raskind, Murray A.

    2016-01-01

    Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer’s disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 μg/μl), animals administered the 5 μg/μl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 μg/μl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 μg/μl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 μg/μl dose of 6-OHDA with a second behavior test, sucrose consumption. FTS increased immobility following 6-OHDA (5 μg/μl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or L-threo-3

  17. R&D 100, 2016: Stress-Induced Fabrication

    ScienceCinema

    Fan, Hongyou; Brennan, Tom; Wise, Jack; Liu, Sheng; Hickman, Randy

    2016-12-09

    Stress-induced fabrication (SIF) uses compressive mechanical stress to create new nanomaterials with lower production costs and enhanced materials performance compared to traditional fabrication routes. Simple, innovative, and with more degrees of freedom than current chemical synthesis methods, SIF uses physical force instead of chemistry applied to form new nanomaterials with precisely controlled structure and tunable properties.

  18. Salubrious effects of oxytocin on social stress-induced deficits

    PubMed Central

    Smith, Adam S.; Wang, Zuoxin

    2012-01-01

    Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While social interactions can attenuate stress and promote health, disruption, confrontations, isolation, or neglect in the social environment can each be major stressors. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. PMID:22178036

  19. R&D 100, 2016: Stress-Induced Fabrication

    SciTech Connect

    Fan, Hongyou; Brennan, Tom; Wise, Jack; Liu, Sheng; Hickman, Randy

    2016-11-07

    Stress-induced fabrication (SIF) uses compressive mechanical stress to create new nanomaterials with lower production costs and enhanced materials performance compared to traditional fabrication routes. Simple, innovative, and with more degrees of freedom than current chemical synthesis methods, SIF uses physical force instead of chemistry applied to form new nanomaterials with precisely controlled structure and tunable properties.

  20. Strategies to ameliorate abiotic stress-induced plant senescence.

    PubMed

    Gepstein, Shimon; Glick, Bernard R

    2013-08-01

    The plant senescence syndrome resembles, in many molecular and phenotypic aspects, plant responses to abiotic stresses. Both processes have an enormous negative global agro-economic impact and endanger food security worldwide. Premature plant senescence is the main cause of losses in grain filling and biomass yield due to leaf yellowing and deteriorated photosynthesis, and is also responsible for the losses resulting from the short shelf life of many vegetables and fruits. Under abiotic stress conditions the yield losses are often even greater. The primary challenge in agricultural sciences today is to develop technologies that will increase food production and sustainability of agriculture especially under environmentally limiting conditions. In this chapter, some of the mechanisms involved in abiotic stress-induced plant senescence are discussed. Recent studies have shown that crop yield and nutritional values can be altered as well as plant stress tolerance through manipulating the timing of senescence. It is often difficult to separate the effects of age-dependent senescence from stress-induced senescence since both share many biochemical processes and ultimately result in plant death. The focus of this review is on abiotic stress-induced senescence. Here, a number of the major approaches that have been developed to ameliorate some of the effects of abiotic stress-induced plant senescence are considered and discussed. Some approaches mimic the mechanisms already used by some plants and soil bacteria whereas others are based on development of new improved transgenic plants. While there may not be one simple strategy that can effectively decrease all losses of crop yield that accrue as a consequence of abiotic stress-induced plant senescence, some of the strategies that are discussed already show great promise.

  1. Anxiety- and depressive-like profiles during early- and mid-adolescence in the female Wistar Kyoto rat.

    PubMed

    D'Souza, Deepthi; Sadananda, Monika

    2017-02-01

    Approaches for the development of preclinical models of depression extensively use adult and male animals owing to the discrepancies arising out of the hormonal flux in adult females and adolescents during attainment of puberty. Thus the increased vulnerability of females towards clinical depression and anxiety-related disorders remains incompletely understood. Development of clinical models of depression in adolescent females is essential in order to evolve effective treatment strategies for adolescent depression. In the present study, we have examined the anxiety and depressive-like profiles in a putative animal model of childhood depression, the Wistar Kyoto (WKY) rat, during early adolescence (∼postnatal day 30) and mid-adolescence (∼postnatal day 40). Female adolescent WKY rats, tested on a series of behavioural tests modelling anxiety- and depressive-like behaviours with age-matched Wistars as controls, demonstrated marked differences during early adolescence in a strain- and age-specific manner. Anxiety indices were obtained from exposure to the elevated plus maze, where social communication vide 50-kHz ultrasonic vocalizations was also assessed, while immobility and other parameters in the forced swim test were screened for depressive-like profiles. Sucrose preference, used as a measure of anhedonia in animals, was lower in WKYs at both ages tested and decreased with age. Anxiety-related behaviours were prominent in WKY rats only during early adolescence. WKY female rats are anxious during early adolescence and exhibit anhedonia as a core symptom of depression during early- and mid-adolescence, thus indicating that inclusion of female animals in preclinical trials is essential and will contribute to gender-based approaches to diagnosis and treatment of adolescent depression in females. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

  2. Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

    PubMed Central

    Tong, Jian-Bin; Wong, Richard; Ching, Yick-Pang; Qiu, Guang; Tang, Siu-Wa; Lee, Tatia M. C.; So, Kwok-Fai

    2011-01-01

    Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress. PMID:21935393

  3. Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice.

    PubMed

    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 (VWR) would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4- and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (VWR) or no wheel (standard) for 30 (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 24 h (aged mice) after injection of LPS, mRNA transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. Prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences in young adult and aged mice. © 2013 S. Karger AG, Basel.

  4. Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin.

    PubMed

    Sulakhiya, Kunjbihari; Keshavlal, Gohil Pratik; Bezbaruah, Babul B; Dwivedi, Shubham; Gurjar, Satendra Singh; Munde, Nitin; Jangra, Ashok; Lahkar, Mangala; Gogoi, Ranadeep

    2016-01-12

    Inflammation and oxidative stress are involved in the pathophysiology of anxiety and depression. Esculetin (ESC), a coumarin derived potent antioxidant, also possessing anti-inflammatory and neuroprotective activity. This study investigated the effect of ESC in lipopolysaccharide (LPS)-induced anxiety- and depressive-like behaviour in mice. ESC (25 and 50mg/kg, p.o.) was administered daily for 14 days, and challenged with saline or LPS (0.83mg/kg; i.p.) on the 15th day. Behavioural paradigms such as elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were employed to assess anxiety- and depressive-like behaviour in mice post-LPS injection. Hippocampal cytokines, MDA and GSH level, and plasma corticosterone (CORT) were measured. ESC pre-treatment significantly (P<0.05) attenuated LPS-induced anxiety-like behaviour by modulating EPM and OFT parameters. Moreover, LPS-induced increase in immobility time in FST and TST were also prevented significantly (P<0.05) by ESC (50mg/kg). ESC pre-treatment ameliorated LPS-induced neuroinflammation by attenuating brain IL-1β, IL-6, TNF-α level, and oxidative stress as well as plasma CORT level. In conclusion, the results suggest that ESC prevented LPS-induced anxiety- and depressive-like behaviour which may be governed by inhibition of cytokine production, oxidative stress and plasma CORT level. The results support the potential usefulness of ESC in the treatment of psychiatric disorders associated with inflammation and oxidative stress.

  5. 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.

  6. 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

  7. Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas.

    PubMed

    Réus, Gislaine Z; Dos Santos, Maria Augusta B; Abelaira, Helena M; Titus, Stephanie E; Carlessi, Anelise S; Matias, Beatriz I; Bruchchen, Livia; Florentino, Drielly; Vieira, Andriele; Petronilho, Fabricia; Ceretta, Luciane B; Zugno, Alexandra I; Quevedo, João

    2016-03-01

    Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.

    PubMed

    Chabry, Joëlle; Nicolas, Sarah; Cazareth, Julie; Murris, Emilie; Guyon, Alice; Glaichenhaus, Nicolas; Heurteaux, Catherine; Petit-Paitel, Agnès

    2015-11-01

    Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Chrysin promotes attenuation of depressive-like behavior and hippocampal dysfunction resulting from olfactory bulbectomy in mice.

    PubMed

    Filho, Carlos Borges; Jesse, Cristiano Ricardo; Donato, Franciele; Del Fabbro, Lucian; Gomes de Gomes, Marcelo; Rossito Goes, André Tiago; Souza, Leandro Cattelan; Boeira, Silvana Peterini

    2016-12-25

    Chrysin is a natural flavonoid which is found in bee propolis, honey and various plants, and antidepressant-like effect of chrysin in chronically stressed mice was previously demonstrated by our group. In this work, we investigated the action of chrysin treatment (5 or 20 mg/kg) for 14 days in the depressant-like behavior and in the hippocampal dysfunction induced by olfactory bulbectomy (OB), an animal model of agitated depression. Results demonstrated that OB occasioned a depressant-like behavior in the splash test, open field test and forced swimming test. Chrysin administration, similarly to fluoxetine (positive control), promoted the attenuation of these behavioral modifications. OB also caused the elevation of tumor necrosis factor-α, interferon-γ, interleukin-1β, interleukin-6, kynurenine (KYN) levels and indoleamine-2,3-dioxygenase activity, as well as occasioned the decrease of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) levels and increase KYN/tryptophan and 5-hydroxyindoleacetic acid/5-HT ratio in the hippocampus. Chrysin therapy prevented against all these alterations in the hippocampus. In addition, chrysin treatment (20 mg/kg) resulted in the up-regulation of BDNF levels in the control animals, reinforcing our hypothesis that up-regulation of BDNF synthesis play a key role in the antidepressant action of chrysin. In conclusion, this study showed that chrysin, similarly to fluoxetine, is capable of promoting the attenuation of depressant-like behavior and hippocampal dysfunction resulting from OB in mice. These results reinforced the potential of chrysin for the treatment or supplementary treatment of depression, as well as showed that chrysin is also effective with 14 days of therapy in a model of agitated depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. 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

  11. 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

  12. Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats.

    PubMed

    Iemolo, Attilio; Valenza, Marta; Tozier, Lisa; Knapp, Clifford M; Kornetsky, Conan; Steardo, Luca; Sabino, Valentina; Cottone, Pietro

    2012-09-01

    The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.

  13. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells

    PubMed Central

    Jia, Yun-Fang; Song, Ning-Ning; Mao, Rong-Rong; Li, Jin-Nan; Zhang, Qiong; Huang, Ying; Zhang, Lei; Han, Hui-Li; Ding, Yu-Qiang; Xu, Lin

    2014-01-01

    Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders. PMID:25294992

  14. 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-E2, 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-E2 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-E2 significantly enhanced frequency of grooming for the OVX rats in the OFT. Moreover, cholecalciferol in high dose administered alone or together with 17β-E2 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.

  15. Neuropsin Inactivation Has Protective Effects against Depressive-Like Behaviours and Memory Impairment Induced by Chronic Stress

    PubMed Central

    Chang, Simon; Bok, Philane; Sun, Cheng-Pu; Edwards, Andrew; Huang, Guo-Jen

    2016-01-01

    Mounting evidence suggests the interaction between stress and genetics contribute to the development of depressive symptoms. Currently, the molecular mechanisms mediating this process are poorly understood, hindering the development of new clinical interventions. Here, we investigate the interaction between neuropsin, a serine protease, and chronic stress on the development of depressive-like behaviours in mice. We found no difference in baseline behaviour between neuropsin knockout and wild-type mice. However, our results show that neuropsin knockout mice are protected against the development of depressive-like behaviours and memory impairment following chronic stress. We hypothesised that this difference in behaviour may be due to an interaction between neuropsin and elevated plasma corticosterone. To test this, we subjected mice to chronic corticosterone injections. These injections resulted in changes to hippocampal structure similar to that observed following chronic stress. We found that inactivation of neuropsin limits the extent of these anatomical changes in both the chronic stress and the corticosterone injection exposed cohorts. We next used viral vectors to knockdown or overexpress neuropsin in the hippocampus to confirm the results of the KO study. Additionally, we found that inactivation of neuropsin limited glutamate dysregulation, associated with increased generation of reactive oxygen species, resulting from prolonged elevated plasma corticosterone. In this study, we demonstrate that neuropsin inactivation protects against the impairment of hippocampal functions and the depressive-like behaviour induced by chronic stress or high levels of corticosterone. Consequently, we suggest neuropsin is a potential target for clinical interventions for the management of stress disorders. PMID:27701413

  16. 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

  17. Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetine

    PubMed Central

    Laugeray, Anthony; Launay, Jean-Marie; Callebert, Jacques; Mutlu, Oguz; Guillemin, Gilles J.; Belzung, Catherine; Barone, Pascal R.

    2016-01-01

    We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure—a validated model of stress-induced depression—results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine. More importantly we demonstrated that 1-methyl-D-tryptophan was able to alleviate most of the behavioural changes resulting from UCMS exposure. We also showed that both fluoxetine and 1-methyl-D-tryptophan robustly reduced peripheral levels of proinflammatory cytokines in UCMS mice suggesting that their therapeutic effects might occur through anti-inflammatory processes. KP inhibition might be involved in the positive effects of fluoxetine on mice behaviour and could be a relevant strategy to counteract depressive-like symptoms. PMID:27828964

  18. 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

    2017-03-01

    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

  19. Antidepressant Effects of TrkB Ligands on Depression-Like Behavior and Dendritic Changes in Mice After Inflammation

    PubMed Central

    Zhang, Ji-chun; Wu, Jin; Fujita, Yuko; Yao, Wei; Ren, Qian; Yang, Chun; Li, Su-xia; Shirayama, Yukihiko

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression. Methods: In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined. Results: LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc. Conclusions: The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively. PMID:25628381

  20. Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry.

    PubMed

    Sharma, S; Fulton, S

    2013-03-01

    The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain obscure. Dopamine- and plasticity-related signalling in mesolimbic reward circuitry is implicated in the pathophysiology and aetiology of depression. To determine the impact of a palatable high-fat diet (HFD) on depressive-like behaviour and biochemical alterations in brain reward circuitry in order to understand the neural processes that may contribute to the development of depression in the context of diet-induced obesity (DIO). Adult male C57Bl6 mice were placed on a HFD or ingredient-matched, low-fat diet for 12 weeks. At the end of the diet regimen, we assessed anxiety and depressive-like behaviour, corticosterone levels and biochemical changes in the midbrain and limbic brain regions. Nucleus accumbens (NAc), dorsolateral striatum (DLS) and ventral tegmental area dissections were subjected to SDS-PAGE and immunoblotting using antibodies against D1A receptor, D2 receptor, brain-derived neurotrophic factor (BDNF), phospho-DARPP-32(thr75), phospho-CREB and ΔFosB. HFD mice showed significant decreases in open arm time and centre time activity in elevated plus maze and open field tasks, respectively, and increased immobility (behavioural despair) in the forced swim test. Corticosterone levels following acute restraint stress were substantially elevated in HFD mice. HFD mice had significantly higher D2R, BDNF and ΔFosB, but reduced D1R, protein expression in the NAc. Notably, the expression of BDNF in both the NAc and DLS and phospho-CREB in the DLS was positively correlated with behavioural despair. Our results demonstrate that chronic consumption of high-fat food and obesity induce plasticity-related changes in reward circuitry that are associated with a depressive-like phenotype. As increases in striatal BDNF and CREB activity are well implicated in depressive behaviour and reward, we suggest these signalling molecules may mediate the

  1. Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain.

    PubMed

    Hu, Bing; Doods, Henri; Treede, Rolf-Detlef; Ceci, Angelo

    2016-04-21

    The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression.

  2. Calcium-Permeable AMPA Receptors in the Nucleus Accumbens Regulate Depression-Like Behaviors in the Chronic Neuropathic Pain State

    PubMed Central

    Goffer, Yossef; Xu, Duo; Eberle, Sarah E.; D'amour, James; Lee, Michelle; Tukey, David; Froemke, Robert C.; Ziff, Edward B.

    2013-01-01

    Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain. PMID:24285907

  3. Melanoma tumors alter proinflammatory cytokine production and monoamine brain function, and induce depressive-like behavior in male mice.

    PubMed

    Lebeña, Andrea; Vegas, Oscar; Gómez-Lázaro, Eneritz; Arregi, Amaia; Garmendia, Larraitz; Beitia, Garikoitz; Azpiroz, Arantza

    2014-10-01

    Depression is a commonly observed disorder among cancer patients; however, the mechanisms underlying the relationship between these disorders are not well known. We used an animal model to study the effects of tumor development on depressive-like behavior manifestation, proinflammatory cytokine expression, and central monoaminergic activity. Male OF1 mice were inoculated with B16F10 melanoma tumor cells and subjected to a 21-day behavioral evaluation comprising the novel palatable food (NPF) test and tail suspension test (TST). The mRNA expression levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, and tumor necrosis factor-alpha (TNF-α), were measured in the hypothalamus and hippocampus and the levels of IL-6 and TNF-α were measured in the blood plasma. We similarly determined the monoamine turnover in various brain areas. The tumors resulted in increasing the immobility in TST and the expression level of IL-6 in the hippocampus. These increases corresponded with a decrease in dopaminergic activity in the striatum and a decrease in serotonin turnover in the prefrontal cortex. Similarly, a high level of tumor development produced increases in the brain expression levels of IL-6 and TNF-α and plasma levels of IL-6. Our findings suggest that these alterations in inflammatory cytokines and monoaminergic system function might be responsible for the manifestation of depressive-like behaviors in tumor-bearing mice.

  4. MODERATE PERINATAL ARSENIC EXPOSURE ALTERS NEUROENDOCRINE MARKERS ASSOCIATED WITH DEPRESSION AND INCREASES DEPRESSIVE-LIKE BEHAVIORS IN ADULT MOUSE OFFSPRING

    PubMed Central

    Martinez, Ebany J.; Kolb, Bethany L.; Bell, Angela; Savage, Daniel D.; Allan, Andrea M.

    2008-01-01

    Arsenic is one of the most common heavy metal contaminants found in the environment, particularly in water. We examined the impact of perinatal exposure to relatively low levels of arsenic (50 parts per billion) on neuroendocrine markers associated with depression and depressive-like behaviors in affected adult C57BL/6J mouse offspring. Whereas most biomedical research on arsenic has focused on its carcinogenic potential, a few studies suggest that arsenic can adversely affect brain development and neural function. Compared to controls, offspring exposed to 50 parts per billion arsenic during the perinatal period had significantly elevated serum corticosterone levels, reduced whole hippocampal CRFR1 protein level and elevated dorsal hippocampal serotonin 5HT1A receptor binding and receptor-effector coupling. 5HT1A receptor binding and receptor-effector coupling were not different in the ventral hippocampal formation, entorhinal or parietal cortices, or inferior colliculus. Perinatal arsenic exposure also significantly increased learned helplessness and measures of immobility in a forced swim task. Taken together, these results suggest that perinatal arsenic exposure may disrupt the regulatory interactions between the hypothalamic-pituitary-adrenal axis and the serotonergic system in the dorsal hippocampal formation in a manner that predisposes affected offspring to depressive-like behavior. These results are the first to demonstrate that relatively low levels of arsenic exposure during development can have long-lasting adverse effects on behavior and neurobiological markers associated with these behavioral changes. PMID:18573533

  5. Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.

    PubMed

    Grizzell, J Alex; Iarkov, Alexandre; Holmes, Rosalee; Mori, Takahashi; Echeverria, Valentina

    2014-07-15

    Chronic stress underlies and/or exacerbates many psychiatric conditions and often results in memory impairment as well as depressive symptoms. Such afflicted individuals use tobacco more than the general population and this has been suggested as a form of self-medication. Cotinine, the predominant metabolite of nicotine, may underlie such behavior as it has been shown to ameliorate anxiety and memory loss in animal models. In this study, we sought to investigate the effects of cotinine on working memory and depressive-like behavior in mice subjected to prolonged restraint. Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests. These antidepressant and nootropic effects of cotinine were associated with an increase in the synaptophysin expression, a commonly used marker of synaptic density, in the hippocampus as well as the prefrontal and entorhinal cortices of restrained mice. The beneficial effects of cotinine in preventing various consequences of chronic stress were underscored by the inhibition of the glycogen synthase kinase 3 β in the hippocampus and prefrontal cortex. Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse.

  6. Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice.

    PubMed

    Grizzell, J Alex; Mullins, Michelle; Iarkov, Alexandre; Rohani, Adeeb; Charry, Laura C; Echeverria, Valentina

    2014-12-01

    Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  7. Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats.

    PubMed

    Tan, Liang; Ge, Hongfei; Tang, Jun; Fu, Chuhua; Duanmu, Wangsheng; Chen, Yujie; Hu, Rong; Sui, Jianfeng; Liu, Xin; Feng, Hua

    2015-02-15

    Traumatic brain injury (TBI) often results in multiple neuropsychiatric sequelae, including cognitive, emotional, and behavioral problems. Among them, depression is a common psychiatric symptom, and links to poorer recovery. Amantadine, as an antiparkinsonian, increases dopamine release, and blocks dopamine reuptake, but has recently received attention for its effectiveness as an antidepressant. In the present study, we first induced a post-TBI depression rat model to probe the efficacy of amantadine therapy in reducing post-TBI depression. The DA concentration in the striatum of the injured rats, as well as the degeneration and apoptosis of dopaminergic neurons in the substantia nigra (SN), were checked along with the depression-like behavior. The results showed that amantadine therapy could significantly ameliorate the depression-like behavior, improving the DA level in the striatum and decreasing the degeneration and apoptosis of dopaminergic neurons in the SN. The results indicated that the anti-depression effect may result from the increase of extracellular DA concentration in the striatum and/or the indirect neuroprotection on the dopaminergic neurons in the SN. We conclude that DA plays a critical role in post-TBI depression, and that amantadine shows its potential value in anti-depression treatment for TBI.

  8. Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour.

    PubMed

    Paternain, Laura; Martisova, Eva; Campión, Javier; Martínez, J Alfredo; Ramírez, Maria J; Milagro, Fermin I

    2016-02-15

    Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDL-cholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.

  9. 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

  10. Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats.

    PubMed

    Martín-Hernández, David; Caso, Javier R; Bris, Álvaro G; Maus, Sandra R; Madrigal, José L M; García-Bueno, Borja; MacDowell, Karina S; Alou, Luis; Gómez-Lus, Maria Luisa; Leza, Juan C

    2016-04-01

    Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease. This study aimed to evaluate whether experimental depression presents with bacterial translocation that in turn can lead to the TLR-4 in the brain affecting the mitogen-activated protein kinases (MAPK) and antioxidant pathways. Male Wistar rats were exposed to chronic mild stress (CMS) and the intestinal integrity, presence of bacteria in tissues and plasma lipopolysaccharide levels were analyzed. We also studied the expression in the prefrontal cortex of activated forms of MAPK and some of their activation controllers and the effects of CMS on the antioxidant Nrf2 pathway. Our results indicate that after exposure to a CMS protocol there is increased intestinal permeability and bacterial translocation. CMS also increases the expression of the activated form of the MAPK p38 while decreasing the expression of the antioxidant transcription factor Nrf2. The actions of antibiotic administration to prevent bacterial translocation on elements of the MAPK and Nrf2 pathways indicate that the translocated bacteria are playing a role in these effects. In effect, our results propose a role of the translocated bacteria in the pathophysiology of depression through the p38 MAPK pathway which could aggravate the neuroinflammation and the oxidative/nitrosative damage present in this pathology. Moreover, our results reveal that the antioxidant factor Nrf2 and its activators may be involved in the consequences of the CMS on the brain. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Salubrious effects of oxytocin on social stress-induced deficits.

    PubMed

    Smith, Adam S; Wang, Zuoxin

    2012-03-01

    Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While positive social interactions can attenuate stress and promote health, the social environment can also be a major source of stress when it includes social disruption, confrontation, isolation, or neglect. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

  12. Swim-stress-induced antinociception in young rats.

    PubMed Central

    Jackson, H. C.; Kitchen, I.

    1989-01-01

    1. Opioid and non-opioid mechanisms have been implicated in the phenomenon of stress-induced antinociception in adult rodents. We have studied stress-induced antinociception in developing rats and characterized differences in the neurochemical basis of this effect in pre- and post-weanling animals. 2. Twenty and 25 day old rats were stressed using warm water (20 degrees C) swimming for 3 or 10 min periods and antinociception was assessed by the tail immersion test (50 degrees C). 3. A 3 min swim in 20 and 25 day old rats produced marked antinociception which was blocked by naloxone, Mr 1452, 16-methyl cyprenorphine and levallorphan but not Mr 1453 or N-methyl levallorphan. The delta-opioid receptor antagonist ICI 174,864 attenuated stress-induced antinociception in 25 day old rats but was without effect in 20 day old animals. 4. A 10 min swim in 25 day old rats produced antinociception which was non-opioid in nature. In contrast, antinociception was not observed in 20 day old rats after a 10 min swim-stress. 5. Pretreatment of animals with dexamethasone blocked 3 min swim-stress antinociception in 20 and 25 day old animals but had no effect on antinociception induced by a 10 min swim. 6. Swim-stress-induced antinociception can be observed in young rats and dissociated into opioid and non-opioid types dependent on the duration of swimming stress. The non-opioid type appears to develop more slowly and cannot be observed in preweanling rats. The opioid type is a predominantly mu-receptor phenomenon in preweanling animals but delta-receptor components are observable in postweanling rats. PMID:2720296

  13. Gender differences in neural correlates of stress-induced anxiety.

    PubMed

    Seo, Dongju; Ahluwalia, Aneesha; Potenza, Marc N; Sinha, Rajita

    2017-01-02

    Although gender differences have been identified as a crucial factor for understanding stress-related anxiety and associated clinical disorders, the neural mechanisms underlying these differences remain unclear. To explore gender differences in the neural correlates of stress-induced anxiety, the current study used functional magnetic resonance imaging to examine brain responses in 96 healthy men and women with commensurable levels of trait anxiety as they engaged in a personalized guided imagery paradigm to provoke stress and neutral-relaxing experiences. During the task, a significant gender main effect emerged, with men displaying greater responses in the caudate, cingulate gyrus, midbrain, thalamus, and cerebellum. In contrast, women showed greater responses in the posterior insula, temporal gyrus, and occipital lobe. Additionally, a significant anxiety ratings × gender interaction from whole-brain regression analyses was observed in the dorsomedial prefrontal cortex, left inferior parietal lobe, left temporal gyrus, occipital gyrus, and cerebellum (P < 0.05, whole-brain family-wise error corrected), with positive associations between activity in these regions and stress-induced anxiety in women, but negative associations in men, indicating that men and women differentially use neural resources when experiencing stress-induced anxiety. The findings suggest that in response to stress, there is a greater use of the medial prefrontal-parietal cortices in experiencing subjective anxiety in women, while decreased use of this circuit was associated with increased subjective anxiety states in men. The current study has implications for understanding gender-specific differences in stress-induced anxiety and vulnerability to stress-related clinical disorders, and for developing more effective treatment strategies tailored to each gender. © 2016 Wiley Periodicals, Inc.

  14. Stress induced telomere shortening: longer life with less mutations?

    PubMed Central

    2014-01-01

    Background Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood. Results With the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells. Conclusions Our results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations. PMID:24580844

  15. Stress-induced changes in wheat grain composition and quality.

    PubMed

    Ashraf, M

    2014-01-01

    Abiotic stresses such as drought, salinity, waterlogging, and high temperature cause a myriad of changes in the metabolism of plants, and there is a lot of overlap in these changes in plants in response to different stresses such as drought and salinity. These stress-induced metabolic changes cause impaired crop growth thereby resulting in poor yield. The metabolic changes taking place in several plant species due to a particular abiotic stress have been revealed from the whole plant to the molecular level by researchers, but most studies have focused on organs such as leaf, stem, and root. Information on such stress-induced changes in seed or grains is infrequent in the literature. From the information that is available, it is now evident that abiotic stress can induce considerable changes in the composition and quality of cereal grains including those of wheat, the premier staple food crop in the world. Thus, the present review discusses how far different types of stresses, mainly salinity, drought, high temperature, and waterlogging, can alter the wheat grain composition and quality. By fully uncovering the stress-induced changes in the nutritional values of wheat grains it would be possible to establish whether balanced supplies of essential nutrients are available to the human population from the wheat crop grown on stress-affected areas.

  16. Environmental stress induces trinucleotide repeat mutagenesis in human cells.

    PubMed

    Chatterjee, Nimrat; Lin, Yunfu; Santillan, Beatriz A; Yotnda, Patricia; Wilson, John H

    2015-03-24

    The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)-the cause of multiple human diseases-have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, nucleotide excision repair, or transcription, processes that are known to promote TNR mutagenesis in other pathways of instability. Instead, we find that these stresses stimulate DNA rereplication, increasing the proportion of cells with >4 C-value (C) DNA content. Knockdown of the replication origin-licensing factor CDT1 eliminates both stress-induced rereplication and CAG repeat mutagenesis. In addition, direct induction of rereplication in the absence of stress also increases the proportion of cells with >4C DNA content and promotes repeat mutagenesis. Thus, environmental stress triggers a unique pathway for TNR mutagenesis that likely is mediated by DNA rereplication. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential.

  17. Environmental stress induces trinucleotide repeat mutagenesis in human cells

    PubMed Central

    Chatterjee, Nimrat; Lin, Yunfu; Santillan, Beatriz A.; Yotnda, Patricia; Wilson, John H.

    2015-01-01

    The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)—the cause of multiple human diseases—have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, nucleotide excision repair, or transcription, processes that are known to promote TNR mutagenesis in other pathways of instability. Instead, we find that these stresses stimulate DNA rereplication, increasing the proportion of cells with >4 C-value (C) DNA content. Knockdown of the replication origin-licensing factor CDT1 eliminates both stress-induced rereplication and CAG repeat mutagenesis. In addition, direct induction of rereplication in the absence of stress also increases the proportion of cells with >4C DNA content and promotes repeat mutagenesis. Thus, environmental stress triggers a unique pathway for TNR mutagenesis that likely is mediated by DNA rereplication. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential. PMID:25775519

  18. Potential role of punicalagin against oxidative stress induced testicular damage

    PubMed Central

    Rao, Faiza; Tian, Hui; Li, Wenqing; Hung, Helong; Sun, Fei

    2016-01-01

    Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg−1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility. PMID:26763544

  19. Potential role of punicalagin against oxidative stress induced testicular damage.

    PubMed

    Rao, Faiza; Tian, Hui; Li, Wenqing; Hung, Helong; Sun, Fei

    2016-01-01

    Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg-1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility.

  20. Calnexin deficiency and endoplasmic reticulum stress-induced apoptosis.

    PubMed

    Zuppini, Anna; Groenendyk, Jody; Cormack, Lori A; Shore, Gordon; Opas, Michal; Bleackley, R Chris; Michalak, Marek

    2002-02-26

    In this study, we used calnexin-deficient cells to investigate the role of this protein in ER stress-induced apoptosis. We found that calnexin-deficient cells are relatively resistant to ER stress-induced apoptosis. However, caspase 3 and 8 cleavage and cytochrome c release were unchanged in these cells, indicating that ER to mitochondria "communication" during apoptotic stimulation is not affected in the absence of calnexin. The Bcl-2:Bax ratio was also not significantly changed in calnexin-deficient cells regardless of whether the ER stress was induced with thapsigargin or not. Ca(2+) homeostasis and ER morphology were unaffected by the lack of calnexin, but ER stress-induced Bap31 cleavage was significantly inhibited. Immunoprecipitation experiments revealed that Bap31 forms complexes with calnexin, which may play a role in apoptosis. The results suggest that calnexin may not play a role in the initiation of the ER stress but that the protein has an effect on later apoptotic events via its influence on Bap31 function.

  1. Aging Leads to Prolonged Duration of Inflammation-Induced Depression-Like Behavior Caused by Bacillus Calmette-Guérin

    PubMed Central

    Kelley, Keith W.; O’Connor, Jason C.; Lawson, Marcus A.; Dantzer, Robert; Rodriguez-Zas, Sandra L.; McCusker, Robert H.

    2013-01-01

    Geriatric depression is a costly health issue, but little is known about its physiological underpinnings. Systemic inflammation sensitizes the innate immune system of aged animals and humans, but it is unknown if chronic, low-grade infections affect the duration of depressive-like behaviors. In this report, we infected adult (4–6 months) and aged (20–24 months) Balb/c mice with an attenuated strain of Mycobacterium bovis, Bacillus Calmette-Guérin (BCG), to induce a chronic infection. We then measured depression-like behaviors that have construct, face and predictive validity for human inflammation-associated clinical depression. Exposure to BCG caused acute sickness responses in both adult and aged mice. However, sickness behavior was prolonged in aged mice, as assessed by both locomotor and rearing activity. Two measures of depression-like behavior, which were tests involving sucrose preference and tail suspension, both showed that adult mice displayed depression-like behaviors at one day and seven days after exposure to BCG. However, aged mice continued to express both of these depression-like behaviors at three weeks following infection. Infection with BCG caused an increase in tryptophan catabolism, as evidenced by a significant rise in the plasma kynurenine/tryptophan ratio that peaked at 7 days post-infection. In aged mice, greater tryptophan catabolism persisted longer and remained elevated at 21 days post-infection. This finding is consistent with the prolonged duration of depression-like behaviors in aged mice. These are the first data using a chronic infection model to establish that recovery from inflammation-induced depression-like behavior and tryptophan catabolism are prolonged in aged animals. PMID:23454036

  2. Delayed degradation of chlorophylls and photosynthetic proteins in Arabidopsis autophagy mutants during stress-induced leaf yellowing.

    PubMed

    Sakuraba, Yasuhito; Lee, Sang-Hwa; Kim, Ye-Sol; Park, Ohkmae K; Hörtensteiner, Stefan; Paek, Nam-Chon

    2014-07-01

    Plant autophagy, one of the essential proteolysis systems, balances proteome and nutrient levels in cells of the whole plant. Autophagy has been studied by analysing Arabidopsis thaliana autophagy-defective atg mutants, but the relationship between autophagy and chlorophyll (Chl) breakdown during stress-induced leaf yellowing remains unclear. During natural senescence or under abiotic-stress conditions, extensive cell death and early yellowing occurs in the leaves of atg mutants. A new finding is revealed that atg5 and atg7 mutants exhibit a functional stay-green phenotype under mild abiotic-stress conditions, but leaf yellowing proceeds normally in wild-type leaves under these conditions. Under mild salt stress, atg5 leaves retained high levels of Chls and all photosystem proteins and maintained a normal chloroplast structure. Furthermore, a double mutant of atg5 and non-functional stay-green nonyellowing1-1 (atg5 nye1-1) showed a much stronger stay-green phenotype than either single mutant. Taking these results together, it is proposed that autophagy functions in the non-selective catabolism of Chls and photosynthetic proteins during stress-induced leaf yellowing, in addition to the selective degradation of Chl-apoprotein complexes in the chloroplasts through the senescence-induced STAY-GREEN1/NYE1 and Chl catabolic enzymes.

  3. Atorvastatin Protects from Aβ1-40-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage.

    PubMed

    Ludka, Fabiana K; Cunha, Maurício P; Dal-Cim, Tharine; Binder, Luisa Bandeira; Constantino, Leandra C; Massari, Caio M; Martins, Wagner C; Rodrigues, Ana Lúcia S; Tasca, Carla I

    2016-10-05

    Intracerebroventricular (icv) amyloid-beta (Aβ)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aβ1-40 infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aβ1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aβ1-40 (400 pmol/site, icv) infusion. Aβ1-40-induced hippocampal cell damage was reversed by atorvastatin treatment. Aβ1-40 infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aβ1-40-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.

  4. Effect of omega-3 polyunsaturated fatty acid treatment over mechanical allodynia and depressive-like behavior associated with experimental diabetes.

    PubMed

    Redivo, Daiany D B; Schreiber, Anne K; Adami, Eliana R; Ribeiro, Deidiane E; Joca, Samia R L; Zanoveli, Janaína M; Cunha, Joice M

    2016-02-01

    Neuropathic pain and depression are very common comorbidities in diabetic patients. As the pathophysiological mechanisms are very complex and multifactorial, current treatments are only symptomatic and often worsen the glucose control. Thus, the search for more effective treatments are extremely urgent. In this way, we aimed to investigate the effect of chronic treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, over the mechanical allodynia and in depressive-like behaviors in streptozotocin-diabetic rats. It was observed that the diabetic (DBT) animals, when compared to normoglycemic (NGL) animals, developed a significant mechanical allodynia since the second week after diabetes induction, peaking at fourth week which is completely prevented by FO treatment (0.5, 1 or 3g/kg). Moreover, DBT animals showed an increase of immobility frequency and a decrease of swimming and climbing frequencies in modified forced swimming test (MFST) since the second week after diabetes injection, lasting up at the 4th week. FO treatment (only at a dose of 3g/kg) significantly decreased the immobility frequency and increased the swimming frequency, but did not induce significant changes in the climbing frequency in DBT rats. Moreover, it was observed that DBT animals had significantly lower levels of BDNF in both hippocampus and pre frontal cortex when compared to NGL rats, which is completely prevented by FO treatment. In conclusion, our study demonstrates that FO treatment was able to prevent the mechanical allodynia and the depressive-like behaviors in DBT rats, which seems to be related to its capacity of BDNF level restoration.

  5. Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder.

    PubMed

    Hlavacova, Natasa; Wes, Paul D; Ondrejcakova, Maria; Flynn, Marianne E; Poundstone, Patricia K; Babic, Stanislav; Murck, Harald; Jezova, Daniela

    2012-03-01

    The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 μg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

  6. Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons.

    PubMed

    Caudal, D; Alvarsson, A; Björklund, A; Svenningsson, P

    2015-11-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-synuclein called Lewy bodies. Viral vector-induced overexpression of α-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague-Dawley rats received bilateral injections of a recombinant adeno-associated virus (AAV) vector expressing human α-synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8 weeks post-injection. We report that nigral α-synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-α-synuclein group exhibited modest, but significant motor impairments 8 weeks after vector administration. The AAV-α-synuclein group displayed depressive-like behavior in the forced swim test after 3 weeks, and reduced sucrose preference at week 8. At both timepoints, overexpression of α-synuclein was linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone. The depressive-like phenotype was also correlated with decreased nigral brain-derived neurotrophic factor and spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated protein. This study demonstrates that AAV-mediated α-synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in experimental Parkinsonism is correlated to dysregulation of the HPA axis and to

  7. Methylene Blue Attenuates Traumatic Brain Injury-Associated Neuroinflammation and Acute Depressive-Like Behavior in Mice

    PubMed Central

    Fenn, Ashley M.; Skendelas, John P.; Moussa, Daniel N.; Muccigrosso, Megan M.; Popovich, Phillip G.; Lifshitz, Jonathan

    2015-01-01

    Abstract Traumatic brain injury (TBI) is associated with cerebral edema, blood brain barrier breakdown, and neuroinflammation that contribute to the degree of injury severity and functional recovery. Unfortunately, there are no effective proactive treatments for limiting immediate or long-term consequences of TBI. Therefore, the objective of this study was to determine the efficacy of methylene blue (MB), an antioxidant agent, in reducing inflammation and behavioral complications associated with a diffuse brain injury. Here we show that immediate MB infusion (intravenous; 15–30 minutes after TBI) reduced cerebral edema, attenuated microglial activation and reduced neuroinflammation, and improved behavioral recovery after midline fluid percussion injury in mice. Specifically, TBI-associated edema and inflammatory gene expression in the hippocampus were significantly reduced by MB at 1 d post injury. Moreover, MB intervention attenuated TBI-induced inflammatory gene expression (interleukin [IL]-1β, tumor necrosis factor α) in enriched microglia/macrophages 1 d post injury. Cell culture experiments with lipopolysaccharide-activated BV2 microglia confirmed that MB treatment directly reduced IL-1β and increased IL-10 messenger ribonucleic acid in microglia. Last, functional recovery and depressive-like behavior were assessed up to one week after TBI. MB intervention did not prevent TBI-induced reductions in body weight or motor coordination 1–7 d post injury. Nonetheless, MB attenuated the development of acute depressive-like behavior at 7 d post injury. Taken together, immediate intervention with MB was effective in reducing neuroinflammation and improving behavioral recovery after diffuse brain injury. Thus, MB intervention may reduce life-threatening complications of TBI, including edema and neuroinflammation, and protect against the development of neuropsychiatric complications. PMID:25070744

  8. Female Flinders Sensitive Line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism.

    PubMed

    Eskelund, Amanda; Budac, David P; Sanchez, Connie; Elfving, Betina; Wegener, Gregers

    2016-08-04

    Clinical studies suggest a link between depression and dysfunctional tryptophan (TRP) metabolism. Even though depression is twice as prevalent in women as men, the impact of the estrous cycle on TRP metabolism is not well-understood. Here we investigated 13 kynurenine and serotonin metabolites in female Flinders Sensitive Line (FSL) rats, a genetic rat model of depression. FSL rats and controls (Flinders Resistant Line rats), 12-20weeks old, were subject to the forced swim test (FST), a commonly used measure of depression-like behavior. Open field was used to evaluate locomotor ability and agoraphobia. Subsequently, plasma and hemispheres were collected and analyzed for their content of TRP metabolites using liquid chromatography-tandem mass spectrometry. Vaginal saline lavages were obtained daily for ⩾2 cycles. To estimate the effects of sex and FST we included plasma from unhandled, naïve male FSL and FRL rats. Female FSL rats showed a depression-like phenotype with increased immobility in the FST, not confounded by anxiety. In the brain, 3-hydroxykynurenine was increased whereas anthranilate and 5-hydroxytryptophan were decreased. In plasma, anthranilate and quinolinate levels were lower in FSL rats compared to the control line, independent of sex and FST. The estrous cycle neither impacted behavior nor TRP metabolite levels in the FSL rat. In conclusion, the female FSL rat is an interesting preclinical model of depression with altered TRP metabolism, independent of the estrous cycle. The status of the pathway in brain was not reflected in the plasma, which may indicate that an inherent local, cerebral regulation of TRP metabolism occurs.

  9. Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

    PubMed Central

    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

    2010-01-01

    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-hydroxyt-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. PMID:18075491

  10. 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

  11. Clomipramine reverses hypoalgesia/hypoesthesia and improved depressive-like behaviors induced by inescapable shock in rats.

    PubMed

    Li, Bing; Yang, Chang-Jiang; Yue, Na; Liu, Yang; Yu, Jin; Wang, Yan-Qing; Liu, Qiong; Wu, Gen-Cheng

    2013-04-29

    An increased vulnerability to pain complaints, along with a simultaneous increase in experimental pain thresholds, shows the paradoxical phenomenon of pain perception in depressive patients. Clomipramine, a tricyclic antidepressant, could also ameliorate syndromes in chronic pain patients. However, few studies have focused on the effect of antidepressants on experimental pain thresholds. By using a rat model, the learned helplessness paradigm, the present study explored the effect of clomipramine on behavioral deficits and experimental pain thresholds to different stimuli in "helpless" rats. Helpless rats were administered clomipramine (10mg/kg, i.p, b.i.d.) for 5 consecutive days. The depressive-like and anxiety-like behaviors were detected by shuttle box, open field and elevated plus maze test before and after inescapable shock and after medication. The sensitivity to the thermal and mechanical stimuli was also measured by the von Frey hair and Hargreaves test at the indicated time points. Helpless rats displayed shorter total travel distance and fewer rearing times in the open field test and decreased percentage of time spent in the open arms in the elevated plus maze test. In addition, they exhibited significant hypoalgesia/hypoesthesia to mechanical and thermal stimuli. Clomipramine alleviate depressive-like and anxiety-like behaviors and increased the sensitivity to von Frey filament stimuli with no effect on the sensitivity to radiant heat stimuli in helpless rats. These suggested that clomipramine could reverse mechanical but not thermal hypoalgesia/hypoesthesia and simultaneously improved behavioral deficits. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. 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

  13. Behavioral and neurobiological effects of deep brain stimulation in a mouse model of high anxiety- and depression-like behavior.

    PubMed

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

    2013-06-01

    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.

  14. Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats.

    PubMed

    Russell, Shayla E; Rachlin, Anna B; Smith, Karen L; Muschamp, John; Berry, Loren; Zhao, Zhiyang; Chartoff, Elena H

    2014-08-01

    Dynorphin, an endogenous ligand at kappa opioid receptors (KORs), produces depressive-like effects and contributes to addictive behavior in male nonhuman primates and rodents. Although comorbidity of depression and addiction is greater in women than men, the role of KORs in female motivated behavior is unknown. In adult Sprague-Dawley rats, we used intracranial self-stimulation to measure effects of the KOR agonist (±)-trans-U-50488 methanesulfonate salt (U-50488) (.0-10.0 mg/kg) on brain stimulation reward in gonadally intact and castrated males and in females at estrous cycle stages associated with low and high estrogen levels. Pharmacokinetic studies of U-50488 in plasma and brain were conducted. Immunohistochemistry was used to identify sex-dependent expression of U-50488-induced c-Fos in brain. U-50488 dose-dependently increased the frequency of stimulation (threshold) required to maintain intracranial self-stimulation responding in male and female rats, a depressive-like effect. However, females were significantly less sensitive than males to the threshold-increasing effects of U-50488, independent of estrous cycle stage in females or gonadectomy in males. Although initial plasma concentrations of U-50488 were higher in females, there were no sex differences in brain concentrations. Sex differences in U-50488-induced c-Fos activation were observed in corticotropin releasing factor-containing neurons of the paraventricular nucleus of the hypothalamus and primarily in non-corticotropin releasing factor-containing neurons of the bed nucleus of the stria terminalis. These data suggest that the role of KORs in motivated behavior of rats is sex-dependent, which has important ramifications for the study and treatment of mood-related disorders, including depression and drug addiction in people. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats

    PubMed Central

    Zhang, Jian-Min; Tonelli, Leonardo; Regenold, William T.; McCarthy, Margaret M.

    2013-01-01

    The prevalence of major depressive disorder (MDD) in adult men is roughly half that of women. Clinical evidence supports a protective effect of androgens against depressive disorders in men. The developing brain is subject to androgen exposure but a potential role for this in depression during adulthood has not been considered. In order to explore this question we treated newborn male rat pups with the androgen receptor antagonist flutamide to block endogenous androgen action and then conducted behavioral tests prior to puberty. Depression-like behaviors were assessed with the Forced Swim Test (FST) and the Sucrose Preference Test (SPT), and anxiety-like behaviors were assessed with the Open Field Test (OFT) and the Novelty-Suppressed Feeding Test (NSFT). Compared to the vehicle-treated controls, neonatal-flutamide treatment caused a significant increase in depression-like behaviors in preadolescent male rats but did not cause any significant difference in anxiety-like behaviors. In separate experiments, male pups with and without flutamide treatment were injected with 5-bromo-2’-deoxyuridine-5’-monophosphate (BrdU) from postnatal day (PND) 1 to 4 to label newly produced cells or the hippocampi were Golgi-Cox imbedded and pyramidal neurons visualized. Three lines of evidence indicate neonatal flutamide treatment inhibits hippocampal neurogenesis and neuronal dendritic spine formation in preadolescent male rats. Compared to vehicle controls, flutamide treatment significantly decreased 1) the number of microtubal associated protein-2+ (MAP-2) neurons in the CA1 region, 2) the number of MAP-2+ neurons in the dentate gyrus (DG) region of the hippocampus, and 3) the density of dendritic spines of pyramidal neurons in the CA1 region. However, there was no effect of flutamide treatment on the number of GFAP+ or GFAP+/BrdU+ cells in the hippocampus. This study suggests that the organizational effect of androgen-induced hippocampal neurogenesis is antidepressant. PMID

  16. Oxytocin mediates stress-induced analgesia in adult mice

    PubMed Central

    Robinson, D A; Wei, F; Wang, G D; Li, P; Kim, S J; Vogt, S K; Muglia, L J; Zhuo, M

    2002-01-01

    As a neurohormone and as a neurotransmitter, oxytocin has been implicated in the stress response. Descending oxytocin-containing fibres project to the dorsal horn of the spinal cord, an area important for processing nociceptive inputs. Here we tested the hypothesis that oxytocin plays a role in stress-induced analgesia and modulates spinal sensory transmission. Mice lacking oxytocin exhibited significantly reduced stress-induced antinociception following both cold-swim (10 °C, 3 min) and restraint stress (30 min). In contrast, the mice exhibited normal behavioural responses to thermal and mechanical noxious stimuli and morphine-induced antinociception. In wild-type mice, intrathecal injection of the oxytocin antagonist dOVT (200 μm in 5 μl) significantly attenuated antinociception induced by cold-swim. Immunocytochemical staining revealed that, in the mouse, oxytocin-containing neurones in the paraventricular nucleus of the hypothalamus are activated by stress. Furthermore, oxytocin-containing fibres were present in the dorsal horn of the spinal cord. To test whether descending oxytocin-containing fibres could alter nociceptive transmission, we performed intracellular recordings of dorsal horn neurones in spinal slices from adult mice. Bath application of oxytocin (1 and 10 μm) inhibited excitatory postsynaptic potentials (EPSPs) evoked by dorsal root stimulation. This effect was reversed by the oxytocin antagonist dOVT (1 μm). Whole-cell recordings of dorsal horn neurones in postnatal rat slices revealed that the effect of oxytocin could be blocked by the addition of GTP-γ-S to the recording pipette, suggesting activation of postsynaptic oxytocin receptors. We conclude that oxytocin is important for both cold-swim and restraint stress-induced antinociception, acting by inhibiting glutamatergic spinal sensory transmission. PMID:11956346

  17. Stress-induced phase transformation in nanocrystalline UO2

    SciTech Connect

    Uberuaga, Blas Pedro; Desai, Tapan

    2009-01-01

    We report a stress-induced phase transfonnation in stoichiometric UO{sub 2} from fluorite to the {alpha}-PbO{sub 2} structure using molecular dynamics (MD) simulations and density functional theory (DFT) calculations. MD simulations, performed on nanocrystalline microstructure under constant-stress tensile loading conditions, reveal a heterogeneous nucleation of the {alpha}-PbO{sub 2} phase at the grain boundaries followed by the growth of this phase towards the interior of the grain. The DFT calculations confinn the existence of the {alpha}-PbO{sub 2} structure, showing that it is energetically favored under tensile loading conditions.

  18. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

    PubMed Central

    Frenois, François; Moreau, Maïté; Connor, Jason O’; Lawson, Marc; Micon, Charlotte; Lestage, Jacques; Kelley, Keith W.; Dantzer, Robert; Castanon, Nathalie

    2007-01-01

    Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830 μg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6 h (at which time sickness was expected to be maximal) or at 24 h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/ΔFosB respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6 but not at 24 h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24 h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24 h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48 h, despite normal food and water consumption by that time. At 24 h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/ΔFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6 h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect. PMID:17482371

  19. Mild Traumatic Brain Injury

    MedlinePlus

    ... Questions Glossary Contact Us Visitor Feedback mild Traumatic Brain Injury mild Traumatic Brain Injury VIDEO STORIES What is TBI Measuring Severity ... most common deployment injuries is a mild Traumatic Brain Injury (TBI). A mild TBI is an injury ...

  20. Functional role of CCCTC binding factor (CTCF) in stress-induced apoptosis

    SciTech Connect

    Li Tie; Lu Luo . E-mail: lluou@ucla.edu

    2007-08-15

    CTCF, a nuclear transcriptional factor, is a multifunctional protein and involves regulation of growth factor- and cytokine-induced cell proliferation/differentiation. In the present study, we investigated the role of CTCF in protecting stress-induced apoptosis in various human cell types. We found that UV irradiation and hyper-osmotic stress induced human corneal epithelial (HCE) and hematopoietic myeloid cell apoptosis detected by significantly increased caspase 3 activity and decreased cell viability. The stress-induced apoptotic response in these cells requires down-regulation of CTCF at both mRNA and protein levels, suggesting that CTCF may play an important role in downstream events of stress-induced signaling pathways. Inhibition of NF{kappa}B activity prevented stress-induced down-regulation of CTCF and increased cell viability against stress-induced apoptosis. The anti-apoptotic effect of CTCF was further studied by manipulating CTCF activities in HCE and hematopoietic cells. Transient transfection of cDNAs encoding full-length human CTCF markedly suppressed stress-induced apoptosis in these cells. In contrast, knocking down of CTCF mRNA using siRNA specific to CTCF significantly promoted stress-induced apoptosis. Thus, our results reveal that CTCF is a down stream target of stress-induced signaling cascades and it plays a significant anti-apoptotic role in regulation of stress-induced cellular responses in HCE and hematopoietic myeloid cells.

  1. Mild balanoposthitis.

    PubMed Central

    Fornasa, C V; Calabrŏ, A; Miglietta, A; Tarantello, M; Biasinutto, C; Peserico, A

    1994-01-01

    AIM--To identify and study cases of mild balanoposthitis (MBP) with penile pathology among patients observed at a dermatology clinic over an 18-month period. MATERIALS--The study included 321 patients with penile pathology. The term MBP was used to describe balanoposthitis of a localised, inflammatory nature with few, non-specific symptoms and a tendency to become chronic or recur. Two hundred and seventy had diseases clearly identifiable by clinical examination or laboratory tests; 51 cases were diagnosed as MBP and these patients had blood tests (to evaluate immune status) and microbiological examination; when these proved negative, a series of patch tests was also used. RESULTS--Of the 51 patients diagnosed as having MBP, the cause was ascertained in 34 cases (infection, mechanical trauma, contact irritation, contact allergy, etc.), whereas no specific aetiological factor was detected to explain the symptoms in the remaining 17 cases. PMID:8001949

  2. Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders

    PubMed Central

    Gu, Simeng; Wang, Wei; Huang, Jason H.

    2016-01-01

    Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC)/norepinephrine (NE) system is regarded as a critical part of the central “stress circuitry,” whose major function is to induce “fight or flight” behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty). The reason for this discrepancy might be that NE is not only for flight (fear), but also for fight (anger). Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. “Adrenaline rush or norepinephrine rush” and fear and anger emotion might act as biomarkers for mental disorders. PMID:27051536

  3. (+)-Catechin protects dermal fibroblasts against oxidative stress-induced apoptosis

    PubMed Central

    2014-01-01

    Background Oxidative stress has been suggested as a mechanism underlying skin aging, as it triggers apoptosis in various cell types, including fibroblasts, which play important roles in the preservation of healthy, youthful skin. Catechins, which are antioxidants contained in green tea, exert various actions such as anti-inflammatory, anti-bacterial, and anti-cancer actions. In this study, we investigated the effect of (+)-catechin on apoptosis induced by oxidative stress in fibroblasts. Methods Fibroblasts (NIH3T3) under oxidative stress induced by hydrogen peroxide (0.1 mM) were treated with either vehicle or (+)-catechin (0–100 μM). The effect of (+)-catechin on cell viability, apoptosis, phosphorylation of c-Jun terminal kinases (JNK) and p38, and activation of caspase-3 in fibroblasts under oxidative stress were evaluated. Results Hydrogen peroxide induced apoptotic cell death in fibroblasts, accompanied by induction of phosphorylation of JNK and p38 and activation of caspase-3. Pretreatment of the fibroblasts with (+)-catechin inhibited hydrogen peroxide-induced apoptosis and reduced phosphorylation of JNK and p38 and activation of caspase-3. Conclusion (+)-Catechin protects against oxidative stress-induced cell death in fibroblasts, possibly by inhibiting phosphorylation of p38 and JNK. These results suggest that (+)-catechin has potential as a therapeutic agent for the prevention of skin aging. PMID:24712558

  4. Caffeine attenuated ER stress-induced leptin resistance in neurons.

    PubMed

    Hosoi, Toru; Toyoda, Keisuke; Nakatsu, Kanako; Ozawa, Koichiro

    2014-05-21

    Exposing the endoplasmic reticulum (ER) to stress causes the accumulation of unfolded proteins, and subsequently results in ER stress. ER stress may be involved in various disorders such as obesity, diabetes, and neurodegenerative diseases. Leptin is an important circulating hormone, that inhibits food intake and accelerates energy consumption, which suppresses body weight gain. Recent studies demonstrated that leptin resistance is one of the main factors involved in the development of obesity. We and other groups recently reported the role of ER stress in the development of leptin resistance. Therefore, identifying drugs that target ER stress may be a promising fundamental strategy for the treatment of obesity. In the present study, we investigated whether caffeine could affect ER stress and the subsequent development of leptin resistance. We showed that caffeine exhibited chaperone activity, which attenuated protein aggregation. Caffeine also inhibited the ER stress-induced activation of IRE1 and PERK, which suggested the attenuation of ER stress. Moreover, caffeine markedly improved ER stress-induced impairments in the leptin-induced phosphorylation of STAT3. Therefore, these results suggest caffeine may have pharmacological properties that ameliorate leptin resistance by reducing ER stress.

  5. Stress-Induced Hormones Cortisol and Epinephrine Impair Wound Epithelization.

    PubMed

    Stojadinovic, Olivera; Gordon, Katherine A; Lebrun, Elizabeth; Tomic-Canic, Marjana

    2012-02-01

    Stress-induced disruption of hormonal balance in animals and humans has a detrimental effect on wound healing. After the injury, keratinocytes migrate over the wound bed to repair a wound. However, their nonmigratory phenotype plays a role in pathogenesis of chronic wounds. Despite many therapeutic approaches, there is a dearth of treatments targeting the molecular mechanisms mediated by stress that prevent epithelization. Recent studies show that epidermal keratinocytes synthesize stress hormones. During acute wound healing, cortisol synthesis in the epidermis is tightly controlled. Further, a key intermediate molecule in the cholesterol synthesis pathway, farnesyl pyrophosphate (FPP), can bind glucocorticoid receptor (GR) and activate GR. Additionally, keratinocytes express beta-2-adrenergic-receptor (β2AR), a receptor for the stress hormone epinephrine. Importantly, migratory rates of keratinocytes are reduced by cortisol, FPP, epinephrine, and other β2AR agonists, thus indicating their role in the inhibition of epithelization. Topical inhibition of local glucocorticoid and FPP synthesis, as well as treatment with β2AR antagonists promotes wound epithelization. Modulation of local stress hormone production may represent an important therapeutic target for wound healing disorders. Topical administration of inhibitors of cortisol synthesis, statins, β2AR antagonists, and systemic beta-blockers can decrease cortisol synthesis, FPP, and epinephrine levels, respectively, thus restoring keratinocyte migration capacity. These treatment modalities could represent a novel therapeutic approach for wound healing disorders. Attenuation of the local stress-induced hormonal imbalance in epidermis may advance therapeutic modalities, thereby leading to enhanced epithelization and improved wound healing.

  6. Stress induced reversible crystal transition in poly(butylene succinate)

    NASA Astrophysics Data System (ADS)

    Liu, Guoming; Zheng, Liuchun; Zhang, Xiuqin; Li, Chuncheng; Wang, Dujin

    2015-03-01

    The plastic deformation mechanism of semi-crystalline polymers is a long-studied topic, which is crucial for establishing structure/property relationships. For polymers with stress induced crystal transition, some open questions still need to be answered, such as on which stage of plastic deformation does the crystal transition take place, and more importantly, what happens on the lamellar structure during crystal transition. In this talk, stress-induced reversible crystal transition in poly(butylene succinate) was systematically investigated by in-situ WAXS and SAXS. A ``lamellar thickening'' phenomenon was observed during stretching, which was shown to mainly originated from the reversible crystal transition. This mechanism was shown to be valid in poly(ethylene succinate). The critical stress for the transition was measured in a series of PBS-based crystalline-amorphous multi-block copolymers. Interestingly, these PBS copolymers exhibited identical critical stress independent of amorphous blocks. The universal critical stress for crystal transition was interpreted through a single-microfibril-stretching mechanism. The work is financially supported by the National Natural Science Foundation of China (Grant No. 51203170).

  7. SOS involvement in stress-inducible biofilm formation.

    PubMed

    Gotoh, H; Kasaraneni, N; Devineni, N; Dallo, S F; Weitao, T

    2010-07-01

    Bacterial biofilm formation can be induced by antimicrobial and DNA damage agents. These agents trigger the SOS response, in which SOS sensor RecA stimulates auto-cleavage of repressor LexA. These observations lead to a hypothesis of a connection between stress-inducible biofilm formation and the RecA-LexA interplay. To test this hypothesis, three biofilm assays were conducted, viz. the standard 96-well assay, confocal laser scanning microscopy, and the newly developed biofilm-on-paper assay. It was found that biofilm stimulation by the DNA replication inhibitor hydroxyurea was dependent on RecA and appeared repressed by the non-cleavable LexA of Pseudomonas aeruginosa. Surprisingly, deletion of lexA led to reduction of both normal and stress-inducible biofilm formation, suggesting that the wild-type LexA contributes to biofilm formation. The decreases was not the result of poor growth of the mutants. These results suggest SOS involvement in hydroxyurea-inducible biofilm formation. In addition, with the paper biofilm assay, it was found that degradation of the biofilm matrix DNA by DNase I appeared to render the biofilms susceptible to the replication inhibitor. The puzzling questions concerning the roles of LexA in DNA release in the biofilm context are discussed.

  8. Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice.

    PubMed

    Moslehi, A; Nabavizadeh, F; Nabavizadeh, Fatemeh; Dehpour, A R; Dehpou, A R; Tavanga, S M; Hassanzadeh, G; Zekri, A; Nahrevanian, H; Sohanaki, H

    2014-09-01

    Endoplasmic reticulum (ER) stress provides abnormalities in insulin action, inflammatory responses, lipoprotein B100 degradation and hepatic lipogenesis. Excess accumulation of triglyceride in hepatocytes may also lead to disorders such as non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Opioid peptides are involved in triglyceride and cholesterol dysregulation, inflammation and cell death. In this study, we evaluated Naltrexone effects on ER stress induced liver injury. To do so, C57/BL6 mice received saline, DMSO and Naltrexone, as control groups. ER stress was induced by tunicamycin (TM) injection. Naltrexone was given before TM administration. Liver blood flow and biochemical serum analysis were measured. Histopathological evaluations, TNF-α measurement and Real-time RT-PCR were also performed. TM challenge provokes steatosis, cellular ballooning and lobular inflammation which significantly reduced in Naltrexone treated animals. ALT, AST and TNF-α increased in the TM group and improved in the Naltrexone plus TM group. Triglyceride and cholesterol levels decreased in TM treated mice with no increase in Naltrexone treated animals. In the Naltrexone plus TM group, gene expression of Bax/Bcl-2 ratio and caspase3 significantly lowered compared with the TM group. In this study, we found that Naltrexone had a notable alleviating role in ER stress induced steatosis and liver injury.

  9. Horizontal stresses induced by vertical processes in planetary lithospheres

    NASA Technical Reports Server (NTRS)

    Banerdt, W. B.

    1993-01-01

    Understanding the state of stress in the elastic lithosphere is of fundamental importance for planetary geophysics, as it is the link between the observed geologic structures on the surface and the processes which form and modify these structures. As such, it can provide valuable constraints for the difficult problem of determining interior structure and processes. On the Earth, most large scale, organized deformation can be related to lateral tectonics associated with plate dynamics; however, the tectonics on many extraterrestrial bodies (such as the Moon, Mars, and most of the outer-planet satellites) appears to be primarily vertical in nature, and the horizontal stresses induced by vertical motions and loads are expected to dominate the deformation of their lithospheres. The largest stress contributions from vertical loading come from the flexure of the lithosphere, which induces both bending moments and membrane stresses. We are concerned here only with nonflexural changes in the state of stress induced by processes such as sedimentary and volcanic deposition, erosional denudation, and changes in the thermal gradient that induce uplift or subsidence. This analysis is important both for evaluating stresses for specific regions in which the vertical stress history can be estimated, as well as for applying the proper loading conditions to global stress models. It is also of interest for providing a reference state of stress for interpreting stress measurements in the crust of the Earth.

  10. Inheritance of stress-induced, ATF-2-dependent epigenetic change.

    PubMed

    Seong, Ki-Hyeon; Li, Dong; Shimizu, Hideyuki; Nakamura, Ryoichi; Ishii, Shunsuke

    2011-06-24

    Atf1, the fission yeast homolog of activation transcription factor-2 (ATF-2), contributes to heterochromatin formation. However, the role of ATF-2 in chromatin assembly in higher organisms remains unknown. This study reveals that Drosophila ATF-2 (dATF-2) is required for heterochromatin assembly, whereas the stress-induced phosphorylation of dATF-2, via Mekk1-p38, disrupts heterochromatin. The dATF-2 protein colocalized with HP1, not only on heterochromatin but also at specific loci in euchromatin. Heat shock or osmotic stress induced phosphorylation of dATF-2 and resulted in its release from heterochromatin. This heterochromatic disruption was an epigenetic event that was transmitted to the next generation in a non-Mendelian fashion. When embryos were exposed to heat stress over multiple generations, the defective chromatin state was maintained over multiple successive generations, though it gradually returned to the normal state. The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure.

  11. Oxidative stress induces mitochondrial fragmentation in frataxin-deficient cells

    SciTech Connect

    Lefevre, Sophie; Sliwa, Dominika; Rustin, Pierre; Camadro, Jean-Michel; Santos, Renata

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Yeast frataxin-deficiency leads to increased proportion of fragmented mitochondria. Black-Right-Pointing-Pointer Oxidative stress induces complete mitochondrial fragmentation in {Delta}yfh1 cells. Black-Right-Pointing-Pointer Oxidative stress increases mitochondrial fragmentation in patient fibroblasts. Black-Right-Pointing-Pointer Inhibition of mitochondrial fission in {Delta}yfh1 induces oxidative stress resistance. -- Abstract: Friedreich ataxia (FA) is the most common recessive neurodegenerative disease. It is caused by deficiency in mitochondrial frataxin, which participates in iron-sulfur cluster assembly. Yeast cells lacking frataxin ({Delta}yfh1 mutant) showed an increased proportion of fragmented mitochondria compared to wild-type. In addition, oxidative stress induced complete fragmentation of mitochondria in {Delta}yfh1 cells. Genetically controlled inhibition of mitochondrial fission in these cells led to increased resistance to oxidative stress. Here we present evidence that in yeast frataxin-deficiency interferes with mitochondrial dynamics, which might therefore be relevant for the pathophysiology of FA.

  12. Anti-depressant-like effect of vitexin in BALB/c mice and evidence for the involvement of monoaminergic mechanisms.

    PubMed

    Can, Özgür Devrim; Demir Özkay, Ümide; Üçel, Umut İrfan

    2013-01-15

    The present study was designed to investigate the putative effect of vitexin, a flavone C-glucoside present in some drugs, medicinal plants and nutraceuticals, on the central nervous system. Vitexin (10-30 mg/kg) did not show significant alterations in the behaviour of mice tested in hole-board, plus-maze or activity cage tests. However, immobility time of the mice significantly reduced by vitexin administrations in both the tail-suspension and modified forced swimming tests. The anti-immobility effect of vitexin in the tail-suspension test was reversed with α-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis, 100mg/kg, i.p.), yohimbine (an α(2)-adrenoceptor antagonist, 1mg/kg, i.p.), NAN 190 (a 5-HT(1A) antagonist, 0.5mg/kg, i.p.), SCH 23390 (a dopamine D(1) antagonist, 0.05 mg/kg, s.c.) and sulpiride (a dopamine D(2)/D(3) antagonist, 50mg/kg, i.p.). The same effect was not reversed, however, by p-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis 100mg/kg, i.p., administered for 4 consecutive days), ketanserin (a 5-HT(2A/2C) antagonist, 1-4 mg/kg, i.p.), ondansetron (a 5-HT(3) antagonist, 0.1-0.4 mg/kg, i.p.), prazosin (an α(1)-adrenoceptor antagonist, 1-4 mg/kg, i.p.), or propranolol (a non-selective β-adrenoceptor antagonist, 5-20mg/kg, i.p.). These results suggest that the anti-depressant-like effect of vitexin is mediated through an increase in catecholamine levels in the synaptic cleft as well as through interactions with the serotonergic 5-HT(1A), noradrenergic α(2), and dopaminergic D(1), D(2), and D(3) receptors. To our knowledge, this is the first study to show findings that indicate an anti-depressant-like effect of vitexin and its underlying mechanisms.

  13. Neonatal tactile stimulation decreases depression-like and anxiety-like behaviors and potentiates sertraline action in young rats.

    PubMed

    Freitas, Daniele; Antoniazzi, Caren T D; Segat, Hecson J; Metz, Vinícia Garzella; Vey, Luciana Taschetto; Barcelos, Raquel C S; Duarte, Thiago; Duarte, Marta M M F; Burger, Marilise Escobar

    2015-12-01

    It is well known that events which occur in early life exert a significant influence on brain development, what can be reflected throughout adulthood. This study was carried out in order to assess the influence of neonatal tactile stimulation (TS) on behavioral and morphological responses related to depression-like and anxiety-like behaviors, assessed following the administration of sertraline (SERT), a selective serotonin re-uptake inhibitor (SSRI). Male pups were submitted to daily TS, from postnatal day 8 (PND8) to postnatal day 14 (PND14), for 10 min every day. On PND50, adult animals were submitted to forced swimming training (15 min). On PND51, half of each experimental group (UH and TS) received a single sub-therapeutic dose of sertraline (SER, 0.3mg/kg body weight, i.p.) or its vehicle (C, control group). Thirty minutes after injection, depression-like behaviors were quantified in forced swimming test (FST, for 5 min). On the following day, anxiety-like behaviors were assessed in elevated plus maze (EPM), followed by biochemical assessments. TS per se increased swimming time, decreasing immobility time in FST. Besides, TS per se was able to increase frequency of head dipping and time spent in the open arms of EPM, resulting in decreased anxiety index. In addition, groups exposed to TS showed decreased plasma levels of corticosterone per se. Interestingly, while TS exposure significantly potentiated the antidepressant activity of a subtherapeutic dose of SERT, this drug was able to exacerbate TS-induced anxiolytic activity, as observed in FST and EPM, respectively. Decreased plasma levels of both corticosterone and cortisol in animals exposed to TS and treated with SERT are able to confirm the interesting interaction between this neonatal handling and the antidepressant drug. From our results, we conclude that neonatal TS is able to exert beneficial influence on the ability to cope with stressful situations in adulthood, preventing depression and favorably

  14. The effects of Valeriana officinalis L. hydro-alcoholic extract on depression like behavior in ovalbumin sensitized rats

    PubMed Central

    Neamati, Ali; Chaman, Fariba; Hosseini, Mahmoud; Boskabady, Mohammad Hossein

    2014-01-01

    Background: Neuroimmune factors have been considered as contributors to the pathogenesis of depression. Beside other therapeutic effects, Valeriana officinalis L., have been suggested to have anti-inflammatory effects. In the present study, the effects of V. officinalis L. hydro alcoholic extract was investigated on depression like behavior in ovalbumin sensitized rats. Materials and Methods: A total of 50 Wistar rats were divided into five groups: Group 1 (control group) received saline instead of Valeriana officinalis L. extract. The animals in group 2 (sensitized) were treated by saline instead of the extract and were sensitized using the ovalbumin. Groups 3-5 (Sent - Ext 50), (Sent - Ext 100) and (Sent - Ext 200) were treated by 50, 100 and 200 mg/kg of V. officinalis L. hydro-alcoholic extract respectively, during the sensitization protocol. Forced swimming test was performed for all groups and immobility time was recorded. Finally, the animals were placed in the open-field apparatus and the crossing number on peripheral and central areas was observed. Results: The immobility time in the sensitized group was higher than that in the control group (P < 0.01). The animals in Sent-Ext 100 and Sent-Ext 200 groups had lower immobility times in comparison with sensitized group (P < 0.05 and P < 0.01). In the open field test, the crossed number in peripheral by the sensitized group was higher than that of the control one (P < 0.01) while, the animals of Sent-Ext 50, Sent-Ext 100 and Sent-Ext 200 groups had lower crossing number in peripheral compared with the sensitized group (P < 0.05 and P < 0.01 respectively). Furthermore, in the sensitized group, the central crossing number was lower than that of the control group (P < 0.001). In the animals treated by 200 mg/kg of the extract, the central crossing number was higher than that of the sensitized group (P < 0. 05). Conclusions: The results of the present study showed that the hydro-alcoholic extract of V. officinalis

  15. The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide - induced depression like behavior in rats

    PubMed Central

    Hosseini, Mahmoud; Zakeri, Samaneh; Khoshdast, Sadieh; Yousefian, Fatemeh T.; Rastegar, Monireh; Vafaee, Farzaneh; Kahdouee, Shamsi; Ghorbani, Fatemeh; Rakhshandeh, Hassan; Kazemi, S. Abolfazl

    2012-01-01

    Background: Neuroimmune factors have been proposed as contributors to the pathogenesis of depression. Beside other therapeutic effects including neuroprotective, antioxidant, anticonvulsant and analgesic effects, Nigella sativa and its main ingredient, thymoquinone (TQ), have been shown to have anti-inflammatory effects. In the present study, the effects of Nigella sativa hydro-alcoholic extract and thymoquinone was investigated on lipopolysaccharide- induced depression like behavior in rats. Materials and Methods: 50 male Wistar rats were divided into 5 groups: Group 1 (control group) received saline instead of NS extract, thymoquinone or lipopolysaccharide. The animals in group 2 (lipopolysaccharide (LPS)) were treated by saline instead of NS extract and were injected LPS (100μg/kg, ip) 2 hours before conducting each forced swimming test. Groups 3 (LPS + NS 200) and 4 (LPS + NS 400) were treated by 200 and 400 mg/kg of NS (ip), respectively, from the day before starting the experiments and before each forced swimming test. These animals were also injected LPS 2hours before conducting each swimming test. The animals in group 5 received TQ instead of NS extract. Forced swimming test was performed 3 times for all groups (in alternative days), and immobility time was recorded. Finally, the animals were placed in an open- field apparatus, and the crossing number on peripheral and central areas was observed. Results: The immobility time in the LPS group was higher than that in the control group in all 3 times (P<0.001). The animals in LPS + NS 200, LPS + NS 400 and LPS + TQ had lower immobility times in comparison with LPS groups (P<0.01, and P<0.01). In the open- field test, the crossing number of peripheral in the LPS group was higher than that of the control one (P<0.01) while the animals of LPS + NS 200, LPS + NS 400 and LPS + TQ groups had lower crossing number of peripheral compared with the LPS group (P <0.05, and P<0.001). Furthermore, in the LPS group, the

  16. Imbalance of leptin pathway and hypothalamus synaptic plasticity markers are associated with stress-induced depression in rats.

    PubMed

    Ge, Jin-Fang; Qi, Cong-Cong; Zhou, Jiang-Ning

    2013-07-15

    Increasing evidences have indicated that chronic stress is a contributing risk factor in the development of psychiatric illnesses including depression. The mechanisms of their psychopathology are multifaceted and include, besides others, alterations in neuroendocrine function and brain plasticity. In the present study, we investigated the behavior of stressed animals by the sucrose preference test, open field test (OFT), forced swimming test (FST), and tail-suspension test (TST). The response of hypothalamic-pituitary-adrenal (HPA) axis, leptin pathway, and synaptic plasticity markers in the hypothalamus were also detected. Our data demonstrated that chronic unpredictable mild stress (CUMS) could induce depression-like behavior in rat model, accompanied with the hyperactivity of HPA axis. The serum leptin level and hypothalamic mRNA expression of leptin receptor (LEPR) were both decreased. Results of Pearson test showed that the decreased serum leptin level was negatively related with the locomotion and rearing frequency in the open-field test, and the hypothalamic mRNA expression of LEPR was inversely related to serum CORT concentration. Moreover, our results showed that the mRNA expression of synaptotagmin I and synapsin I was both increased in the hypothalamus of CUMS rats, providing new evidence for the synaptic plasticity change in the hypothalamus of depressive rats. Furthermore, our results demonstrated that the mRNA expression of synaptotagmin I, but not synapsin I, was correlated with the depression-like behaviors and HPA axis hyperactivity in CUMS rats. Together with our previous results, the current findings suggested that a CUMS rat model could be effectively used to study molecular mechanisms underling the depressive symptomatology. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Preconditioning stress prevents cold restraint stress-induced gastric lesions in rats: roles of COX-1, COX-2, and PLA2.

    PubMed

    Tanaka, Akiko; Hatazawa, Ryo; Takahira, Yuka; Izumi, Nahoko; Filaretova, Ludmila; Takeuchi, Koji

    2007-02-01

    We investigated the protective effect of mild stress on gastric lesions induced by cold-restraint stress, especially concerning prostaglandins (PGs)/cyclo-oxygenase (COX) isozymes. Rats were exposed to severe stress (cold-restrai