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Sample records for mild stress-induced depressive-like

  1. A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice.

    PubMed

    Pesarico, Ana Paula; Sartori, Gláubia; Brüning, César A; Mantovani, Anderson C; Duarte, Thiago; Zeni, Gilson; Nogueira, Cristina Wayne

    2016-07-01

    Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression. PMID:27036647

  2. 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. PMID:26071959

  3. Not only serotonergic system, but also dopaminergic system involved in albiflorin against chronic unpredictable mild stress-induced depression-like behavior in rats.

    PubMed

    Song, Jingjing; Hou, Xintong; Hu, Xinyu; Lu, Chengyu; Liu, Chungang; Wang, Juan; Liu, Wei; Teng, Lirong; Wang, Di

    2015-12-01

    Albiflorin (AF), separated from the root of Paeonia lactiflora Pall, possesses neuro-protective and anti-inflammatory activities. Based on previous results, our present research aims to investigate the antidepressant-like activity of AF in chronic unpredictable mild stress (CUMS)-induced rat model of depression. Eight weeks of CUMS process successfully established depression-like rat model, as evidenced by the enhanced immobility time in forced swimming test and the reduced sucrose preference, which were reversed to near normal by AF (20 mg/kg and 40 mg/kg) and fluoxetine (3 mg/kg; positive drug) treated. Compared to non-treated depression-like rats, the increased levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HTAA) in serum and hypothalamus, and the reduced expressions of 5-HT1A receptor and 5-HT2A receptor in hypothalamus were observed after AF and fluoxetine oral administration indicating that AF-mediated antidepressant-like effect may be related to the normalization of serotonergic system. Additionally, four-week AF treated rats significantly showed improvement in the reduced dopamine and noradrenalin concentration in serum and hypothalamus as observed on depression-like rats. Altered levels of tyrosine hydroxylase, dopamine D2 receptor and dopamine transporter in hypothalamus reverted to the normal level after treatment with both AF and fluoxetine. All these data demonstrate that not only serotonergic system, but also dopaminergic system is involved in AF-mediated antidepressant-like effect in CUMS-induced rat model of depression. PMID:26475043

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

    PubMed

    Han, Jing; Wang, Dong-Sheng; Liu, Shui-Bing; Zhao, Ming-Gao

    2016-05-01

    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

  5. 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

  6. 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

  7. 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. PMID:27113683

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

    PubMed

    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

  9. 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

    2016-01-01

    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

  10. 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

  11. Repeated fluvoxamine treatment recovers juvenile stress-induced morphological changes and depressive-like behavior in rats.

    PubMed

    Lyttle, Kerise; Ohmura, Yu; Konno, Kohtarou; Yoshida, Takayuki; Izumi, Takeshi; Watanabe, Masahiko; Yoshioka, Mitsuhiro

    2015-08-01

    Human studies have suggested that early life stress such as child abuse could enhance susceptibility to depressive disorders. Moreover, the abnormalities of the prefrontal cortex have been associated with depression. Although clinical studies have implied the negative effects of early life stress on brain development, the causality and the detailed morphogenetic changes has not been clearly elucidated. In the present study, we determined the effect of juvenile stress exposure on the presentation of depressive-like behavior and the neural mechanisms involved using a rodent model. Rat pups were exposed to footshock stress during postnatal days 21-25 followed by repeated oral administration of fluvoxamine (0 or 10mg/kg/d × 14 days), which is a selective serotonin reuptake inhibitor. At the postadolescent stage forced swim test assessment of depressive-like behavior and Golgi-Cox staining of medial prefrontal cortex pyramidal neurons followed by morphological analyses were carried out. Post-adolescent behavioral and morphological studies identified the presentation of increased depressive-like behaviors and reduced spine densities and dendritic lengths of layer II/III pyramidal neuron in the infralimbic cortex, but not in the prelimbic cortex of rats exposed to juvenile stress. Repeated fluvoxamine treatment recovered the increased depressive-like behavior and reduced spine densities/dendritic lengths observed in rats exposed to footshock stress. Cortical thicknesses in the infralimbic cortex and prelimbic cortex were also reduced by juvenile stress, but these reductions were not recovered by fluvoxamine treatment. The results demonstrate cortical sensitivities to stress exposures during the juvenile stage which mediate behavioral impairments, and provide a clue to find therapeutics for early life stress-induced emotional dysfunctions. PMID:25960352

  12. Gastrodin reversed the traumatic stress-induced depressed-like symptoms in rats.

    PubMed

    Lee, Bombi; Sur, Bongjun; Yeom, Mijung; Shim, Insop; Lee, Hyejung; Hahm, Dae-Hyun

    2016-10-01

    Exposure to severe stress can lead to the development of neuropsychiatric disorders such as depression and post-traumatic stress disorder (PTSD) in at-risk individuals. Gastrodin (GAS), a primary constituent of an Oriental herbal medicine, has been shown to effectively treat various mood disorders. Thus, the present study aimed to determine whether GAS would ameliorate stress-associated depression-like behaviors in a rat model of single prolonged stress (SPS)-induced PTSD. Following the SPS procedure, rats received intraperitoneal administration of GAS (20, 50, or 100 mg/kg) once daily for 2 weeks. Subsequently, the rats performed the forced swimming test, and norepinephrine (NE) levels in the hippocampus were measured. Daily GAS (100 mg/kg) significantly reversed depression-like behaviors and restored SPS-induced increases in hippocampal NE concentrations as well as tyrosine hydroxylase expression in the locus coeruleus. Furthermore, the administration of GAS attenuated SPS-induced decreases in the hypothalamic expression of neuropeptide Y and the hippocampal mRNA expression of brain-derived neurotrophic factor. These findings indicate that GAS possesses antidepressant effects in the PTSD and may be an effective herbal preparation for the treatment of PTSD. PMID:27417451

  13. 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. PMID:21093519

  14. Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7.

    PubMed

    Xu, Chang; Ma, Xin-Ming; Chen, Hui-Bin; Zhou, Meng-He; Qiao, Hui; An, Shu-Cheng

    2016-10-01

    Neuroimaging studies show that patients with major depression have reduced volume of the orbitofrontal cortex (OFC). Although the serotonin (5-HT) 2A receptor, which is abundant in the OFC, has been implicated in depression, the underlying mechanisms in the development of stress-induced depression remain unclear. Kalirin-7 (Kal7) is an essential component of mature excitatory synapses for maintaining dendritic spines density, size and synaptic functions. The aim of this study was to investigate the role of orbitofrontal 5-HT and 5-HT2A receptors in depressive-like behaviors and their associations with Kal7 and dendritic spines using chronic unpredictable mild stress (CUMS), an established animal model of depression. CUMS had no effect on the levels of 5-HT or the 5-HT2A receptor in the OFC. However, CUMS or microinjection of the 5-HT2A/2C receptor agonist (±)-1-(2, 5-Dimethoxy-4-iodophenyl)- 2-aminopropane hydrochloride (DOI, 5 μg/0.5 μL) into the OFC induced depressive-like behaviors, including anhedonia in the sucrose preference test and behavioral despair in the tail suspension test, a significant reduction in body weight gain and locomotor activity in the open field test, which were accompanied by decreased expression of Kal7 and PSD95 as well as decreased density of dendritic spines in the OFC. These alterations induced by CUMS were reversed by pretreatment with the 5-HT2A receptor antagonist Ketanserin (Ket, 5 μg/0.5 μL into the OFC). These results suggest that CUMS alters structural plasticity through activation of the orbital 5-HT2A receptor and is associated with decreased expression of Kal7, thereby resulting in depressive-like behaviors in rats, suggesting an important role of Kal7 in the OFC in depression. PMID:26921771

  15. Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.

    PubMed

    Cheng, Yuyan; Pardo, Marta; Armini, Rubia de Souza; Martinez, Ana; Mouhsine, Hadley; Zagury, Jean-Francois; Jope, Richard S; Beurel, Eleonore

    2016-03-01

    Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and

  16. Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway.

    PubMed

    Xu, Ying; Zhang, Chong; Wu, Feiyan; Xu, Xiaoxiao; Wang, Gang; Lin, Mengmeng; Yu, Yingcong; An, Yiran; Pan, Jianchun

    2016-08-01

    Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress. PMID:26946512

  17. 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

  18. Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice.

    PubMed

    Hellwig, Sabine; Brioschi, Simone; Dieni, Sandra; Frings, Lars; Masuch, Annette; Blank, Thomas; Biber, Knut

    2016-07-01

    Microglia are suggested to be involved in several neuropsychiatric diseases. Indeed changes in microglia morphology have been reported in different mouse models of depression. A crucial regulatory system for microglia function is the well-defined CX3C axis. Thus, we aimed to clarify the role of microglia and CX3CR1 in depressive behavior by subjecting CX3CR1-deficient mice to a particular chronic despair model (CDM) paradigm known to exhibit face validity to major depressive disorder. In wild-type mice we observed the development of chronic depressive-like behavior after 5days of repetitive swim stress. 3D-reconstructions of Iba-1-labeled microglia in the dentate molecular layer revealed that behavioral effects were associated with changes in microglia morphology towards a state of hyper-ramification. Chronic treatment with the anti-depressant venlafaxine ameliorated depression-like behavior and restored microglia morphology. In contrast, CX3CR1 deficient mice showed a clear resistance to either (i) stress-induced depressive-like behavior, (ii) changes in microglia morphology and (iii) antidepressant treatment. Our data point towards a role of hyper-ramified microglia in the etiology of chronic depression. The lack of effects in CX3CR1 deficient mice suggests that microglia hyper-ramification is controlled by neuron-microglia signaling via the CX3C axis. However, it remains to be elucidated how hyper-ramified microglia contribute to depressive-like behavior. PMID:26576722

  19. 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. PMID:24839933

  20. 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. PMID:26890656

  1. 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. PMID:25576700

  2. Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice.

    PubMed

    Zhao, Yunan; Wang, Zhongli; Dai, Jianguo; Chen, Lin; Huang, Yufang; Zhan, Zhen

    2012-03-17

    Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5mg/kg) and medium-dose (1mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress. PMID:22198054

  3. Stress-induced increases in depression-like and cocaine place-conditioned behaviors are reversed by disruption of memories during reconsolidation.

    PubMed

    Hymel, Kristen A; Eans, Shainnel O; L Sitchenko, Kaitlin; Gomes, Stacey M; Lukowsky, Alison L; Medina, Jessica M; Sypek, Elizabeth I; Carey, Amanda N; McLaughlin, Jay P

    2014-09-01

    Maladaptive behavioral responses characteristic of post-traumatic stress disorders are notably resistant to treatment. We hypothesized that the pharmacological disruption of memories activated during reconsolidation might reverse established stress-induced increases in depression-like behaviors and cocaine reward. C57BL/6J mice were subjected to repeated social defeat stress (SDS), and examined for time spent immobile in a subsequent forced swim test (FST). An additional set of SDS-exposed mice were place-conditioned with cocaine, and tested for cocaine-conditioned place preference (CPP). All stress-exposed mice were then subjected to a single additional trial of SDS while under the influence of propranolol or cycloheximide to disrupt memory reconsolidation, then given one additional FST or CPP test the next day. Mice subjected to repeated SDS subsequently demonstrated increases in time spent immobile in the FST or in the cocaine-paired chamber. Vehicle-treatment followed by additional SDS exposure did not alter these behaviors, but propranolol or cycloheximide treatment reversed each of the potentiated responses in a dose-dependent manner. Overall, these results demonstrate that while repeated exposure to a social defeat stressor subsequently increased depression-like behavior and cocaine-CPP, disruption of traumatic memories made labile by re-exposure to SDS during reconsolidation may have therapeutic value in the treatment of established post-traumatic stress disorder-related behaviors. PMID:25083575

  4. 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

  5. The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats.

    PubMed

    Liu, Z; Qi, Y; Cheng, Z; Zhu, X; Fan, C; Yu, S Y

    2016-05-13

    Depression is a common neuropsychiatric disorder which has been associated with a wide range of structural and functional changes within specific brain regions. Ginsenoside Rg1 has been shown to exert a number of neuroprotective effects as demonstrated in various in vivo and in vitro studies. However, little information is available regarding the site and mechanisms of ginsenoside Rg1 in promoting antidepressant effects. The present study aimed to investigate the neuroprotective and ameliorating effects of ginsenoside Rg1 on depression-like behavior as induced by chronic unpredictable mild stress (CUMS). The results showed that CUMS was effective in producing depression-like behaviors in rats as indicated by decreased responses in sucrose preference and forced swim tests which were associated with ultrastructural changes in neurons within the amygdala. Moreover, levels of PKA and CREB phosphorylation and the expression of brain-derived neurotrophic factor (BDNF) were decreased in the amygdala of CUMS rats. Remarkably, chronic ginsenoside Rg1 (40mg/kg, i.p., 5weeks) treatment significantly ameliorated these behavioral and biochemical alterations associated with CUMS-induced depression. Taken together, the results of the present study demonstrate that ginsenoside Rg1 exhibits antidepressant-like effects against CUMS-induced depression. This amelioration of depression-like behaviors by ginsenoside Rg1 appears to be mediated, at least in part, by a CREB-regulated increase of BDNF expression in the amygdala of rats. Therefore, these findings reveal the therapeutic potential of ginsenoside Rg1 for use in clinical trials in the treatment of depression. PMID:26926964

  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 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

  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

    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

  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. PMID:26796696

  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. Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice.

    PubMed

    Wu, Ruiyong; Shui, Li; Wang, Siyang; Song, Zhenzhen; Tai, Fadao

    2016-10-01

    Bilobalide (BB), a unique constituent of Ginkgo biloba, has powerful neuroprotection and stress-alleviating properties. However, whether BB exerts a positive effect on depression and cognitive deficit induced by chronic stress is not known. The present study was designed to investigate the influence of BB on depression and cognitive impairments induced by chronic unpredictable mild stress (CUMS) in mice. During daily exposure to stressors for 5 consecutive weeks, mice were administered BB at the doses of 0, 3, or 6 mg/kg/day intraperitoneally. We replicated the finding that CUMS induced depression-like behavior and cognitive deficits as the CUMS+vehicle (VEH) group showed a significant increase in immobility in the tail suspension test, a decrease in the discrimination index of the novel object recognition task, and increased latency to platform and decreased number of platform crossings in the Morris water maze compared with the control+VEH group. Chronic administration of BB effectively reversed these alterations. In addition, the CUMS+VEH group showed significantly higher levels of baseline serum corticosterone than those of the control+VEH group and BB dose-dependently inhibited this effect. Our results suggest that BB may be useful for inhibition of depression-like behavior and cognitive deficits, and this protective effect was possibly exerted partly through an action on the hypothalamic-pituitary-adrenal axis. PMID:27509313

  11. Resveratrol reverses chronic restraint stress-induced depression-like behaviour: Involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats.

    PubMed

    Wang, Xueer; Xie, Yunkai; Zhang, Tiantian; Bo, Shishi; Bai, Xuemei; Liu, Hansen; Li, Tong; Liu, Song; Zhou, Yaru; Cong, Xiang; Wang, Zhen; Liu, Dexiang

    2016-07-01

    Chronic stress occurs in everyday life and induces depression-like behaviors, associated with proteins alterations and apoptosis in brain. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic restraint stress (CRS) - induced depression-like behaviors and explores underlying mechanisms. Male Wistar rats were subjected to CRS protocol for a period of 3 weeks to induce depressive-like behavior. The results showed that resveratrol (80mg/kg/i.p) administrated for 3 weeks significantly reversed the CRS-induced behavioral abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CRS exposure significantly decreased BDNF levels and phosphorylation of extracellular signal-regulated kinase (pERK) in hippocampus and prefrontal cortex (PFC), accompanied by decreased Bcl-2 mRNA expression and increased Bax mRNA expression, while resveratrol treatment normalized these levels. All of these effects of resveratrol were essentially identical to that observed with fluoxetine. In conclusion, our studies showed that resveratrol exerted antidepressant-like effects in CRS rats, mediated in part by the apoptotic machinery and up-regulating BDNF and pERK levels in the brain region. PMID:27346276

  12. 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. PMID:25200517

  13. 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

    2015-12-01

    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

  14. 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

  15. Unpredictable chronic mild stress not chronic restraint stress induces depressive behaviours in mice.

    PubMed

    Zhu, Shenghua; Shi, Ruoyang; Wang, Junhui; Wang, Jun-Feng; Li, Xin-Min

    2014-10-01

    The chronic stress model was developed on the basis of the stress-diathesis hypothesis of depression. However, these behavioural responses associated with different stress paradigms are quite complex. This study examined the effects of two chronic stress regimens on anxiety-like and depressive behaviours. C57BL/6 mice were subjected to unpredictable chronic mild stress or to chronic restraint stress for 4 weeks. Subsequently, both anxiety-like behaviours (open field, elevated plus maze and novelty suppressed feeding) and depression-like behaviours (tail suspension, forced swim and sucrose preference) were evaluated. Both chronic stress models generated anxiety-like behaviours, whereas only unpredictable chronic mild stress could induce depressive behaviours such as increased immobility and decreased sucrose consumption. These results of the present study provide additional evidence on how chronic stress affects behavioural responses and point to the importance of the validity of animal models of chronic stress in studying depression. PMID:25089805

  16. 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. PMID:26901349

  17. 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

  18. MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning.

    PubMed

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

    2009-10-01

    3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide 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. Whereas 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

  19. 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

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

    PubMed

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

    2016-01-01

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

  1. Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression.

    PubMed

    Li, Lu-Fan; Yang, Jie; Ma, Shi-Ping; Qu, Rong

    2013-07-01

    Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain. PMID:23632393

  2. Antidepressant-like activity of 10-hydroxy-trans-2-decenoic Acid, a unique unsaturated Fatty Acid of royal jelly, in stress-inducible depression-like mouse model.

    PubMed

    Ito, Satoru; Nitta, Yuji; Fukumitsu, Hidefumi; Soumiya, Hitomi; Ikeno, Kumiko; Nakamura, Tadashi; Furukawa, Shoei

    2012-01-01

    Symptoms of depression and anxiety appeared in mice after they had been subjected to a combination of forced swimming for 15 min followed by being kept in cages that were sequentially subjected to leaning, drenching, and rotation within 1-2 days for a total of 3 weeks. The animals were then evaluated by the tail-suspension test, elevated plus-maze test, and open-field test at 1 day after the end of stress exposure. Using these experimental systems, we found that 10-hydroxy-trans-2-decenoic acid (HDEA), an unsaturated fatty acid unique to royal jelly (RJ), protected against the depression and anxiety when intraperitoneally administered once a day for 3 weeks simultaneously with the stress loading. Intraperitoneally administered RJ, a rich source of HDEA, was also protective against the depression, but RJ given by the oral route was less effective. Our present results demonstrate that HDEA and RJ, a natural source of it, were effective in ameliorating the stress-inducible symptoms of depression and anxiety. PMID:21799699

  3. Umbelliferone attenuates unpredictable chronic mild stress induced-insulin resistance in rats.

    PubMed

    Su, Qiang; Tao, Weiwei; Wang, Hanqing; Chen, Yanyan; Huang, Huang; Chen, Gang

    2016-05-01

    The aim of this study was to investigate whether umbelliferone (Umb) could attenuate insulin resistance in unpredictable chronic mild stress (CUMS)-induced rats. Behavioral changes were evaluated through sucrose preference test (SPT), open-field test, forced swimming test, and tail suspension test (TST), suggesting that Umb (20 and 40 mg/kg) could effectively improve depression symptoms. Oral glucose tolerance test and serum insulin indicated that Umb attributed to the control of blood glucose levels. The phosphorylation of insulin receptor, insulin receptor substrate (IRS)-1, glycogen synthase kinase-3β, PI3K, and Akt was increased in Umb (20 and 40 mg/kg) treatment according to Western blot analysis. Taken together, the current results suggested the ameliorative effect of Umb against insulin resistance in the CUMS-induced rats. © 2016 IUBMB Life, 68(5):403-409, 2016. PMID:27027512

  4. Treadmill exercise alleviates chronic mild stress-induced depression in rats

    PubMed Central

    Lee, Taeck-Hyun; Kim, Kijeong; Shin, Mal-Soon; Kim, Chang-Ju; Lim, Baek-Vin

    2015-01-01

    Depression is a major cause of disability and one of the most common public health problems. In the present study, antidepressive effect of treadmill exercise on chronic mild stress (CMS)-induced depression in rats was investigated. For this, sucrose intake test, immunohistochemistry for 5-bromo-2′-deoxyuridine, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot analysis for brain-derived neurotrophic factor, cyclic adenosine monophosphate response element binding protein, and endothelial nitric oxide synthase were conducted. Following adaptation to the animal vivarium and two baseline fluid intake tests, the animals were divided into four groups: the control group, the CMS-induced depression group, the CMS-induced depression and exercise group, and the CMS-induced depression and fluoxetine-treated group. The animals in the CMS groups were exposed to the CMS conditions for 8 weeks and those in the control group were exposed to the control conditions for 8 weeks. After 4 weeks of CMS, the rats in the CMS-induced depression and exercise group were made to run on a motorized treadmill for 30 min once a day for 4 weeks. In the present results, treadmill exercise alleviated CMS-induced depressive symptoms. Treadmill exercise restored sucrose consumption, increased cell proliferation, and decreased apoptotic cell death. The present results suggest the possibility that exercise may improve symptoms of depression. PMID:26730380

  5. Treadmill exercise alleviates chronic mild stress-induced depression in rats.

    PubMed

    Lee, Taeck-Hyun; Kim, Kijeong; Shin, Mal-Soon; Kim, Chang-Ju; Lim, Baek-Vin

    2015-12-01

    Depression is a major cause of disability and one of the most common public health problems. In the present study, antidepressive effect of treadmill exercise on chronic mild stress (CMS)-induced depression in rats was investigated. For this, sucrose intake test, immunohistochemistry for 5-bromo-2'-deoxyuridine, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot analysis for brain-derived neurotrophic factor, cyclic adenosine monophosphate response element binding protein, and endothelial nitric oxide synthase were conducted. Following adaptation to the animal vivarium and two baseline fluid intake tests, the animals were divided into four groups: the control group, the CMS-induced depression group, the CMS-induced depression and exercise group, and the CMS-induced depression and fluoxetine-treated group. The animals in the CMS groups were exposed to the CMS conditions for 8 weeks and those in the control group were exposed to the control conditions for 8 weeks. After 4 weeks of CMS, the rats in the CMS-induced depression and exercise group were made to run on a motorized treadmill for 30 min once a day for 4 weeks. In the present results, treadmill exercise alleviated CMS-induced depressive symptoms. Treadmill exercise restored sucrose consumption, increased cell proliferation, and decreased apoptotic cell death. The present results suggest the possibility that exercise may improve symptoms of depression. PMID:26730380

  6. 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. PMID:21614890

  7. Chronic mild stress facilitates melanoma tumor growth in mouse lines selected for high and low stress-induced analgesia.

    PubMed

    Ragan, Agnieszka R; Lesniak, Anna; Bochynska-Czyz, Marta; Kosson, Anna; Szymanska, Hanna; Pysniak, Kazimiera; Gajewska, Marta; Lipkowski, Andrzej W; Sacharczuk, Mariusz

    2013-09-01

    Both chronic stress conditions and hyperergic reaction to environmental stress are known to enhance cancer susceptibility. We described two mouse lines that displayed high (HA) and low (LA) swim stress-induced analgesia (SSIA) to investigate the relationship between inherited differences in sensitivity to stress and proneness to an increased growth rate of subcutaneously inoculated melanoma. These lines display several genetic and physiological differences, among which distinct sensitivity to mutagens and susceptibility to cancer are especially noticeable. High analgesic mice display high proneness both to stress and a rapid local spread of B16F0 melanoma. However, stress-resistant LA mice do not develop melanoma tumors after inoculation, or if so, tumors regress spontaneously. We found that the chronic mild stress (CMS) procedure leads to enhanced interlinear differences in melanoma susceptibility. Tumors developed faster in stress conditions in both lines. However, LA mice still displayed a tendency for spontaneous regression, and 50% of LA mice did not develop a tumor, even under stressed conditions. Moreover, we showed that chronic stress, but not tumor progression, induces depressive behavior, which may be an important clue in cancer therapy. Our results clearly indicate how the interaction between genetic susceptibility to stress and environmental stress determine the risk and progression of melanoma. To our knowledge, HA/LA mouse lines are the first animal models of distinct melanoma progression mediated by inherited differences in stress reactivity. PMID:23688070

  8. Cannabinoid modulation of chronic mild stress-induced selective enhancement of trace fear conditioning in adolescent rats.

    PubMed

    Reich, Christian G; Iskander, Anthony N; Weiss, Michael S

    2013-10-01

    History of stress is considered a major risk factor for the development of major depression and posttraumatic stress disorder (PTSD). Elucidating the neurobiological mechanisms of Pavlovian fear conditioning may provide insight into the etiology of PTSD. In the current study, adolescent male Sprague-Dawley rats were exposed to 3 weeks of a chronic-mild-unpredictable stress (CMS) protocol. Immediately following the CMS, the animals were subjected to hippocampal-dependent (trace and contextual) and hippocampal-independent (delay) fear conditioning. CMS exposure enhanced trace freezing behavior compared to non-stress controls. This effect was not observed in contextual or delay conditioned animals. Given that the endocannabinoid system is negatively affected by CMS procedures, separate groups of stressed rats were administered the CB1 receptor agonist, ACEA (0.1 mg/kg), prior to trace fear conditioning or a memory-recall test. Regardless of administration time, ACEA significantly reduced freezing behavior in stressed animals. Furthermore, when administered during the first memory recall test, ACEA enhanced long-term extinction in both stress and non-stress groups. The results demonstrate that chronic unpredictable stress selectively enhances hippocampal-dependent episodic fear memories. Pathologies of the episodic memory and fear response may increase the susceptibility of developing PTSD. Reduction in fear responses via exogenous activation of the CB1 receptor suggests that a deficiency in the endocannabinoid system contributes to this pathology. PMID:23926242

  9. Chronic unpredicted mild stress-induced depression alter saxagliptin pharmacokinetics and CYP450 activity in GK rats.

    PubMed

    Xia, Zhengchao; Wei, Hongyan; Duan, Jingjing; Zhou, Ting; Yang, Zhen; Xu, Feng

    2016-01-01

    Background. This study was to explore the pharmacokinetics of saxagliptin (Sax) in Goto-Kakizaki (GK) rats complicated with depression induced by chronic unpredicted mild stress (CUMS). The comorbidity of diabetic patients with depression is becoming more and more epidemic. Whether depression mental disorder alters the pharmacokinetics of hypoglycemic drugs in diabetes patients is not clear. Methods. Five-week-old male GK rats were kept in the cage for 7 weeks in a specific pathogen free (SPF)-grade lab until the emergence of diabetes and were then divided into two groups: control group and depression model group. Rats in the CUMS-induced depression group were exposed to a series of stressors for 8 weeks. Plasma serotonin and dopamine levels and behavior of open-field test were used to confirm the establishment of the depression model. All rats were given 0.5 mg/kg Sax orally after 8 weeks and blood samples were collected at different time points. The Sax concentration was assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The CYP450 activity of the liver microsomes was determined by using cocktails of probe drugs in which the activities of CYP enzymes were assessed through the determination of the production of the probe drugs. Results. Statistically significant differences in Sax pharmacokinetics were observed for area under curve, clearance, peak concentration, peak time and mean residence time between the depression rats and the control rats, while no statistical differences were observed for half-time and distribution volume by HPLC-MS/MS analysis. The CYP450 activity had different changes in the depression group. Conclusions. These results indicated that CUMS-induced depression alters the drug metabolic process of Sax and CYP450 activity of the liver microsomal enzymes in GK rats. PMID:26819853

  10. Chronic unpredicted mild stress-induced depression alter saxagliptin pharmacokinetics and CYP450 activity in GK rats

    PubMed Central

    Xia, Zhengchao; Wei, Hongyan; Duan, Jingjing; Zhou, Ting; Yang, Zhen

    2016-01-01

    Background. This study was to explore the pharmacokinetics of saxagliptin (Sax) in Goto–Kakizaki (GK) rats complicated with depression induced by chronic unpredicted mild stress (CUMS). The comorbidity of diabetic patients with depression is becoming more and more epidemic. Whether depression mental disorder alters the pharmacokinetics of hypoglycemic drugs in diabetes patients is not clear. Methods. Five-week-old male GK rats were kept in the cage for 7 weeks in a specific pathogen free (SPF)-grade lab until the emergence of diabetes and were then divided into two groups: control group and depression model group. Rats in the CUMS-induced depression group were exposed to a series of stressors for 8 weeks. Plasma serotonin and dopamine levels and behavior of open-field test were used to confirm the establishment of the depression model. All rats were given 0.5 mg/kg Sax orally after 8 weeks and blood samples were collected at different time points. The Sax concentration was assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The CYP450 activity of the liver microsomes was determined by using cocktails of probe drugs in which the activities of CYP enzymes were assessed through the determination of the production of the probe drugs. Results. Statistically significant differences in Sax pharmacokinetics were observed for area under curve, clearance, peak concentration, peak time and mean residence time between the depression rats and the control rats, while no statistical differences were observed for half-time and distribution volume by HPLC-MS/MS analysis. The CYP450 activity had different changes in the depression group. Conclusions. These results indicated that CUMS-induced depression alters the drug metabolic process of Sax and CYP450 activity of the liver microsomal enzymes in GK rats. PMID:26819853

  11. Hypothalamic Proteomic Analysis Reveals Dysregulation of Glutamate Balance and Energy Metabolism in a Mouse Model of Chronic Mild Stress-Induced Depression.

    PubMed

    Rao, Chenglong; Shi, Haiyang; Zhou, Chanjuan; Zhu, Dan; Zhao, Mingjun; Wang, Ziye; Yang, Yongtao; Chen, Jin; Liao, Li; Tang, Jianyong; Wu, You; Zhou, Jian; Cheng, Ke; Xie, Peng

    2016-09-01

    Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity is observed in many patients suffering from depression. However, the mechanism underlying the dysfunction of the HPA axis is not well understood. Moreover, dysfunction of the hypothalamus, the key brain region of the HPA axis, has not been well-explored. The aim of our study was to examine possible alterations in hypothalamus protein expression in a model of depression using proteomic analysis. In order to achieve this aim, mice were exposed to chronic unpredictable mild stress (CUMS), as the paradigm results in hyperactivity of the HPA axis. Differential protein expression between the hypothalamic proteomes of CUMS and control mice was then assessed through two-dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry. Thirty-seven proteins with a threshold of a 1.5-fold change and a p value ≤0.05 were identified as being differentially expressed between CUMS and control mice, and were quantified for bioinformatics analysis. Glycometabolism, citrate cycle (TCA cycle) and oxidation respiratory chain were found to have changed significantly. Glial fibrillary acidic protein and glutamine synthetase were further validated by Western Blot. Our results demonstrated that CUMS mice exhibited a dramatic protein change both in glutamate metabolism and energy mobilization, which may shed some light on the role of the hypothalamus in the pathology of stress-induced depression. PMID:27230881

  12. Antidepressant-like effect of essential oil of Perilla frutescens in a chronic, unpredictable, mild stress-induced depression model mice.

    PubMed

    Ji, Wei-Wei; Li, Rui-Peng; Li, Meng; Wang, Shu-Yuan; Zhang, Xian; Niu, Xing-Xing; Li, Wei; Yan, Lu; Wang, Yang; Fu, Qiang; Ma, Shi-Ping

    2014-10-01

    Perilla frutescens (Perilla leaf), a garnishing vegetable in East Asian countries, as well as a plant-based medicine, has been used for centuries to treat various conditions, including depression. Several studies have demonstrated that the essential oil of P. frutescens (EOPF) attenuated the depressive-like behavior in mice. The present study was designed to test the anti-depressant effects of EOPF and the possible mechanisms in an chronic, unpredictable, mild stress (CUMS)-induced mouse model. With the exposure to stressor once daily for five consecutive weeks, EOPF (3, 6, and 9 mg·kg(-1)) and a positive control drug fluoxetine (20 mg·kg(-1)) were administered through gastric intubation to mice once daily for three consecutive weeks from the 3(rd) week. Open-field test, sucrose consumption test, tail suspension test (TST), and forced swimming test (FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in mouse hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). The results showed that CUMS significantly decreased the levels of 5-HT and 5-HIAA in the hippocampus, with an increase in plasma IL-6, IL-1β, and TNF-α levels. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. EOPF administration could effectively reverse the alterations in the concentrations of 5-HT and 5-HIAA; reduce the IL-6, IL-1β, and TNF-α levels. Moreover, EOPF could effectively reverse alterations in immobility duration, sucrose consumption, and open-field activity. However, the effect was not dose-dependent. In conclusion, EOPF administration exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of EOPF might be related to the relation between

  13. 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

    2015-05-01

    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. PMID:25732137

  14. Mechanism of heat stress-induced cellular senescence elucidates the exclusive vulnerability of early S-phase cells to mild genotoxic stress

    PubMed Central

    Velichko, Artem K.; Petrova, Nadezhda V.; Razin, Sergey V.; Kantidze, Omar L.

    2015-01-01

    Heat stress is one of the best-studied cellular stress factors; however, little is known about its delayed effects. Here, we demonstrate that heat stress induces p21-dependent cellular senescence-like cell cycle arrest. Notably, only early S-phase cells undergo such an arrest in response to heat stress. The encounter of DNA replication forks with topoisomerase I-generated single-stranded DNA breaks resulted in the generation of persistent double-stranded DNA breaks was found to be a primary cause of heat stress-induced cellular senescence in these cells. This investigation of heat stress-induced cellular senescence elucidates the mechanisms underlying the exclusive sensitivity of early S-phase cells to ultra-low doses of agents that induce single-stranded DNA breaks. PMID:26032771

  15. 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. PMID:27025444

  16. 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

  17. Metabonomic Evaluation of Chronic Unpredictable Mild Stress-Induced Changes in Rats by Intervention of Fluoxetine by HILIC-UHPLC/MS

    PubMed Central

    Zhao, Longshan; Xiong, Zhili; Lu, Xiumei; Zheng, Shuning; Wang, Fang; Ge, Lin; Su, Guangyue; Yang, Jingyu; Wu, Chunfu

    2015-01-01

    Hydrophilic interaction-ultra high performance liquid chromatography (HILIC-UHPLC) allows the analysis of highly polar metabolites, providing complementary information to reversed-phase (RP) chromatography. By optimization of the preparation and analytical conditions in HILIC mode, HILIC-UHPLC/MS was applied for the global metabolic profiling of rat plasma samples generated in an experimental model of chronic unpredictable mild stress (CUMS), and the concomitant investigation of the protective effect of fluoxetine was also evaluated. Identification of plasma metabolic profiles indicated that significant changes in specific metabolites occurred after fluoxetine exposure, including increased phenylalanine, serine, acetyl-L-carnitine, carnitine and decreased creatine, betaine, proline, tryptophan, tyrosine, C16:0 LPC. Some novel biomarkers from this HILIC-UHPLC/MS approach were betaine, proline, tyrosine creatine and serine compared with the results of RP-UHPLC/MS. The complementary nature of this technique is confirmed and is on agreement with previously published studies. PMID:26080063

  18. 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. PMID:25037773

  19. Hydrogen Sulfide Protects against Chronic Unpredictable Mild Stress-Induced Oxidative Stress in Hippocampus by Upregulation of BDNF-TrkB Pathway

    PubMed Central

    Zou, Wei; Wang, Chun-Yan; Tan, Hui-Ying; Zeng, Hai-Ying; Zhang, Ping; Gu, Hong-Feng

    2016-01-01

    Chronic unpredictable mild stress (CUMS) induces hippocampal oxidative stress. H2S functions as a neuroprotectant against oxidative stress in brain. We have previously shown the upregulatory effect of H2S on BDNF protein expression in the hippocampus of rats. Therefore, we hypothesized that H2S prevents CUMS-generated oxidative stress by upregulation of BDNF-TrkB pathway. We showed that NaHS (0.03 or 0.1 mmol/kg/day) ameliorates the level of hippocampal oxidative stress, including reduced levels of malondialdehyde (MDA) and 4-hydroxy-2-trans-nonenal (4-HNE), as well as increased level of glutathione (GSH) and activity of superoxide dismutase (SOD) in the hippocampus of CUMS-treated rats. We also found that H2S upregulated the level of BDNF and p-TrkB protein in the hippocampus of CUMS rats. Furthermore, inhibition of BDNF signaling by K252a, an inhibitor of the BDNF receptor TrkB, blocked the antioxidant effects of H2S on CUMS-induced hippocampal oxidative stress. These results reveal the inhibitory role of H2S in CUMS-induced hippocampal oxidative stress, which is through upregulation of BDNF/TrkB pathway. PMID:27525050

  20. Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis.

    PubMed

    Cai, Li; Li, Rong; Tang, Wen-jian; Meng, Gang; Hu, Xiang-yang; Wu, Ting-ni

    2015-08-01

    Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis. PMID:25914157

  1. Metabonomic identification of the effects of the Zhimu-Baihe saponins on a chronic unpredictable mild stress-induced rat model of depression.

    PubMed

    Du, Hongli; Wang, Keqing; Su, Li; Zhao, Hongxia; Gao, Songyan; Lin, Qishan; Ma, Xiaofang; Zhu, Baokang; Dong, Xin; Lou, Ziyang

    2016-09-01

    The herbal pair Zhimu-Baihe (Zhimu: Anemarrhena asphodeloides; Baihe: Lilium brownii var. viridulum) is a traditional Chinese medicament used for the treatment of depression. However, the relevant mechanisms of action has not been clarified. This study investigated the anti-depressant activity of the total saponins from Zhimu and Baihe and the mechanisms underlying using a chronic unpredictable mild stress (CUMS)-induced rat model of depression. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was applied to determine the levels of three monoamine neurotransmitters, 5-hydroxytryptamine (5-HT), noradrenaline (NE) and dopamine (DA), in the rat hippocampus. Optimized pretreatment of samples and mass spectrometry conditions were used to analyse the metabonomic profile of the hippocampus. The 5-HT and NE levels in the CUMS group were reduced compared with the control group, whereas all groups had similar DA levels. The metabonomic profile of the hippocampus revealed 32 differential metabolites between the CUMS and control group, among which 18 metabolites were significantly recovered in the Anemarrhena saponins and Lilium saponins (AL) combination intervention group. These results suggested an anti-depressant effect of AL. Moreover, 24 metabolites in AL group were better recovered compared with the Anemarrhena saponins (AS) or Lilium saponins (LS) intervention groups, suggesting a synergetic effect of AS and LS in the treatment of depression. The anti-depressant effect might be related to the regulation of several metabolic pathways, including monoamine neurotransmitter synthesis (especially 5-HT and NE), and amino acid, fatty acid, and phospholipid metabolism in rats. PMID:27371920

  2. 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. PMID:26348076

  3. Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus.

    PubMed

    Wang, Yujun; Xu, Yongjun; Sheng, Hui; Ni, Xin; Lu, Jianqiang

    2016-07-01

    Exercise has benefit for perimenopause women in many ways, such as affective disorders. Our previous study has demonstrated that inflammation in hippocampus contributes to development of depression-like behavior in ovariectomized (OVX) rats. Recently, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated to be involved in lipopolysaccharide (LPS)- and chronic stress-induced depression-like behavior in rodents. We sought to investigate whether ovariectomy-induced depression-like behavior is associated with NLRP3 inflammasome activation in brain and the effect of exercise on NLRP3 inflammasome activation in this model. The results showed that ovariectomy resulted in depression-like behavior in mice and an increase in levels of IL-1β and IL-18 in hippocampus. Exercise ameliorated the depression-like behavior and decreased levels of IL-1β and IL-18 in hippocampus. The level of IL-1β and IL-18 in hippocampus correlated to depression-like behavior in OVX mice. The levels of NLRP3, cleaved caspase-1 P10 and CD11b in hippocampus were increased in OVX mice compared with control group. Exercise could reduce the levels of NLRP3, cleaved caspase-1 P10 and CD11b in OVX mice. Our study suggests that NLRP3 inflammasome activation contribute to inflammation in hippocampus upon to deprivation of ovary. Exercise amelioration of depression-like behavior is associated with suppression of NLRP3 inflammasome activation in hippocampus of this model. PMID:27036651

  4. Electroconvulsive stimulation reverses anhedonia and cognitive impairments in rats exposed to chronic mild stress.

    PubMed

    Henningsen, K; Woldbye, D P D; Wiborg, O

    2013-12-01

    Electroconvulsive therapy remains the most effective treatment for depression including a fast onset of action. However, this therapeutic approach suffers from some potential drawbacks. In the acute phase this includes amnesia. Electroconvulsive stimulation (ECS) has previously been shown to reverse a depression-like state in the chronic mild stress model of depression (CMS), but the effect of ECS on cognition has not previously been investigated. In this study the CMS model was used to induce a depressive-like condition in rats. The study was designed to investigate the acute effect of ECS treatment on working memory and the chronic effect of repeated ECS treatments on depression-like behavior and working memory. The results indicated that, in the acute phase, ECS treatment induced a working memory deficit in healthy controls unexposed to stress, while repeated treatments reversed stress-induced decline in working memory, as well as recovering rats submitted to the CMS paradigm from the anhedonic-like state. Like in the clinical setting, a single ECS exposure was ineffective in inducing remission from a depression-like state. PMID:23597878

  5. 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

  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. 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

  8. 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

    2016-01-01

    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

  9. 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

  10. 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

  11. 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

  12. 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. PMID:27082990

  13. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats

    PubMed Central

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

    2014-01-01

    Background Coping strategy impacts susceptibility to psychosocial stress. The locus coeruleus (LC) and dorsal raphe (DR) are monoamine nuclei that are implicated in stress-related disorders. This study was designed to identify genes in these nuclei that distinguish active and passive coping strategies in response to social stress. Methods Rats were exposed to repeated resident-intruder stress and coping strategy determined. Gene and protein expression in the LC and DR were determined by PCR array, ELISA, and compared between active and passive stress coping and unstressed rats. The effect of daily IL-1 receptor antagonist (IL-1ra, ICV) prior to stress on anhedonia was also determined. Results Rats exhibited passive or active coping strategies based on a short (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, IL1β 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-1ra, consistent with a role for IL1β in stress vulnerability. Conclusions This study highlighted distinctions in gene expression related to coping strategy in response to social stress. Passive coping was associated with a bias towards pro-inflammatory processes, particularly IL1β, whereas active coping and resistance to stress-related pathology was associated with suppression of inflammatory processes. PMID:25676490

  14. 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

  15. 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

  16. Zinc deficiency induces depression-like symptoms in adult rats.

    PubMed

    Tassabehji, Nadine M; Corniola, Rikki S; Alshingiti, Almamoun; Levenson, Cathy W

    2008-10-20

    There is mounting evidence suggesting a link between serum zinc levels and clinical depression. Not only is serum zinc negatively correlated with the severity of symptoms, but zinc levels appear to be lowest in patients who do not respond to antidepressant drug therapy. It is not known if reduced zinc levels are contributing to depression, or the result of dietary or other factors associated with major depression. Thus, we designed this study to test the hypothesis that dietary zinc deficiency would induce depression-like behaviors in rats. Two-month-old male rats were fed zinc adequate (ZA, 30 ppm), deficient (ZD, 1 ppm), or supplemented (ZS, 180 ppm) diets for 3 weeks. Consistent with the development of depression, ZD rats displayed anorexia (p<0.001), anhedonia (reduced saccharin:water intake, p< 0.001), and increased anxiety-like behaviors in a light-dark box test (p<0.05). Furthermore, the antidepressant drug fluoxetine (10 mg/kg body wt) reduced behavioral despair, as measured by the forced swim test, in rats fed the ZA and ZS rats (p<0.05), but was ineffective in ZD rats. Together these studies suggest that zinc deficiency leads to the development of depression-like behaviors that may be refractory to antidepressant treatment. PMID:18655800

  17. Does stress induce bowel dysfunction?

    PubMed

    Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y

    2014-08-01

    Psychological stress is known to induce somatic symptoms. Classically, many gut physiological responses to stress are mediated by the hypothalamus-pituitary-adrenal axis. There is, however, a growing body of evidence of stress-induced corticotrophin-releasing factor (CRF) release causing bowel dysfunction through multiple pathways, either through the HPA axis, the autonomic nervous systems, or directly on the bowel itself. In addition, recent findings of CRF influencing the composition of gut microbiota lend support for the use of probiotics, antibiotics, and other microbiota-altering agents as potential therapeutic measures in stress-induced bowel dysfunction. PMID:24881644

  18. Sub-chronic exposure to noise affects locomotor activity and produces anxiogenic and depressive like behavior in rats.

    PubMed

    Naqvi, Fizza; Haider, Saida; Batool, Zehra; Perveen, Tahira; Haleem, Darakhshan J

    2012-01-01

    Noise is defined as a displeasing and unwanted sound. It is one of the most encountered stressor to which mankind is exposed. Frustration, poor reading, impaired hearing and difficulty in problem solving activities are the common consequences of noise stress. It has been reported to produce atrophy of dendrites and alterations in neurotransmitter levels. Long term exposure to inescapable noise stress induces exhaustion, defeat, annoyance followed by decreased muscle movement, social contacts and mood changes. The present study was aimed to investigate the detrimental effects of noise exposure on behavior of rats and its association with altered neurochemistry. Changes in neurotransmitter levels in different brain regions including hippocampus have been reported following noise exposure and these changes in neurotransmitters levels have also been associated with altered behavior. In the present study, locomotor activity in rats was assessed by open field test (OFT) while anxiety and depressive behavior was monitored by elevated plus maze (EPM) and tail suspension (TST) tests. The results showed that 15 days sub-chronic exposure to noise stress induced anxiety and depression like behavior in male rats. These behavioral deficits observed in the present study suggest that an altered brain serotonergic and dopaminergic activity may be involved in the various psychological disorders following exposure to noise stress. PMID:22580521

  19. Stress-induced cervical lesions.

    PubMed

    Braem, M; Lambrechts, P; Vanherle, G

    1992-05-01

    The increasing occurrence of dental lesions at the cervical surfaces requires more knowledge of the causes of the process. Acidic and abrasive mechanisms have clearly been documented as causes but the stress theory by Lee and Eakle is still controversial. This report describes several incidences of possible stress-induced lesions according to the characteristics described by Lee and Eakle. The occurrences of subgingival lesions lend credence to the stress-induction theory by exclusion of other superimposing etiologic factors. With the current concepts, a perceptive approach to the treatment of cervical lesions can be executed. PMID:1527763

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

    PubMed

    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

    2016-08-01

    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. 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

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

    PubMed

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

    2015-10-01

    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 a 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

  3. 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

  4. [D2-type dopaminergic receptors and anxiety-depression-like behavior in female rats].

    PubMed

    Fedotova, Iu O

    2012-01-01

    Results of a comparative study of the effects of chronic administration of the D2-receptor agonist quinperole (0.1 mg/kg, i.p.) and the D2-receptor antagonist sulpiride (10.0 mg/kg, i.p.) for 14 days on anxiety- and depressive-like behavior in key phases of the ovarian cycle in adult female rats are presented. The model of depression in rats was implemented in Porsolt test, while the anxiety level was assessed in the elevated plus maze test. It is established that the chronic administration of quinperole produced an anxiolytic action in female rats during diesrous, estrous and proestrous phases, but failed to modify depression-like behavior during the entire ovarian cycle. Sulpiride administration resulted in anxiogenic effect in all phases of the ovarian cycle. It was also found that sulpiride produced some modulation of depression-like behavior in connection to ovarian cycle phases, which was a prodepressive action at a moderate level of estrogens and an antidepressant effect at a reduced/enhanced level of estrogen. It is suggested that the extent of involvement of D2-receptors in the mechanisms of anxiety-depressive-like behavior can vary depending on alterations of the hormonal balance during the ovarian cycle. The data obtained are indicative of a close interaction between ovarian hormonal and dopaminergic systems of the brain involved in the mechanisms of anxiety and depression. PMID:22550850

  5. Superoxide dismutase overexpression protects against glucocorticoid-induced depressive-like behavioral phenotypes in mice.

    PubMed

    Uchihara, Yuki; Tanaka, Ken-ichiro; Asano, Teita; Tamura, Fumiya; Mizushima, Tohru

    2016-01-22

    In the stress response, activation of the hypothalamic-pituitary-adrenal axis, and particularly the release of glucocorticoids, plays a critical role. However, dysregulation of this system and sustained high plasma levels of glucocorticoids can result in depression. Recent studies have suggested the involvement of reactive oxygen species (ROS), such as superoxide anion, in depression. However, direct evidence for a role of ROS in the pathogenesis of this disorder is lacking. In this study, using transgenic mice expressing human Cu/Zn-superoxide dismutase (SOD1), an enzyme that catalyzes the dismutation of superoxide anions, we examined the effect of SOD1 overexpression on depressive-like behavioral phenotypes in mice. Depressive-like behaviors were induced by daily subcutaneous administration of the glucocorticoid corticosterone for 4 weeks, and was monitored with the social interaction test, the sucrose preference test and the forced swim test. These tests revealed that transgenic mice overexpressing SOD1 are more resistant to glucocorticoid-induced depressive-like behavioral disorders than wild-type animals. Furthermore, compared with wild-type mice, transgenic mice showed a reduction in the number of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress)-positive cells in the hippocampal CA3 region following corticosterone administration. These results suggest that overexpression of SOD1 protects mice against glucocorticoid-induced depressive-like behaviors by decreasing cellular ROS levels. PMID:26721432

  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. PMID:21312047

  7. 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. PMID:24191918

  8. Depression-like responses induced by daytime light deficiency in the diurnal grass rat (Arvicanthis niloticus).

    PubMed

    Leach, Greg; Adidharma, Widya; Yan, Lily

    2013-01-01

    Seasonal Affective Disorder (SAD) is one of the most common mood disorders with depressive symptoms recurring in winter when there is less sunlight. The fact that light is the most salient factor entraining circadian rhythms leads to the phase-shifting hypothesis, which suggests that the depressive episodes of SAD are caused by misalignments between the circadian rhythms and the habitual sleep times. However, how changes in environmental lighting conditions lead to the fluctuations in mood is largely unknown. The objective of this study is to develop an animal model for some of the features/symptoms of SAD using the diurnal grass rats Arvichantis niloticus and to explore the neural mechanisms underlying the light associated mood changes. Animals were housed in either a 12∶12 hr bright light∶dark (1000lux, BLD) or dim light∶dark (50lux, DLD) condition. The depression-like behaviors were assessed by sweet-taste Saccharin solution preference (SSP) and forced swimming test (FST). Animals in the DLD group showed higher levels of depression-like behaviors compared to those in BLD. The anxiety-like behaviors were assessed in open field and light/dark box test, however no significant differences were observed between the two groups. The involvement of the circadian system on depression-like behaviors was investigated as well. Analysis of locomotor activity revealed no major differences in daily rhythms that could possibly contribute to the depression-like behaviors. To explore the neural substrates associated with the depression-like behaviors, the brain tissues from these animals were analyzed using immunocytochemistry. Attenuated indices of 5-HT signaling were observed in DLD compared to the BLD group. The results lay the groundwork for establishing a novel animal model and a novel experimental paradigm for SAD. The results also provide insights into the neural mechanisms underlying light-dependent mood changes. PMID:23437327

  9. Depressive-like behavioral response of adult male rhesus monkeys during routine animal husbandry procedure.

    PubMed

    Hennessy, Michael B; McCowan, Brenda; Jiang, Jing; Capitanio, John P

    2014-01-01

    Social isolation is a major risk factor for the development of depressive illness; yet, no practical nonhuman primate model is available for studying processes involved in this effect. In a first study, we noted that adult male rhesus monkeys housed individually indoors occasionally exhibited a hunched, depressive-like posture. Therefore, Study 2 investigated the occurrence of a hunched posture by adult males brought from outdoor social groups to indoor individual housing. We also scored two other behaviors-lying on the substrate and day time sleeping-that convey an impression of depression. During the first week of observation following individual housing, 18 of 26 adult males exhibited the hunched posture and 21 of 26 displayed at least one depressive-like behavior. Over 2 weeks, 23 of 26 males showed depressive-like behavior during a total of only 20 min observation. Further, the behavior during the first week was positively related to the level of initial response to a maternal separation procedure experienced in infancy. In Study 3, more than half of 23 adult males of a new sample displayed depressive-like behavior during 10 min of observation each of Weeks 7-14 of individual housing. The surprisingly high frequency of depressive-like behavior in Studies 2 and 3 may have been due to recording behavior via camera with no human in the room to elicit competing responses. These results suggest that a common animal husbandry procedure might provide a practical means for examining effects of social isolation on depression-related endpoints in a nonhuman primate. The findings also suggest that trait-like differences in emotional responsiveness during separation in infancy may predict differences in responsiveness during social isolation in adulthood. PMID:25249954

  10. Depression-Like Responses Induced by Daytime Light Deficiency in the Diurnal Grass Rat (Arvicanthis niloticus)

    PubMed Central

    Leach, Greg; Adidharma, Widya; Yan, Lily

    2013-01-01

    Seasonal Affective Disorder (SAD) is one of the most common mood disorders with depressive symptoms recurring in winter when there is less sunlight. The fact that light is the most salient factor entraining circadian rhythms leads to the phase-shifting hypothesis, which suggests that the depressive episodes of SAD are caused by misalignments between the circadian rhythms and the habitual sleep times. However, how changes in environmental lighting conditions lead to the fluctuations in mood is largely unknown. The objective of this study is to develop an animal model for some of the features/symptoms of SAD using the diurnal grass rats Arvichantis niloticus and to explore the neural mechanisms underlying the light associated mood changes. Animals were housed in either a 12∶12 hr bright light∶dark (1000lux, BLD) or dim light∶dark (50lux, DLD) condition. The depression-like behaviors were assessed by sweet-taste Saccharin solution preference (SSP) and forced swimming test (FST). Animals in the DLD group showed higher levels of depression-like behaviors compared to those in BLD. The anxiety-like behaviors were assessed in open field and light/dark box test, however no significant differences were observed between the two groups. The involvement of the circadian system on depression-like behaviors was investigated as well. Analysis of locomotor activity revealed no major differences in daily rhythms that could possibly contribute to the depression-like behaviors. To explore the neural substrates associated with the depression-like behaviors, the brain tissues from these animals were analyzed using immunocytochemistry. Attenuated indices of 5-HT signaling were observed in DLD compared to the BLD group. The results lay the groundwork for establishing a novel animal model and a novel experimental paradigm for SAD. The results also provide insights into the neural mechanisms underlying light-dependent mood changes. PMID:23437327

  11. 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. PMID:25623236

  12. G9a-Mediated Regulation of OXT and AVP Expression in the Basolateral Amygdala Mediates Stress-Induced Lasting Behavioral Depression and Its Reversal by Exercise.

    PubMed

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

    2016-07-01

    Chronic stress produces behavioral depression. Conversely, physical exercise is held to be beneficial in the treatment of depression. Although genomic mechanisms are likely involved in these behavioral changes, underlying mechanisms are not clearly understood. In the present study, we investigated whether stress effects and their reversal by exercise occur via genomic mechanisms in the amygdala, a core part of the limbic system important for regulating mood states. Mice treated with chronic restraint showed lasting depression-like behaviors, which were counteracted by treatment with scheduled forceful exercise. Microarray analysis identified a number of genes whose expression in the amygdala was either upregulated or downregulated after repeated stress, and these changes were reversed by exercise. Of these genes, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) were selected as representative stress-induced and exercise-responded genes in the BLA. Stereotaxic injection of OXT or AVP receptor agonists within the BLA in normal mice produced depression-like behaviors, whereas small interfering RNA (siRNA)-mediated suppression of the OXT or AVP transcripts in the BLA was sufficient to block stress-induced depressive behaviors. Stress-induced depression-like behaviors were accompanied by a global reduction of G9a histone methyltransferase and H3K9me2 at the OXT and AVP promoters. Conversely, repeated exercise increased the levels of G9a and H3K9me2 at the OXT and AVP promoters in the BLA, which was associated with the suppression of OXT and AVP expressions. These results identify G9a-induced histone methylation at the OXT and AVP promoters in the BLA as a mechanism for mediating stress-induced lasting behavioral depression and its reversal by exercise. PMID:25863961

  13. 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. PMID:23006866

  14. 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. PMID:20888697

  15. 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. PMID:26049060

  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. 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

  18. Effect of Antidepressants on Immunological Reactivity in ASC Mice with Genetically Determined Depression-Like State.

    PubMed

    Gevorgyan, M M; Idova, G V; Al'perina, E L; Tikhonova, M A; Kulikov, A V

    2016-06-01

    The effect of chronic treatment with antidepressant drugs fluoxetine (20 mg/kg) and imipramine (25 mg/kg) on the number of antibody-producing cells and the main T cell subpopulations in ASC mice characterized by genetic predisposition to depression-like states was studied at the peak of the SE-induced immune response (5×10(8)). Fluoxetine produced an immunostimulatory effect manifested in an increase in the relative and absolute number of IgM antibody-producing cells in the spleen and index of immunoreactivity (CD4/CD8). Administration of fl uoxetine to parental mouse strains without depression (CBA and AKR) had no effect (CBA) or reduced the immune response. The CD4/CD8 ratio did not increase under these conditions. Imipramine was ineffective in the correction of immune reactions in a depression-like state. PMID:27383160

  19. 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

  20. 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. PMID:24901001

  1. Microglia activation is associated with IFN-α induced depressive-like behavior.

    PubMed

    Wachholz, Simone; Eßlinger, Manuela; Plümper, Jennifer; Manitz, Marie-Pierre; Juckel, Georg; Friebe, Astrid

    2016-07-01

    Inflammatory immune activation has been frequently associated with the development of major depression. This association was confirmed in patients receiving long-term treatment with pro-inflammatory interferon-α (IFN-α). Microglia, the resident immune cells in the brain, might serve as an important interface in this immune system-to-brain communication. The aim of the present study was to investigate the role of microglia in an IFN-α mouse model of immune-mediated depression. Male BALB/c mice were treated with daily injections of IFN-α for two weeks. Depressive-like behavior was analyzed in the forced swim and tail suspension test. Activation of microglia was measured by flow cytometry. Pro-inflammatory M1 type (MHC-II, CD40, CD54, CD80, CD86, CCR7), anti-inflammatory M2 type (CD206, CD200R), and maturation markers (CD11c, CCR7) were tested, as well as the chemokine receptor CCR2. IFN-α led to a significant increase in depressive-like behavior and expression of the pro-inflammatory surface markers MHC-II, CD86, and CD54, indicating M1 polarization. Because IFN-α-treated mice showed great individual variance in the behavioral response to IFN-α, they were further divided into vulnerable and non-vulnerable subgroups. Only IFN-α vulnerable mice (characterized by their development of depressive-like behavior in response to IFN-α) showed an increased expression of MHC-II and CD86, while CD54 was similarly enhanced in both subgroups. Thus, IFN-α-induced activation of microglia was specifically associated with depressive-like behavior. PMID:26408795

  2. The Melanin-Concentrating Hormone (MCH) System in an Animal Model of Depression-Like Behavior

    PubMed Central

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

    2011-01-01

    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. PMID:22209364

  3. TCM Formula Xiaoyaosan Decoction Improves Depressive-Like Behaviors in Rats with Type 2 Diabetes

    PubMed Central

    Li, Na; Liu, Qun; Li, Xiao-Juan; Bai, Xiao-Hui; Liu, Yue-Yun; Zhao, Hong-Bo; Jin, Zhong-Ye; Jing, Yu-Xia; Yan, Zhi-Yi; Chen, Jia-Xu

    2015-01-01

    The mechanism of depression with type 2 diabetes remains elusive, requiring further study. Objective. To evaluate the effect of TCM formula Xiaoyaosan on depressive-like behaviors in rats with type 2 diabetes. Methods. Rats were divided into 5 groups and drugs were administered during the model period of 21 days. The model of depressive-like behaviors in rats with type 2 diabetes was induced by a high fat diet, low doses of STZ injection, and chronic restraint stress for 21 days. The body weight, fasting blood glucose, ITT, OGTT, 5-HT, DA, depression behaviors, and morphological changes of formation were measured and observed. Results. After modeling, marked changes were found in model rats; behavioral analyses of rats indicated that this modeling method negatively impacts locomotor function. In the H&E staining, changes were found predominately in the CA1 and DG subregions of the hippocampus. After 21 days of treatment by fluoxetine and Xiaoyaosan, rats' body weights, behaviors and fasting blood glucose, and hippocampal formation were modified. Conclusions. A new model of depressive-like behaviors in rats with type 2 diabetes was successfully created. Xiaoyaosan and fluoxetine in this study independently contribute to exacerbate the disease progression. PMID:26508978

  4. Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance.

    PubMed

    Cui, Wanpeng; Mizukami, Hiroaki; Yanagisawa, Michiko; Aida, Tomomi; Nomura, Masatoshi; Isomura, Yoshikazu; Takayanagi, Ryoichi; Ozawa, Keiya; Tanaka, Kohichi; Aizawa, Hidenori

    2014-12-01

    The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brainstem. This area has recently attracted a surge of interest in psychiatry because studies have reported the pathological activation of the habenula in patients with major depression and in animal models. The LHb plays a significant role in the pathophysiology of depression; however, how habenular neurons are activated to cause various depression symptoms, such as reduced motivation and sleep disturbance, remain unclear. We hypothesized that dysfunctional astrocytes may cause LHb hyperactivity due to the defective uptake activity of extracellular glutamate, which induces depressive-like behaviors. We examined the activity of neurons in habenular pathways and performed behavioral and sleep analyses in mice with pharmacological and genetic inhibition of the activity of the glial glutamate transporter GLT-1 in the LHb. The habenula-specific inhibition of GLT-1 increased the neuronal firing rate and the level of c-Fos expression in the LHb. Mice with reduced GLT-1 activity in the habenula exhibited a depressive-like phenotype in the tail suspension and novelty-suppressed feeding tests. These animals also displayed increased susceptibility to chronic stress, displaying more frequent avoidant behavior without affecting locomotor activity in the open-field test. Intriguingly, the mice showed disinhibition of rapid eye movement sleep, which is a characteristic sleep pattern in patients with depression. These results provide evidence that disrupting glutamate clearance in habenular astrocytes increases neuronal excitability and depressive-like phenotypes in behaviors and sleep. PMID:25471567

  5. 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. PMID:27106565

  6. 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. PMID:24406442

  7. Linoleic acid derivative DCP-LA ameliorates stress-induced depression-related behavior by promoting cell surface 5-HT1A receptor translocation, stimulating serotonin release, and inactivating GSK-3β.

    PubMed

    Kanno, Takeshi; Tanaka, Akito; Nishizaki, Tomoyuki

    2015-04-01

    Impairment of serotonergic neurotransmission is the major factor responsible for depression and glycogen synthase kinase 3β (GSK-3β) participates in serotonergic transmission-mediated signaling networks relevant to mental illnesses. In the forced-swim test to assess depression-like behavior, the immobility time for mice with restraint stress was significantly longer than that for nonstressed control mice. Postsynaptic cell surface localization of 5-HT1A receptor, but not 5-HT2A receptor, in the hypothalamus for mice with restraint stress was significantly reduced as compared with that for control mice, which highly correlated to prolonged immobility time, i.e., depression-like behavior. The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) restored restraint stress-induced reduction of cell surface 5-HT1A receptor and improved depression-like behavior in mice with restraint stress. Moreover, DCP-LA stimulated serotonin release from hypothalamic slices and cancelled restraint stress-induced reduction of GSK-3β phosphorylation at Ser9. Taken together, the results of the present study indicate that DCP-LA could ameliorate depression-like behavior by promoting translocation of 5-HT1A receptor to the plasma membrane on postsynaptic cells, stimulating serotonin release, and inactivating GSK-3β. PMID:24788685

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

    PubMed

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

    2005-10-01

    Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression. PMID:16033993

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

    PubMed Central

    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. PMID:25147515

  10. Stress-Induced Cardiomyopathy Presenting as Shock

    PubMed Central

    Yoo, Tae Kyung; Lee, Jong-Young; Oh, Sam Sae; Song, Young Seok; Lee, Seung Jae; Ko, Kyung Jin

    2016-01-01

    Stress-induced cardiomyopathy has become a more recognized and reported entity. It can be caused by emotional or physical stress, which causes excessive catecholamine release. Typically, the clinical course is benign with conservative treatment being effective. However, stress-induced cardiomyopathy can be fatal. A 41-year-old female presented with cardiogenic shock followed by sudden back pain. Initial echocardiographic finding showed severely decreased ejection fraction with akinesia at all mid-to-apical walls with relatively preserved basal wall contractility. The coronary artery was intact on coronary angiography. Cardiac resuscitation and extra-corporeal membrane oxygenation was needed to manage the cardiogenic shock. Recovery was complete after 2 weeks. PMID:27081451

  11. Depression-like behavior in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization.

    PubMed

    Ge, Jin-Fang; Peng, Yun-Yun; Qi, Cong-Cong; Chen, Fang-Han; Zhou, Jiang-Ning

    2014-04-01

    The purpose of this study was to investigate the depression-like behavior performances of subclinical hypothyroidism (SCH) rat. SCH rat model was induced by hemi-thyroid electrocauterization, and the behavior performances were measured by sucrose preference test, force swimming test (FST), and tail suspension test (TST). SCH rat model was established successfully by hemi-thyroid electrocauterization. In the behavior tasks, SCH rats displayed depression-like behavior were indicated as a significant elevation of immobility time in both the TST and FST, though the sucrose preference was not significantly decreased. The index of left adrenal cortex in both SCH and clinical hypothyroidism (CH) group significantly increased, and many large lipid vacuoles were observed in the zona fasciculata cells. The serum corticosterone concentration and hypothalamic corticotropin-releasing hormone mRNA expression 2 h after behavior test was markedly up-regulated in CH rats, but not SCH rats, indicated that SCH induced a less impairment of HPA axis than CH did. The important finding of this study was that the concentration of hippocampal T3 was lower in SCH group than that of the sham group. Furthermore, the results of Pearson correlation test showed that the immobility behaviors in TST and FST were both negatively correlated with hippocampal T3 concentration. Taking together, our results indicated that SCH could result in depression-like behavior, accompanied with subtle hyperactivity of HPA axis. The reduced hippocampal T3 prior to the reduction of thyroid hormone in serum might be taken as an early sign of hippocampus impairment in the progression from SCH to CH. PMID:23794115

  12. Alcohol Induced Depressive-Like Behavior is Associated with a Reduction in Hippocampal BDNF

    PubMed Central

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

    2011-01-01

    Strong positive correlation between depression and alcoholism is evident in epidemiological reports. However, a causal relationship for this co-morbidity has not been established. We have observed that chronic daily exposure to a relatively high dose of alcohol can induce depressive-like behavior in rats and that pretreatment with nomifensine or imipramine can block the “depressogenic” effects of alcohol. Since brain derived neurotrophic factor (BDNF) is considered to play an important role in depressive-like behaviors and its elevation, particularly in the hippocampus, appears to be critical for the action of many antidepressants, we hypothesized that: 1. WKY rats, a putative animal model of depression, will show a lower hippocampal BDNF compared to their control Wistar rats, 2. Alcohol-induced depressive like behavior will be associated with a significant decrease in hippocampal BDNF and 3. Treatments with antidepressants will normalize hippocampal BDNF. These postulates were verified by measuring hippocampal BDNF in Wistar and WKY rats at baseline, following chronic (10 day) treatment with alcohol and combination of alcohol with nomifensine or imipramine. Alcohol was administered via inhalation chamber (3 hr/day) such that a blood alcohol level of approximately 150 mg% was achieved. Nomifensine (10 mg/kg) or impiramine (10 mg/kg) were administered i.p daily immediately after alcohol exposure. BDNF was measured by standard Elisa kit. The results support a role for central BDNF in depressogenic effects of alcohol and antidepressant effects of nomifensine and imipramine. Moreover, depression per se as manifested in WKY rats may be associated with a reduction in hippocampal BDNF. PMID:21930150

  13. Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype

    PubMed Central

    Fukui, Masato; Rodriguiz, Ramona M.; Zhou, Jiechun; Jiang, Sara X.; Phillips, Lindsey E.; Caron, Marc G.; Wetsel, William C.

    2010-01-01

    The vesicular monoamine transporter 2 (VMAT2) is localized primarily within the CNS and is responsible for transporting monoamines from the cytoplasm into secretory vesicles. Because reserpine (a VMAT inhibitor) can precipitate depressive-like symptoms in humans, we investigated whether Vmat2 heterozygous (HET) mice present with depressive-like behaviors. The mutants showed locomotor and rearing retardation in the open field and appeared anhedonic to 1 and 1.5% sucrose solutions. Immobility times for Vmat2 heterozygotes were prolonged in forced swim and imipramine normalized this behavior. HET animals also showed enhanced immobility in tail suspension and this response was alleviated by fluoxetine, reboxetine, and bupropion. Stimulated GTPγS binding indicated that α2-adrenergic receptors in HET hippocampus were more sensitive to UK 14,304 (5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine) stimulation than in wild type (WT) mice. In learned helplessness, mice were exposed to a shuttle box for 4 d or were given inescapable foot-shocks for the same time period. On day 5, all animals were tested in shock escape. Failure rates and the latency to escape were similar for WT and HET mice that were only pre-exposed to the test apparatus. In foot-shock groups, learned helplessness was more robust in heterozygotes than in WT controls. Basal secretion of serum corticosterone was not distinguished by genotype; however, corticosterone levels in mutants were more responsive to stress. Anxiety-like responses of WT and HET animals in the open field, light-dark exploration, zero maze, and novelty-suppressed feeding tests were indistinguishable. Collectively, these findings suggest that Vmat2 heterozygotes display a depressive-like phenotype that is devoid of anxiety-like behavior. PMID:17898223

  14. 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. PMID:25316382

  15. Mouse Models for Studying Depression-Like States and Antidepressant Drugs.

    PubMed

    Bergner, Carisa L; Smolinsky, Amanda N; Hart, Peter C; Dufour, Brett D; Egan, Rupert J; LaPorte, Justin L; Kalueff, Allan V

    2016-01-01

    Depression is a common psychiatric disorder, with diverse symptoms and high comorbidity with other brain dysfunctions. Due to this complexity, little is known about the neural and genetic mechanisms involved in depression pathogenesis. In a large proportion of patients, current antidepressant treatments are often ineffective and/or have undesirable side effects, fueling the search for more effective drugs. Animal models mimicking various symptoms of depression are indispensable in studying the biological mechanisms of this disease. Here, we summarize several popular methods for assessing depression-like symptoms in mice, and their utility in screening antidepressant drugs. PMID:27150095

  16. A neuroendocrine mechanism of co-morbidity of depression-like behavior and myocardial injury in rats.

    PubMed

    Xinxing, Wang; Wei, Liu; Lei, Wu; Rui, Zhan; Baoying, Jin; Lingjia, Qian

    2014-01-01

    Depression is generally a recurrent psychiatric disorder. Evidence shows that depression and cardiovascular diseases are common comorbid conditions, but the specific pathological mechanisms remain unclear. The purpose of this study is to determine the effects of depression induced by chronic unpredictable mild stress (CUMS) on myocardial injury and to further elucidate the biological mechanism of depression. Rats were used as a model. The CUMS procedure lasted for a total of 8 weeks. After 4 weeks of CUMS, treated rats exhibited a reduced sucrose preference and changes in scores on an open field test, body weight and content of 5-HT in the brain as compared with the values of these variables in controls. These changes indicated depression-like changes in CUMS rats and demonstrated the feasibility of the depression model. In addition, pathological changes in the myocardium and increased cardiomyocyte apoptosis demonstrated that myocardial injury had occurred after 6 weeks of CUMS and had increased significantly by the end of 8 weeks of CUMS. Plasma serotonin (5-HT), norepinephrine (NE) and epinephrine (E), all depression-related neuroendocrine factors, were measured by HPLC-ECD techniques, and the content of plasma corticosterone (GC) was evaluated by an I(125)-cortisol radioactivity immunoassay in control and CUMS rats. The results indicated that 5-HT had decreased, whereas NE, E and GC had increased in CUMS rats, and these factors might be associated with depression-induced myocardial injury. The effects of 5-HT, NE and GC on the survival rate of cultured cardiomyocytes were determined using an orthogonal design. The results showed that 5-HT was a more important factor affecting cell survival than GC or NE. The results suggested that normal blood levels of 5-HT had a cytoprotective effect. The neuroendocrine disorders characterized by decreased 5-HT combined with increased GC and NE mediated the occurrence of depression-induced myocardial injury. PMID:24551098

  17. A Neuroendocrine Mechanism of Co-Morbidity of Depression-Like Behavior and Myocardial Injury in Rats

    PubMed Central

    Lei, Wu; Rui, Zhan; Baoying, Jin; Lingjia, Qian

    2014-01-01

    Depression is generally a recurrent psychiatric disorder. Evidence shows that depression and cardiovascular diseases are common comorbid conditions, but the specific pathological mechanisms remain unclear. The purpose of this study is to determine the effects of depression induced by chronic unpredictable mild stress (CUMS) on myocardial injury and to further elucidate the biological mechanism of depression. Rats were used as a model. The CUMS procedure lasted for a total of 8 weeks. After 4 weeks of CUMS, treated rats exhibited a reduced sucrose preference and changes in scores on an open field test, body weight and content of 5-HT in the brain as compared with the values of these variables in controls. These changes indicated depression-like changes in CUMS rats and demonstrated the feasibility of the depression model. In addition, pathological changes in the myocardium and increased cardiomyocyte apoptosis demonstrated that myocardial injury had occurred after 6 weeks of CUMS and had increased significantly by the end of 8 weeks of CUMS. Plasma serotonin (5-HT), norepinephrine (NE) and epinephrine (E), all depression-related neuroendocrine factors, were measured by HPLC-ECD techniques, and the content of plasma corticosterone (GC) was evaluated by an I125–cortisol radioactivity immunoassay in control and CUMS rats. The results indicated that 5-HT had decreased, whereas NE, E and GC had increased in CUMS rats, and these factors might be associated with depression-induced myocardial injury. The effects of 5-HT, NE and GC on the survival rate of cultured cardiomyocytes were determined using an orthogonal design. The results showed that 5-HT was a more important factor affecting cell survival than GC or NE. The results suggested that normal blood levels of 5-HT had a cytoprotective effect. The neuroendocrine disorders characterized by decreased 5-HT combined with increased GC and NE mediated the occurrence of depression-induced myocardial injury. PMID:24551098

  18. Influence of light at night on murine anxiety- and depressive-like responses.

    PubMed

    Fonken, Laura K; Finy, M Sima; Walton, James C; Weil, Zachary M; Workman, Joanna L; Ross, Jessica; Nelson, Randy J

    2009-12-28

    Individuals are increasingly exposed to light at night. Exposure to constant light (LL) disrupts circadian rhythms of locomotor activity, body temperature, hormones, and the sleep-wake cycle in animals. Other behavioural responses to LL have been reported, but are inconsistent. The present experiment sought to determine whether LL produces changes in affective responses and whether behavioural changes are mediated by alterations in glucocorticoid concentrations. Relative to conspecifics maintained in a light/dark cycle (LD, 16:8 light/dark), male Swiss-Webster mice exposed to LL for three weeks increased depressive-like behavioural responses as evaluated by the forced swim test and sucrose anhedonia. Furthermore, providing a light escape tube reversed the effects of LL in the forced swim test. LL mice displayed reduced anxiety as evaluated by the open field and elevated-plus maze. Glucocorticoid concentrations were reduced in the LL group suggesting that the affective behavioural responses to LL are not the result of elevated corticosterone. Additionally, mice housed in LD with a clear tube displayed increased paired testes mass as compared to LL mice. Taken together, these data provide evidence that exposure to unnatural lighting can induce significant changes in affect, increasing depressive-like and decreasing anxiety-like responses. PMID:19591880

  19. [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. PMID:24450162

  20. Social isolation differentially affects anxiety and depressive-like responses of bulbectomized mice.

    PubMed

    Linge, Raquel; Pazos, Ángel; Díaz, Álvaro

    2013-05-15

    Social isolation in rodents may interfere in their behavioural responses on paradigms used to test anxiety- and depressive-like states. Herein we study the influence of social isolation upon the behavioural responses of olfactory bulbectomized mice (OBX). In the open-field test (OFT), social isolation enhanced OBX-induced hyperactivity and exploratory behaviour. However, OBX-induced anxiety in the OFT (central activity) was less apparent after isolation, due to the increased level of anxiety showed by the sham-isolated counterparts. In the novelty-suppressed feeding (NSF), isolation derived in an increased latency to feeding of both OBX and sham mice. The isolation did not affect the response of OBX mice and sham mice in the forced-swimming test (FST). Interestingly, OBX animals exhibited an increased immobility time during the FST, though a dramatic decrease in the climbing scores. Finally, OBX-induced anhedonia in the sucrose intake test was not affected by housing conditions. Our findings demonstrate that social isolation influences the performance of OBX mice in some behavioural paradigms, thus facilitating the characterization of depressive-like states, and by contrast, hindering anxiety-related behaviours. This fact should be taken into account in order to minimize economical and time-consuming efforts when assessing potential antidepressant and anxiolytic drugs. PMID:23416113

  1. 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

    2015-12-01

    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

  2. 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. PMID:27067014

  3. Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior.

    PubMed

    Hu, Pu; Wang, Yu; Liu, Ji; Meng, Fan-Tao; Qi, Xin-Rui; Chen, Lin; van Dam, Anne-Marie; Joëls, Marian; Lucassen, Paul J; Zhou, Jiang-Ning

    2016-07-01

    Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc. PMID:26860546

  4. Depression-like behavior and reduced plasma testosterone levels in the senescence-accelerated mouse.

    PubMed

    Egashira, Nobuaki; Koushi, Emi; Okuno, Ryoko; Shirakawa, Atsunori; Mishima, Kenichi; Iwasaki, Katsunori; Oishi, Ryozo; Fujiwara, Michihiro

    2010-05-01

    During aging, levels of testosterone gradually decline in men and low levels of testosterone in aged men are accompanied by increased incidence of depressive disorders. The senescence-accelerated-prone mouse 10 (SAMP10) is well known as an animal model of aging. The purpose of this study was to investigate the motor function, anxiety levels, depression-related emotional responses, attentional function and plasma levels of testosterone and dehydroepiandrosterone (DHEA) in SAMP10. SAMP10 exhibited a significant prolongation of immobility time compared to that of the aged-matched control senescence-accelerated-resistant mouse 1 (SAMR1) in the tail suspension test for measuring depression. Moreover, significant low levels of plasma testosterone but not DHEA were found in SAMP10, and the testosterone levels were inversely correlated with the depression-like behavior. By contrast, we did not observe any significant differences between SAMP10 and SAMR1 in the open-field, rota-rod, elevated plus-maze, marble-burying behavior, or prepulse inhibition test. The results of the present study indicate that testosterone may play an important role in the depression-like behavior in SAMP10. PMID:20117148

  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. Environmental enrichment ameliorates depressive-like symptoms in young rats bred for learned helplessness.

    PubMed

    Richter, S Helene; Zeuch, Benjamin; Riva, Marco A; Gass, Peter; Vollmayr, Barbara

    2013-09-01

    The incidence of major depression is known to be influenced by both genetic and environmental factors. In the current study, we therefore set out to investigate depressive-like behavior and its modification by environmental enrichment using rats bred for 'learned helplessness'. 45 males of congenitally helpless (cLH, n=22) and non-helpless (cNLH, n=23) rats of two different generations were used to systematically investigate differential effects of environmental enrichment on learned helpless behavior, anhedonic-like behavior (sweetened condensed milk consumption) and spontaneous behavior in the home cage. While enrichment was found to reduce learned helpless behavior in 14 weeks old, but not 28 weeks old cLH rats, it did not affect the consumption of sweetened condensed milk. Regarding the home cage behavior, no consistent changes between rats of different strains, housing conditions, and ages were observed. We could thus demonstrate that a genetic predisposition for learned helplessness may interact with environmental conditions in mediating some, but not all depressive-like symptoms in congenitally learned helpless rats. However, future efforts are needed to isolate the differential benefits of environmental factors in mediating the different depression-related symptoms. PMID:23791932

  7. Prenatal exposure to nanoparticulate titanium dioxide enhances depressive-like behaviors in adult rats.

    PubMed

    Cui, Yonghua; Chen, Xiaoyun; Zhou, Zhu; Lei, Yu; Ma, Mengnan; Cao, Renjing; Sun, Tianjin; Xu, Jialei; Huo, Mingyue; Cao, Renjing; Wen, Chenghong; Che, Yi

    2014-02-01

    Titanium dioxide nanoparticles (TiO2 NPs) have the potential to produce reactive oxygen species and can be transferred from the mother to the fetal brain. The central nervous system exhibits remarkable plasticity in early life and can be altered significantly by environmental stressors encountered during fetal period. Additionally, prenatal stressors are involved with emotional problems in adulthood. The purpose of the current study is to evaluate whether prenatal exposure to TiO2 NPs could induce oxidative damage in the offspring brain and eventually affect the emotional behaviors in adulthood. The results showed that prenatal exposure to TiO2 NPs impaired the antioxidant status, caused a significant oxidative damage to nucleic acids and lipids in the brain of newborn pups, and enhanced the depressive-like behaviors during adulthood in the force swimming test and the sucrose preference test. These results suggest that the stress during fetal life induced by prenatal exposure to TiO2 NPs could be implicated in depressive-like behaviors in adulthood. PMID:23972732

  8. Imipramine reverses depressive-like parameters in pneumococcal meningitis survivor rats.

    PubMed

    Barichello, Tatiana; Milioli, Graziele; Generoso, Jaqueline S; Cipriano, Andreza L; Costa, Caroline S; Moreira, Ana Paula; Vilela, Márcia Carvalho; Comim, Clarissa M; Teixeira, Antonio Lucio; Quevedo, João

    2012-06-01

    Pneumococcal meningitis is a severe infectious disease of the central nervous system, associated with acute inflammation and might cause damage to the host, such as deafness, blindness, seizure, and learning deficits. However, infectious diseases can play a significant role in the etiology of neuropsychiatric disturbances. In this context, we evaluated depressive-like parameters; corticosterone and ACTH levels in pneumococcal meningitis surviving rats. Wistar rats underwent a magna cistern tap receiving either 10 μL sterile saline or a Streptococcus pneumoniae suspension at the concentration of 5 × 10(9) cfu/mL. After 3 days of meningitis induction procedure, the animals were treated with imipramine at 10 mg/kg or saline for 14 days (3rd-17th day). The consumption of sweet food was measured for 7 days (10th-17th day). The meningitis group decreased the sucrose intake and increased the levels of corticosterone and ACTH levels in the serum and TNF-α in the cortex; however, the treatment with imipramine reverted the reduction of sweet food consumption, normalized hormonal levels and TNF-α in the cortex. Our results supported the hypothesis that the pneumococcal meningitis surviving rats showed depressive-like behavior and alterations in the hypothalamus-pituitary-adrenal axis. PMID:22160551

  9. Heat Stress-Induced DNA Damage

    PubMed Central

    Kantidze, O.L.; Velichko, A.K.; Luzhin, A.V.; Razin, S.V.

    2016-01-01

    Although the heat-stress response has been extensively studied for decades, very little is known about its effects on nucleic acids and nucleic acid-associated processes. This is due to the fact that the research has focused on the study of heat shock proteins and factors (HSPs and HSFs), their involvement in the regulation of transcription, protein homeostasis, etc. Recently, there has been some progress in the study of heat stress effects on DNA integrity. In this review, we summarize and discuss well-known and potential mechanisms of formation of various heat stress-induced DNA damage. PMID:27437141

  10. Ketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of neuroinflammation and soluble amyloid-beta peptide in depressive-like rats.

    PubMed

    Zhu, Xianlin; Li, Ping; Hao, Xuechao; Wei, Ke; Min, Su; Luo, Jie; Xie, Fei; Jin, Juying

    2015-07-10

    Electroconvulsive therapy (ECT) is an effective treatment for depression, but can result in memory deficits. This study aimed to determine whether ketamine could alleviate electroconvulsive shock (ECS, an analog of ECT in animals)-induced memory impairment and the potential molecular mechanism. Chronic unpredictable mild stress was used to generate animal models of depressive-like symptoms. Sixty adult male Sprague-Dawley rats were randomly divided into the following five groups: control group (group C); depressive-like model group (group D); ECS group (group DE); ketamine+ECS group (group DKE); and ketamine group (group DK). The sucrose preference test and Morris water maze were used to assess behavioral changes. The expression levels of Iba-1, IL-1β and TNF-α were measured by immunohistochemistry and real-time PCR. Enzyme-linked immunosorbent assays were used to detect the levels of soluble Aβ. We found that ECS up-regulated the expression of Iba-1, promoted the release of IL-1β and TNF-α, increased the levels of Aβ1-40 and Aβ1-42 in the hippocampus, and aggravated memory impairment of the depressive-like rats. However, ketamine reversed these ECS-induced molecular changes and effectively attenuated ECS-induced memory impairment. This cognitive protective effect of ketamine may be attributed to its suppression of ECS-induced neuroinflammation and reduction of the levels of soluble Aβ. PMID:25980993

  11. [Selection for the predisposition to catalepsy enhances depressive-like traits in mice].

    PubMed

    Bazovkina, D V; Kulikova, A V; Kondaurova, E M; Popova, N K

    2005-09-01

    Immobility reaction or catalepsy is a natural passive defensive (lurking) behavioral response to the appearance of a predator. Selection for high predisposition to catalepsy has been performed in a population of (CBA x (CBA x AKR)) backcrosses of the crossing between mouse lines sensitive and resistant to catalepsy (VBA and AKR, respectively). A rapid increase in the number of animals with catalepsy has been observed: from 23% in backcrosses to 71% in the S3 generation. Selection for catalepsy does not affect mouse anxiety in the open field and plus-maze tests. However, S8 and S9 mice are characterized by a decreased motor activity in the open-field test and an increased immobility in the forced swim and tail suspension tests, which is interpreted as an increase in "depressiveness." The results indicate that genetically determined catalepsy is related to depressive-like characteristics of defensive behavior. PMID:16240633

  12. 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. PMID:27609268

  13. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not in males.

    PubMed

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

    2015-03-01

    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

  14. Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats.

    PubMed

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

    2012-04-01

    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

  15. 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

  16. Homer1a-dependent recovery from depression-like behavior by photic stimulation in mice.

    PubMed

    Sun, Peng; Zhang, Qing; Zhang, Yu; Wang, Furong; Chen, Rui; Yamamoto, Ryo; Kato, Nobuo

    2015-08-01

    A significant number of depressed people are resistant to drug therapy. Promising alternative therapy may be brain stimulation achievable by diverse methods. In a mouse model of depression, we previously investigated the mechanisms by which repetitive transcranial magnetic stimulation (rTMS) reverses depression-like behavior, and found an essential involvement of the immediate early gene product Homer1a. Home1a is known to be expressed not just by rTMS but also by photic stimulation (PS) via activation of the retino-geniculo-cortical pathway, suggesting that PS may have an antidepressant effect. This was tested by using a two-phase version of forced swimming (FS), in which the first phase consists of a 10-min swimming for 5 consecutive days and the second phase takes place at a 4-week interval for testing behavior. During the 4-week period, PS was applied everyday (300lx, 2Hz for 6h daily). After the last swimming, the brains were removed and subjected to quantitative RT-PCR and electrophysiological analysis. The 4-week-long PS alleviated depression-like behavior to the extent comparable to that obtained with rTMS previously. Homer1a expression was drastically reduced by FS and recovered by PS. Consistently with our previous studies, activity of the large conductance calcium-activated potassium (BK) channel was facilitated by PS in a Homer1a-dependent manner. PS may thus have a potential utility for depression therapy. Furthermore, given that Homer1a is implicated in various neuropsychiatric disorders, brain stimulations that induce Homer1a expression, such as rTMS or PS, may have a wider applicability than currently thought. PMID:25982087

  17. Perinatal exposure to di-(2-ethylhexyl) phthalate affects anxiety- and depression-like behaviors in mice.

    PubMed

    Xu, Xiaohong; Yang, Yanling; Wang, Ran; Wang, Yu; Ruan, Qin; Lu, Yang

    2015-04-01

    Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disrupter. The present study investigated the effect of DEHP on emotional behavior of mice following perinatal exposure (10, 50, and 200 mg kg(-1) d(-1)) from gestation day 7 through postnatal day 21. The results showed that, in pubertal males (6-w-old), DEHP decreased the time spent in the open arms and the number of entries into them in elevated plus maze and decreased the time in the mirrored chamber and in the light-box; in pubertal females, DEHP decreased the time spent in the open arms and the number of entries into them, suggesting that DEHP exposure made a anxiogenic effect in pubertal offspring regardless of sex. While DEHP effect on anxiety of adult (12-w-old) displayed sex differences, with decreased time spent in the open arms in the adult females. Perinatal exposure to DEPH significantly extended the time of immobility in forced swim task of pubertal offspring and adulthood regardless of sex. Furthermore, DEHP down-regulated the expressions of androgen receptor (AR) in pubertal male hippocampus and of estrogen receptor (ER) β in pubertal female and adult hippocampus of both sexes and inhibited the phosphorylation of ERK1/2 of hippocampus in pubertal mice and adult males. These results suggest that exposure to DEHP early in life affected the anxiety- and depressive-like behaviors of pubertal offspring and even adult. The disruption of gonadal hormones' modulation of behaviors due to down-regulation of AR or ERβ in the hippocampus may be associated with the aggravated anxiety- and depression-like status induced by DEHP. PMID:25441928

  18. 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. PMID:27079240

  19. 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

  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

    2015-08-01

    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

  1. 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

  2. Neonatal glucocorticoid treatment increased depression-like behaviour in adult rats.

    PubMed

    Ko, Meng-Chang; Hung, Yu-Hui; Ho, Pei-Yin; Yang, Yi-Ling; Lu, Kwok-Tung

    2014-12-01

    Synthetic glucocorticoid dexamethasone (DEX) is frequently used as a therapeutic agent to lessen the morbidity of chronic lung disease in premature infants. Previous studies suggested that neonatal DEX treatment altered brain development and cognitive function. It has been recognized that the amygdala is involved in emotional processes and also a critical site of neuronal plasticity for fear conditioning. Little is known about the possible long-term adverse effect of neonatal DEX treatment on amygdala function. The present study was aimed to evaluate the possible effect of neonatal DEX treatment on the synaptic function of amygdala in adult rats. Newborn Wistar rats were subjected to subcutaneous tapering-dose injections of DEX (0.5, 0.3 and 0.1 mg/kg) from post-natal day one to three, PN1-PN3. Animals were then subjected to a forced swimming test (FST) and electrophysiological recording aged eight weeks. The results of the FST showed neonatal DEX treatment increased depression-like behaviour in adulthood. After acute stress evoking, the percentage of time spent free floating is significantly increased in the DEX treated group compared with the control animals. Furthermore, neonatal DEX treatment elevated long-term potentiation (LTP) response and the phosphorylation level of MAPK in the lateral nucleus of amygdala (LA). Intracerebroventricular infusion of the MAPK inhibitor, PD98059, showed significant rescue effects including reduced depression-like behaviour and restoration of LTP to within normal range. In conclusion, our results suggested that MAPK signalling cascade in the LA plays an important role in the adverse effect of neonatal DEX treatment on amygdala function, which may result in adverse consequences in adult age, such as the enhancement of susceptibility for a depressive disorder in later life. PMID:24945924

  3. 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

  4. Alteration by p11 of mGluR5 localization regulates depression-like behaviors

    PubMed Central

    Lee, Ko-Woon; Westin, Linda; Kim, Jeongjin; Chang, Jerry C.; Oh, Yong-Seok; Amreen, Bushra; Gresack, Jodi; Flajolet, Marc; Kim, Daesoo; Aperia, Anita; Kim, Yong; Greengard, Paul

    2016-01-01

    Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors (SSRIs). Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membranes, and p11 increases cell surface availability of the receptor. While p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, MPEP, induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity. PMID:26370144

  5. 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

    2015-01-01

    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

  6. 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. PMID:26542811

  7. The effects of EGb761 on lipopolysaccharide-induced depressive-like behaviour in C57BL/6J mice

    PubMed Central

    Zhao, Yuehan; Zhang, Yongdong

    2015-01-01

    There is an increasing body of evidence for the involvement of inflammation and brain-derived neurotrophic factor (BDNF) in depression. Ginkgo extract EGb761 possesses anti-inflammatory, anti-oxidative, anti-arteriosclerosis, and neuroprotective activities. But the effect of EGb761 on lipopolysaccharide (LPS)-induced depressive-like behaviours has not been investigated. The present study mainly aimed to examine the antidepressant-like activities of Ginkgo extract EGb761 in mice after lipopolysaccharide administration. C57BL/6J male mice were pretreated with EGb761 or vehicle for 10 days. Then, a single dose of lipopolysaccharide was intraperitoneally administrated to mice to induce depressive-like behaviour. Forced swim test (FST), tail suspension test (TST), and sucrose preference test were performed to evaluate the depressive-like behaviours of the mice. Locomotor activity was examined by open field test. Levels of brain-derived neurotrophic factor, TNF-α, IL-1β, IL-6, IL-17A, and IL-10 in hippocampus tissue homogenate were measured using ELISA kits. We found that LPS administration induced significant depressive-like behaviours, higher levels of tumour necrosis factor α (TNF-α), interleukin (IL) 1β, IL-6, and IL-17A, but lower levels of BDNF and IL-10 in hippocampus tissue homogenate of the mice from the vehicle group compared to the control mice. Pretreatment with middle dose (100 mg/kg/day) and high dose (150 mg/kg/day) of EGb761 significantly attenuated depressive-like behaviours without affecting spontaneous locomotor activity, and inhibited the changes of hippocampal cytokines and BDNF induced by LPS administration. We conclude that EGb761 has antidepressant-like activities in mice with LPS-induced depressive-like behaviours. PMID:26155178

  8. 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

  9. Mice heterozygous for cathepsin D deficiency exhibit mania-related behavior and stress-induced depression.

    PubMed

    Zhou, Rui; Lu, Yi; Han, Yong; Li, Xia; Lou, Huifang; Zhu, Liya; Zhen, Xuechu; Duan, Shumin

    2015-12-01

    Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization. PMID:26092248

  10. DESIPRAMINE BLOCKS ALCOHOL-INDUCED ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS IN TWO RAT STRAINS

    PubMed Central

    GETACHEW, BRUK; HAUSER, SHEKETHA R.; TAYLOR, ROBERT E.; TIZABI, YOUSEF

    2011-01-01

    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

  11. 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. PMID:26987370

  12. Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses.

    PubMed

    Aubrecht, Taryn G; Weil, Zachary M; Nelson, Randy J

    2014-04-15

    Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post-weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15-56) periods and also exposed a subset of dams to restraint during gestation (1 h-2×/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses. PMID:24486255

  13. Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses

    PubMed Central

    Aubrecht, Taryn G.; Weil, Zachary M.; Nelson, Randy J.

    2014-01-01

    Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post-weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15–56) periods and also exposed a subset of dams to restraint during gestation (1 h–2×/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses. PMID:24486255

  14. Glucagon orchestrates stress-induced hyperglycaemia.

    PubMed

    Harp, J B; Yancopoulos, G D; Gromada, J

    2016-07-01

    Hyperglycaemia is commonly observed on admission and during hospitalization for medical illness, traumatic injury, burn and surgical intervention. This transient hyperglycaemia is referred to as stress-induced hyperglycaemia (SIH) and frequently occurs in individuals without a history of diabetes. SIH has many of the same underlying hormonal disturbances as diabetes mellitus, specifically absolute or relative insulin deficiency and glucagon excess. SIH has the added features of elevated blood levels of catecholamines and cortisol, which are not typically present in people with diabetes who are not acutely ill. The seriousness of SIH is highlighted by its greater morbidity and mortality rates compared with those of hospitalized patients with normal glucose levels, and this increased risk is particularly high in those without pre-existing diabetes. Insulin is the treatment standard for SIH, but new therapies that reduce glucose variability and hypoglycaemia are desired. In the present review, we focus on the key role of glucagon in SIH and discuss the potential use of glucagon receptor blockers and glucagon-like peptide-1 receptor agonists in SIH to achieve target glucose control. PMID:27027662

  15. 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. PMID:26739514

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

    PubMed

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

    2015-08-14

    We sought to examine interactions of the prion protein (PrP(C)) with monoaminergic systems due to: the role of PrP(C) in both Prion and Alzheimer diseases, which include clinical depression among their symptoms, the implication of monoamines in depression, and the hypothesis that PrP(C) serves as a scaffold for signaling systems. To that effect we compared both behavior and monoaminergic markers in wild type (WT) and PrP(C)-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 PrP(C) with both the 5HT5A and D1, but not D4 receptors. The data are consistent with the scaffolding of monoaminergic signaling modules by PrP(C), and may help understand the pathogenesis of clinical depression and neurodegenerative disorders. PMID:26152722

  17. 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

    2010-04-01

    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. PMID:20184944

  18. 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. PMID:26481320

  19. 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

  20. Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour.

    PubMed

    Jaehne, Emily J; Klarić, Thomas S; Koblar, Simon A; Baune, Bernhard T; Lewis, Martin D

    2015-03-15

    The transcription factor neuronal PAS domain-containing protein 4 (Npas4), which regulates the formation of inhibitory synapses on excitatory neurons, has been suggested as a candidate gene for neurological and psychiatric conditions such as bipolar depression, autism spectrum and cognitive disorders. A mouse model of Npas4 deficiency has been developed to investigate any role in these disorders. Behavioural characterisation of Npas4(-/-), Npas4(+/-) and Npas4(+/+) mice has been conducted using the open field, elevated zero maze (EZM), Y-maze, sociability test and forced swim test (FST) to investigate a range of behaviours. Npas4(-/-) mice spent more time in the open arm of the EZM than other genotypes, suggesting decreased anxiety-like behaviour. Npas4(+/-) mice, however, were more immobile in the FST than other genotypes, suggesting increased depression-like behaviour, and also showed impaired spatial recognition memory in the Y-maze. There were no differences between genotype in social behaviour. These results suggest that differential levels of Npas4 expression in the brain may regulate anxiety, depression and cognition related disorders. PMID:25549857

  1. 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. PMID:27086220

  2. 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'. PMID:19939573

  3. 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 (30mg/kg) and imipramine (20mg/kg) supplement alone and combination of zinc (15mg/kg) and imipramine (5mg/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. PMID:26985741

  4. Inflammatory mechanisms contribute to microembolism-induced anxiety-like and depressive-like behaviors.

    PubMed

    Nemeth, Christina L; Miller, Andrew H; Tansey, Malú G; Neigh, Gretchen N

    2016-04-15

    Poor vascular health, atherosclerosis, or cardiac procedures in the elderly result in clinically silent microvascular infarcts that increase susceptibility to larger ischemic episodes and can precipitate changes in mood and cognition. Although the mechanisms that underlie ischemia-induced behavioral changes have not been fully elucidated, chronic inflammation has been implicated in the pathogenesis. Independent of brain injury, elevated levels of inflammatory cytokines can lead to sickness behaviors and symptoms of depression. Furthermore, in the presence of brain injury, inflammatory activation may serve as the linchpin that precipitates dysregulation of biological systems leading to changes to behavior. In the current study, we tested the hypothesis that cerebral inflammation caused by diffuse ischemia is necessary for the expression of post-injury anxiety- and depressive- like behavior. Using a microsphere embolism (ME) rodent model, we demonstrate prolonged elevations in expression of inflammatory genes in the hippocampus ipsilateral to the injury which are reflected in the contralateral hemisphere by two weeks following injury. Prophylactic administration of meloxicam, a preferential inhibitor of COX-2 activity, prevented both central inflammation and deficits in affective-like behaviors. Furthermore, meloxicam was more efficacious than the selective serotonin reuptake inhibitor fluoxetine in prevention of microembolism-induced changes in inflammation and behavior. These data demonstrate that inflammatory activation is necessary for microembolism-induced behavioral changes and suggest that anti-inflammatory treatments may be an effective therapeutic strategy in patients with risk factors for vascular depression or prior to invasive cardiac procedures. PMID:26826540

  5. 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

  6. Protective effect of liquiritigenin on depressive-like behavior in mice after lipopolysaccharide administration.

    PubMed

    Su, Qiang; Tao, Weiwei; Huang, Huang; Du, Yan; Chu, Xing; Chen, Gang

    2016-06-30

    Liquiritigenin (Liq), the main active ingredient of traditional Chinese medicine licorice, possesses anti-inflammatory and neuroprotective properties. The current investigation was designed to explore whether liquiritigenin could relieve lipopolysaccharide (LPS)-induced depression-like behavior in mice and the underlying mechanism. Liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) were pretreated intragastrically once daily for 7 consecutive days. LPS (0.5mg/kg) was injected subcutaneously to establish the depression model 30min after pretreatment on day 7. Interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in serum and hippocampus were detected by enzyme-linked immunosorbent assay (ELISA). Behavioral assessment was conduct 24h post LPS injection. The expressions of p65NF-κB, IκBα, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in hippocampus were determined by western blot. The obtained results showed that liquiritigenin effectively reduced the levels of pro-inflammatory cytokines and the expressions of p-p65NF-κB and p-IκBα. Furthermore, liquiritigenin preconditioning could down-regulate the immobility time in tail suspension test (TST), forced swimming test (FST) and up-regulate BDNF and TrkB contents in hippocampus. Thus, it is assumed that the antidepressant activity of liquiritigenin might be attributed to its anti-inflammatory property and BDNF/TrkB signaling pathway. PMID:27107388

  7. NEUROPATHIC PAIN-INDUCED DEPRESSIVE-LIKE BEHAVIOR AND HIPPOCAMPAL NEUROGENESIS AND PLASTICITY ARE DEPENDENT ON TNFR1 SIGNALING

    PubMed Central

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

    2014-01-01

    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. PMID:24938671

  8. Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice

    PubMed Central

    Patel, Sagar; Grizzell, J. Alex; Holmes, Rosalee; Zeitlin, Ross; Solomon, Rosalynn; Sutton, Thomas L.; Rohani, Adeeb; Charry, Laura C.; Iarkov, Alexandre; Mori, Takashi; Echeverria Moran, Valentina

    2014-01-01

    Alzheimer's disease (AD) is associated with cognitive and non-cognitive symptoms for which there are currently no effective therapies. We have previously reported that cotinine, a natural product obtained from tobacco leaves, prevented memory loss and diminished amyloid-β (Aβ) plaque pathology in transgenic 6799 mice (Tg6799 mice) when treated prior to the development of the pathology. We have also shown that cotinine reduces depressive-like behavior in normal and chronically stressed C57BL/6 mice. Here, we extend our previous studies by investigating the effects of cotinine on the progression of AD-like pathology, depressive-like behavior, and the mechanisms underlying its beneficial effects in Tg6799 mice when left untreated until after a more advanced stage of the disease's development. The results show that vehicle-treated Tg6799 mice displayed an accentuated loss of working memory and an abundant Aβ plaque pathology that were accompanied by higher levels of depressive-like behavior as compared to control littermates. By contrast, prolonged daily cotinine treatment to Tg6799 mice, withheld until after a mid-level progression of AD-like pathology, reduced Aβ levels/plaques and depressive-like behavior. Moreover, this treatment paradigm dramatically improved working memory as compared to control littermates. The beneficial effects of cotinine were accompanied by an increase in the expression of the active form of protein kinase B and the postsynaptic density protein 95 in the hippocampi and frontal cortices of Tg6799 mice. This suggests that cotinine halts the progression of AD-like pathology while reducing depressive-like behavior by stimulating signaling pathways supporting synaptic plasticity in Tg6799 mice. The potential use of cotinine to treat cognitive and non-cognitive symptoms of AD is discussed. PMID:25100990

  9. Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice

    PubMed Central

    Zheng, Lian-Shun; Kaneko, Naoko; Sawamoto, Kazunobu

    2015-01-01

    Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments. PMID:25674053

  10. 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. PMID:26215574

  11. 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. PMID:26555429

  12. Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice.

    PubMed

    Bocco, Barbara M L C; Werneck-de-Castro, João Pedro; Oliveira, Kelen C; Fernandes, Gustavo W; Fonseca, Tatiana L; Nascimento, Bruna P P; McAninch, Elizabeth A; Ricci, Esther; Kvárta-Papp, Zsuzsanna; Fekete, Csaba; Bernardi, Maria Martha; Gereben, Balázs; Bianco, Antonio C; Ribeiro, Miriam O

    2016-09-01

    Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T4-to-T3 conversion, given their much greater dependence on the D2 pathway for T3 production. T3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T3, ie, Mbp (∼43%), Mag (∼34%), Hr (∼49%), and Aldh1a1 (∼61%) and increased expression of 3 of 12 genes negatively regulated by T3, ie, Dgkg (∼17%), Syce2 (∼26%), and Col6a1 (∼3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (∼18%), Ntf3 (∼43%), Nmdar (∼26%), and GR (∼20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders. PMID:27501182

  13. 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. PMID:22410342

  14. Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice.

    PubMed

    Zhu, Lingpeng; Nang, Chen; Luo, Fen; Pan, Hong; Zhang, Kai; Liu, Jingyan; Zhou, Rui; Gao, Jin; Chang, Xiayun; He, He; Qiu, Yue; Wang, Jinglei; Long, Hongyan; Liu, Yu; Yan, Tianhua

    2016-09-01

    Esculetin is one of the major bioactive compounds of Cichorium intybus L. The main purpose of the present study was to investigate the effects and possible underlying mechanism of esculetin (Esc) on lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice. Mice were pretreatment with esculetin (Esc, 20, 40mg/kg, intragastric administration) and a positive control drug fluoxetine (Flu, 20mg/kg, intragastric administration) once daily for 7 consecutive days. At the 7th day, LPS (0.83mg/kg) was intraperitoneal injection 30min after drug administration. Higher dose (40mg/kg) of esculetin and fluoxetine significantly decreased immobility time in TST and FST. There was no significant effect on locomotor activity in mice by the drugs. Esculetin significantly reduced LPS-induced elevated levels of pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and hippocampus. Esculetin attenuated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression by inhibiting nuclear factor-κB (NF-κB) pathway in hippocampus. In addition, neuroprotection of esculetin was attributed to the upregulations of Brain derived neurotrophic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) protein expression in hippocampus. The obtained results demonstrated that esculetin exhibited antidepressant-like effects which might be related to the inhibition of NF-κB pathway and the activation of BDNF/TrkB signaling. PMID:27133730

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

    PubMed

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

    2015-05-01

    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

  16. 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

  17. Repeated Three-Hour Maternal Separation Induces Depression-Like Behavior and Affects the Expression of Hippocampal Plasticity-Related Proteins in C57BL/6N Mice

    PubMed Central

    Bian, Yaoyao; Yang, Lili; Wang, Zhongli; Wang, Qing; Zeng, Li; Xu, Guihua

    2015-01-01

    Adverse early life experiences can negatively affect behaviors later in life. Maternal separation (MS) has been extensively investigated in animal models in the adult phase of MS. The study aimed to explore the mechanism by which MS negatively affects C57BL/6N mice, especially the effects caused by MS in the early phase. Early life adversity especially can alter plasticity functions. To determine whether adverse early life experiences induce changes in plasticity in the brain hippocampus, we established an MS paradigm. In this research, the mice were treated with mild (15 min, MS15) or prolonged (180 min, MS180) maternal separation from postnatal day 2 to postnatal day 21. The mice underwent a forced swimming test, a tail suspension test, and an open field test, respectively. Afterward, the mice were sacrificed on postnatal day 31 to determine the effects of MS on early life stages. Results implied that MS induces depression-like behavior and the effects may be mediated partly by interfering with the hippocampal GSK-3β-CREB signaling pathway and by reducing the levels of some plasticity-related proteins. PMID:26798520

  18. 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. PMID:24096191

  19. Female Rats Exposed to Stress and Alcohol Show Impaired Memory and Increased Depressive-like Behaviors

    PubMed Central

    Gomez, J.L.; Luine, V.N.

    2013-01-01

    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 6hr/day/7days, and alcohol was administered immediately following restraint via gastric gavage at a dose of 2.0 g/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 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. PMID:24096191

  20. Prenatal stress produces sex-specific changes in depression-like behavior in rats: implications for increased vulnerability in females.

    PubMed

    Sickmann, H M; Arentzen, T S; Dyrby, T B; Plath, N; Kristensen, M P

    2015-10-01

    Stress during rat gestation can elicit depression-like physiological and behavioral responses in the offspring. However, human clinical depression is more prevalent among females than males. Accordingly, we examined how repeated variable prenatal stress (PS) alters rat anxiety- and depression-like behavior as well as circadian patterning of motor activity in both male and female offspring. For this purpose, we exposed pregnant Sprague-Dawley rats to multiple stressors during gestational days 13-21. Subsequently, we monitored locomotor and rearing/climbing activities in home-like cages for 24 h and measured anxiety- (elevated plus maze, EPM) and depression-like (forced swim test, FST) behaviors in the offspring at a young adult age. As a stressful event later in life (in addition to PS) may be needed to actually trigger an episode of clinical depression, half of the animals were exposed to an acute stressor (elevated platform) before EPM testing. Dams exposed to the stressor battery had increased plasma corticosterone levels compared with controls. Male PS offspring displayed changes in locomotor and rearing/climbing activity relative to controls. Additionally, anxiety measures in the EPM were affected in control animals after acute stressor exposure, however, this response was blunted in PS offspring. Moreover, FST immobility, as an indicator of depressive-like behavior, was increased in female but not male PS rats. Altogether, our results identify both sex- and circadian phase-specific effects of PS. These findings indicate that the PS rat model reflects multiple clinical depression characteristics, including elevated female vulnerability. PMID:26152908

  1. 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. PMID:26589802

  2. Serotonin7 receptors in the lateral habenular nucleus regulate depressive-like behaviors in the hemiparkinsonian rats.

    PubMed

    Han, Ling Na; Zhang, Li; Sun, Yi Na; Du, Cheng Xue; Zhang, Yu Ming; Wang, Tao; Zhang, Jin; Liu, Jian

    2016-08-01

    Preclinical studies indicate that serotonin7 (5-HT7) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT7 receptor agonist AS19 (1, 2 and 4μg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6μg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4μg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6μg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors. PMID:27178363

  3. The effects of early-life predator stress on anxiety- and depression-like behaviors of adult rats.

    PubMed

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

    2014-01-01

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

  4. Increased Mesohippocampal Dopaminergic Activity and Improved Depression-Like Behaviors in Maternally Separated Rats Following Repeated Fasting/Refeeding Cycles

    PubMed Central

    Jahng, Jeong Won; Yoo, Sang Bae; Kim, Jin Young; Kim, Bom-Taeck; Lee, Jong-Ho

    2012-01-01

    We have previously reported that rats that experienced 3 h of daily maternal separation during the first 2 weeks of birth (MS) showed binge-like eating behaviors with increased activity of the hypothalamic-pituitary-adrenal axis when they were subjected to fasting/refeeding cycles repeatedly. In this study, we have examined the psychoemotional behaviors of MS rats on the fasting/refeeding cycles, together with their brain dopamine levels. Fasting/refeeding cycles normalized the ambulatory activity of MS rats, which was decreased by MS experience. Depression-like behaviors, but not anxiety, by MS experience were improved after fasting/refeeding cycles. Fasting/refeeding cycles did not significantly affect the behavioral scores of nonhandled (NH) control rats. Fasting/refeeding cycles increased dopamine levels not only in the hippocampus but also in the midbrain dopaminergic neurons in MS rats, but not in NH controls. Results demonstrate that fasting/refeeding cycles increase the mesohippocampal dopaminergic activity and improve depression-like behaviors in rats that experienced MS. Together with our previous paper, it is suggested that increased dopamine neurotransmission in the hippocampus may be implicated in the underlying mechanisms by which the fasting/refeeding cycles induce binge-like eating and improve depression-like behaviors in MS rats. PMID:22934157

  5. 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

    2015-12-01

    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. PMID:26485503

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

    PubMed Central

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

    2014-01-01

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

  7. 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

  8. The Pharmacokinetic-Pharmacodynamic Model of Azithromycin for Lipopolysaccharide-Induced Depressive-Like Behavior in Mice

    PubMed Central

    Hao, Kun; Qi, Qu; Hao, Haiping; Wang, Guangji; Chen, Yuancheng; Liang, Yan; Xie, Lin

    2013-01-01

    A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like behavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored by lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was investigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of proinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics were constructed from transduction and indirect response models. A delay in the onset of increased proinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized by series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect response model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would peak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after peak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior indexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines level in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease progression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in the different time phases and conditions. PMID:23358536

  9. Possible Biomarkers of Chronic Stress Induced Exhaustion - A Longitudinal Study

    PubMed Central

    Wallensten, Johanna; Åsberg, Marie; Nygren, Åke; Szulkin, Robert; Wallén, Håkan; Mobarrez, Fariborz; Nager, Anna

    2016-01-01

    Background Vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) have previously been suggested to be potential biomarkers for chronic stress induced exhaustion. The knowledge about VEGF has increased during the last decades and supports the contention that VEGF plays an important role in stress and depression. There is scarce knowledge on the possible relationship of EGF and MCP-1 in chronic stress and depression. This study further examines the role of VEGF, EGF and MCP-1 in women with chronic stress induced exhaustion and healthy women during a follow-up period of two years. Methods and Findings Blood samples were collected from 105 women with chronic stress induced exhaustion on at least 50% sick leave for at least three months, at inclusion (T0), after 12 months (T12) and after 24 months (T24). Blood samples were collected at inclusion (T0) in 116 physically and psychiatrically healthy women. The plasma levels of VEGF, EGF and MCP-1 were analyzed using Biochip Array Technology. Women with chronic stress induced exhaustion had significantly higher plasma levels of VEGF and EGF compared to healthy women at baseline, T12 and at T24. There was no significant difference in plasma levels of MCP-1. Plasma levels of VEGF and EGF decreased significantly in women with chronic stress induced exhaustion during the two years follow-up. Conclusions The replicated findings of elevated levels of VEGF and EGF in women with chronic stress induced exhaustion and decreasing plasma levels of VEGF and EGF during the two years follow-up add important knowledge to the pathophysiology of chronic stress induced exhaustion. PMID:27145079

  10. 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

    Szot, Patricia; Franklin, Allyn; Miguelez, Cristina; Wang, Yangqing; Vidaurrazaga, Igor; Ugedo, Luisa; Sikkema, Carl; Wilkinson, Charles W; Raskind, Murray A

    2016-02-01

    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. FST 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

  11. A novel model of early experiences involving neonatal learning of a T-maze using maternal contact as a reward or its denial as an event of mild emotional adversity.

    PubMed

    Stamatakis, Antonios; Diamantopoulou, Anastasia; Panagiotaropoulos, Theofanis; Raftogianni, Androniki; Stylianopoulou, Fotini

    2014-12-01

    We developed a novel animal model of early life experiences in which rat pups are trained during postnatal days (PND) 10-13 in a T-maze with maternal contact as a reward (RER group) or its denial (DER group) as a mildly aversive event. Both groups of animals learn the T-maze, albeit the RER do so more efficiently. Training results in activation of the basal ganglia in the RER and of the hippocampus and prefrontal cortex in the DER. Moreover, on PND10 DER training leads to increased corticosterone levels and activation of the amygdala. In adulthood, male DER animals show better mnemonic abilities in the Morris water maze while the RER exhibit enhanced fear memory. Furthermore, DER animals have a hypofunctioning serotonergic system and express depressive-like behavior and increased aggression. However, they have increased hippocampal glucocorticoid receptors, indicative of efficient hypothalamic-pituitary-adrenal axis function, and an adaptive pattern of stress-induced corticosterone response. The DER experience with its relatively negative emotional valence results in a complex behavioral phenotype, which cannot be considered simply as adaptive or maladaptive. PMID:25231083

  12. 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. Stem Cells 2016;34:960-971. PMID:26676373

  13. IL-13 Augments Compressive Stress-Induced Tissue Factor Expression in Human Airway Epithelial Cells.

    PubMed

    Mitchel, Jennifer A; Antoniak, Silvio; Lee, Joo-Hyeon; Kim, Sae-Hoon; McGill, Maureen; Kasahara, David I; Randell, Scott H; Israel, Elliot; Shore, Stephanie A; Mackman, Nigel; Park, Jin-Ah

    2016-04-01

    Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress-induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma. PMID:26407210

  14. 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. PMID:26852948

  15. 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. PMID:26620836

  16. 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. PMID:26432993

  17. Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPARγ.

    PubMed

    Zhou, Libin; Yin, Jun; Wang, Conghui; Liao, Jiawei; Liu, George; Chen, Ling

    2014-08-01

    The Seipin gene was originally found to be responsible for type 2 congenital lipodystrophy and involved in lipid droplet formation. Seipin is highly expressed in the central nervous system as well. Seipin mutations have been identified in motor neuron diseases such as Silver syndrome and spastic paraplegia. In this study, we generated neuron-specific seipin knockout mice (seipin-nKO) to investigate the influence of seipin deficiency on locomotion and affective behaviors. In comparison with control mice, 8-week-old male seipin-nKO mice, but not female mice, displayed anxiety- and depression-like behaviors as assessed by open-field, elevated plus-maze, forced swim and tail suspension tests. However, neither male nor female seipin-nKO mice showed locomotion deficits in swimming tank and rotarod tests. Interestingly, the mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) in the hippocampus and cortex were lower in male seipin-nKO mice, but not female mice, than controls. In seipin-nKO mice, plasma levels of sex hormones including 17β-estradiol (E2) in females and testosterone in males as well as corticosterone were not altered compared with controls. The treatment of male seipin-nKO mice with E2 ameliorated the anxiety- and depression-like behaviors and remarkably increased PPARγ levels. The PPARγ agonist rosiglitazone alleviated affective disorders in male seipin-nKO mice. Notably, anxiety- and depression-like behaviors appeared in female seipin-nKO mice after ovariectomy, which was associated with low PPARγ expression. Collectively, these results indicate that neuronal seipin deficiency causing reduced PPARγ levels leads to affective disorders in male mice that are rescued by E2-increased PPARγ expression. PMID:24651066

  18. Minocycline Attenuates Depressive-Like Behaviour Induced by Rat Model of Testicular Torsion: Involvement of Nitric Oxide Pathway.

    PubMed

    Saravi, Seyed Soheil Saeedi; Mousavi, Seyyedeh Elaheh; Saravi, Seyed Sobhan Saeedi; Dehpour, Ahmad Reza

    2016-04-01

    Testicular torsion/detorsion (T/D) can induce depression in pre- and post-pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive-like behaviour, as well as antidepressant-like activity of minocycline and possible involvement of nitric oxide (NO)/cyclic GMP pathway in this paradigm in male rats undergoing testicular T/D. Unilateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with N(ω) -nitro-l-arginine methyl ester (l-NAME), non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), specific inducible NOS inhibitor; l-arginine, an NO precursor; and selective PDE5I, sildenafil. After assessment of locomotor activity in open-field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease in plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D-operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant-like effect in the operated rats in the FST (p < 0.001). Furthermore, combination of subeffective doses of minocycline (80 mg/kg) and either l-NAME (10 mg/kg) or AG (50 mg/kg) demonstrated a significant robust antidepressant-like activity in T/D group (p < 0.01). Consequently, NO/cGMP pathway was involved in testicular T/D-induced depressive-like behaviour and antidepressant-like activity of minocycline in the animal model. Moreover, a contribution was observed between either decreased testosterone or elevated serum nitrite levels and depressive-like behaviour following testicular T/D. PMID:26381433

  19. 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

  20. 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

    2016-01-01

    Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1(-/-) mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1(-/-) mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1(-/-) prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1(-/-) mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1(-/-) mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression. PMID:27404284

  1. Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking.

    PubMed

    Holleran, Katherine M; Wilson, Hadley H; Fetterly, Tracy L; Bluett, Rebecca J; Centanni, Samuel W; Gilfarb, Rachel A; Rocco, Lauren E R; Patel, Sachin; Winder, Danny G

    2016-07-01

    Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders. PMID:26751284

  2. 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

  3. 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. PMID:26414405

  4. 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

  5. Effects of environmental stress on the depression-like behaviors and the diurnal rhythm of corticosterone and melatonin in male rats.

    PubMed

    Yuan, Ming; Liu, Li-Jing; Xu, Ling-Zhi; Guo, Tian-You; Yue, Xiao-Dong; Li, Su-Xia

    2016-06-25

    Environmental stress (ES) is commonly used in producing chronic unpredictable mild stress to study pathogenesis of depression, including the regulatory role of circadian system on depression. However, the direct effect of ES on the circadian system has been rarely explored. The present study was aimed to investigate the effect of ES on depression-like behaviors and diurnal rhythm of plasma hormone/peptide levels in male rats. Rats were allocated into control group (CON group), low frequency ES group (LF group) and high frequency ES group (HF group). Sucrose preference test (SPT), open field test (OFT), weight gain, food and water intake were conducted to assess depression- and anxiety-like behaviors. A total of 7 times of the tail venous blood was collected with an interval of 4 h during 24 h from other rats who subjected to the same procedures of ES but not the behavioral tests. The alterations of diurnal rhythm of peripheral plasma corticosterone (CORT) and melatonin, and changes of the cholecystokinin (CCK), neuropeptide Y and leptin levels at zeitgeber time (ZT) 0 were detected by using enzyme-linked immunosorbent assay (ELISA). We found that ES led to a disturbance of diurnal rhythm of CORT and melatonin in the plasma. Besides, it also increased plasma leptin level and decreased body weight gain, but it did not produce depression- and anxiety-like behaviors compared with those rats in the control group. In short, our findings indicated that the ES could induce a disturbance of diurnal rhythm of plasma CORT and melatonin in male rats. PMID:27350193

  6. TSC2 mediates hyperosmotic stress-induced inactivation of mTORC1

    PubMed Central

    Plescher, Monika; Teleman, Aurelio A.; Demetriades, Constantinos

    2015-01-01

    mTOR complex 1 (mTORC1) regulates cell growth and metabolism. mTORC1 activity is regulated via integration of positive growth-promoting stimuli and negative stress stimuli. One stress cells confront in physiological and pathophysiological contexts is hyperosmotic stress. The mechanism by which hyperosmotic stress regulates mTORC1 activity is not well understood. We show here that mild hyperosmotic stress induces a rapid and reversible inactivation of mTORC1 via a mechanism involving multiple upstream signaling pathways. We find that hyperosmotic stress causes dynamic changes in TSC2 phosphorylation by upstream kinases, such as Akt, thereby recruiting TSC2 from the cytoplasm to lysosomes where it acts on Rheb, the direct activator of mTORC1. This work puts together a signaling pathway whereby hyperosmotic stress inactivates mTORC1. PMID:26345496

  7. 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

  8. Maternal infection during late pregnancy increases anxiety- and depression-like behaviors with increasing age in male offspring.

    PubMed

    Enayati, Mohsen; Solati, Jalal; Hosseini, Mohammad-Hassan; Shahi, Hamid-Reza; Saki, Golshid; Salari, Ali-Akbar

    2012-02-10

    Scientific reports suggest that the exposure to long-term stressors throughout or during late gestation increase anxiety- and depression-like behaviors of offspring in their later life. Moreover, several studies concluded that increasing age correlates with increased anxiety behaviors in humans and rodents. In the present study, we assessed the effects of prenatally administration of equal lipopolysaccharide (LPS) doses in various points of late gestation (days 15, 16, and 17) period, on neuroendocrine and immunological responses of pregnant mice, and subsequent long-lasting consequences of anxiety and depression with increasing age in male offspring at postnatal days (PD) 40 and 80. Four hours after the LPS injection, levels of corticosterone (COR) and pro-inflammatory cytokines (PIC) in pregnant mice, as compared to the control dams, were increased significantly. Furthermore, maternal inflammation raised the levels of COR, anxiety- and depression-like behaviors with increasing age in male offspring in comparison with saline male offspring. These data support other studies demonstrating that maternal stress increases the levels of anxiety and depression in offspring. Additionally, our data confirm other findings indicating that increasing age correlates with increased anxiety or depression behaviors in humans and rodents. Findings of this study suggest that time course of an inflammation response or stressor application during various stages of gestation and ages of offspring are important factors for assessing neuropsychiatric disorders. PMID:21893170

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

    PubMed

    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. [A pharmaco-ethological study of the GABA-ergic mechanisms regulating the depression-like behavior of mice].

    PubMed

    Belozertseva, I V; Andreev, B V

    1997-01-01

    It is known that repeated stress may result in depression-like alterations of behavior. This behavior is characterized by decreased social exploratory activity and increase in occurrence of defensive postures in a social interaction test in mice. The passive defensive behavior is effectively antagonized by antidepressant drugs thus providing a useful animal model of depression. Effects of several GABAergic drugs were studied in opponent test in individually housed male mice. For two weeks preceding the test, mice were repeatedly exposed to foot shock stimulation and/or social confrontation with an aggressive mouse. Muscimol, a selective agonist of GABA(A) receptors, decreased the frequency and duration of defensive postures and increased the duration of some forms of individual activity (grooming and eating), like the agonist of GABA(B) receptors baclofen. Muscimol was the only compound that facilitated exploratory activity towards an unfamiliar partner and did not suppress the locomotion. Effects of another agonist of GABA(B) receptors phenibut and inhibitor of GABA transaminase valproate Na were less specific and consisted in general suppression of behavior (prevalence of static forms of behavior). It can be thought that GABA(A) receptors are essential for regulation of depression-like behavior of mice. PMID:9472168

  11. 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. PMID:26628207

  12. 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

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

    PubMed

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

    2016-09-01

    Early life stressful events have detrimental effects on the brain and behavior, which are associated with the development of depression. Immune-inflammatory responses have been reported to contribute in the pathophysiology of depression. Many studies have reported on the beneficial effects of exercise against stress. However, underlying mechanisms through which exercise exerts its effects were poorly studied. Therefore, it applied maternal separation (MS), as a valid animal model of early-life adversity, in rats from postnatal day (PND) 2 to 14 for 180min per day. At PND 28, male Wistar albino rats were subjected to 5 experimental groups; 1) controls 2) MS rats 3) MS rats treated with fluoxetine 5mg/kg to PND 60, 4) MS rats that were subjected to voluntary running wheel (RW) exercise and 5) MS rats that were subjected to mandatory treadmill (TM) exercise until adulthood. At PND 60, depressive-like behaviors were assessed by using forced swimming test (FST), splash test, and sucrose preference test (SPT). Our results revealed that depressive-like behaviors following MS stress were associated with an increase in expression of toll-like receptor 4 (Tlr-4) and its main signaling protein, Myd88, in the hippocampal formation. Also, we found that voluntary (and not mandatory) physical exercise during adolescence is protected against depressant effects of early-life stress at least partly through mitigating the innate immune responses in the hippocampus. PMID:27184238

  14. 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. PMID:26686392

  15. Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.

    PubMed

    Tamano, Haruna; Fukura, Kotaro; Suzuki, Miki; Sakamoto, Kazuhiro; Yokogoshi, Hidehiko; Takeda, Atsushi

    2013-06-01

    Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine-administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect. PMID:23458739

  16. Serotonin₆ receptors in the dorsal hippocampus regulate depressive-like behaviors in unilateral 6-hydroxydopamine-lesioned Parkinson's rats.

    PubMed

    Liu, Kun-Cheng; Li, Jun-Yi; Tan, Hui-Hui; Du, Cheng-Xue; Xie, Wen; Zhang, Yu-Ming; Ma, Wei-Lin; Zhang, Li

    2015-08-01

    Preclinical studies indicate both activation and blockade of serotonin6 (5-HT6) receptors may produce antidepressant-like effects. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT6 receptors in the dorsal hippocampus (DH) involve in the regulation of PD-associated depression. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. In sham-operated rats, intra-DH injection of 5HT6 receptor agonist WAY208466 or antagonist SB258585 increased sucrose consumption and decreased immobility time, indicating the induction of antidepressant effects. In the lesioned rats, WAY208466 also produced antidepressant effects, whereas SB258585 decreased sucrose consumption and increased immobility time, indicating the induction of depressive-like behaviors. Neurochemical results showed that WAY208466 did not change dopamine (DA) levels in the medial prefrontal cortex (mPFC), DH and habenula, and noradrenaline (NA) levels in the DH and habenula in sham-operated rats, and SB258585 increased DA and NA levels in these structures. Further, WAY208466 increased DA levels in the mPFC, DH and habenula, and NA level in the habenula in the lesioned rats, and SB258585 decreased DA levels in the mPFC and habenula. Additionally, the lesion did not change the density of neuronal glutamate transporter EAAC1/5-HT6 receptor co-expressing neurons in the DH. Compared to sham-operated rats, these findings suggest that the effects of 5-HT6 receptors in PD-associated depression may be mediated through different neurochemical mechanisms, and the DH is an important site involved in these effects. PMID:25863121

  17. 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

    2016-08-01

    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. PMID:27210075

  18. 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

    2015-06-01

    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

  19. 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

  20. 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

  1. Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior.

    PubMed

    McCoy, C R; Golf, S R; Melendez-Ferro, M; Perez-Costas, E; Glover, M E; Jackson, N L; Stringfellow, S A; Pugh, P C; Fant, A D; Clinton, S M

    2016-06-01

    Individual differences in human temperament can increase the risk of 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 the 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

  2. 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. PMID:26546881

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

    PubMed

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

    2015-03-01

    Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. PMID:25554480

  4. 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

  5. Origin of yielding in metallic glass: Stress-induced flow

    NASA Astrophysics Data System (ADS)

    Liu, Z. Y.; Chen, M. W.; Liu, C. T.; Yang, Y.

    2014-06-01

    Yielding in crystalline metals is well known to be governed by dislocation dynamics; however, the structural origin of yielding in metallic glasses (MGs) still remains as an issue of intense debate despite that substantial research efforts have been expended. In this Letter, based on well-designed cyclic microcompression tests, we provide compelling experimental evidence revealing that yielding of MGs is essentially a stress-induced viscous flow process, during which the measured viscosity ranges from 1014 Pa.s to 1011 Pa.s and decreases with the increase of applied stress, resembling the "shear-thinning" behavior of non-Newtonian liquids. This stress-induced non-Newtonian flow finally leads to shear instability, which manifests itself as the phenomenon of delayed yielding common to a variety of MGs.

  6. Social factors modulate restraint stress induced hyperthermia in mice.

    PubMed

    Watanabe, Shigeru

    2015-10-22

    Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. PMID:26232073

  7. 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. PMID:25775519

  8. 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

  9. 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

  10. OGG1 is essential in oxidative stress induced DNA demethylation.

    PubMed

    Zhou, Xiaolong; Zhuang, Ziheng; Wang, Wentao; He, Lingfeng; Wu, Huan; Cao, Yan; Pan, Feiyan; Zhao, Jing; Hu, Zhigang; Sekhar, Chandra; Guo, Zhigang

    2016-09-01

    DNA demethylation is an essential cellular activity to regulate gene expression; however, the mechanism that triggers DNA demethylation remains unknown. Furthermore, DNA demethylation was recently demonstrated to be induced by oxidative stress without a clear molecular mechanism. In this manuscript, we demonstrated that 8-oxoguanine DNA glycosylase-1 (OGG1) is the essential protein involved in oxidative stress-induced DNA demethylation. Oxidative stress induced the formation of 8-oxoguanine (8-oxoG). We found that OGG1, the 8-oxoG binding protein, promotes DNA demethylation by interacting and recruiting TET1 to the 8-oxoG lesion. Downregulation of OGG1 makes cells resistant to oxidative stress-induced DNA demethylation, while over-expression of OGG1 renders cells susceptible to DNA demethylation by oxidative stress. These data not only illustrate the importance of base excision repair (BER) in DNA demethylation but also reveal how the DNA demethylation signal is transferred to downstream DNA demethylation enzymes. PMID:27251462

  11. 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

  12. 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. PMID:26763544

  13. 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

  14. Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress.

    PubMed

    Dang, Ruili; Cai, Hualin; Zhang, Ling; Liang, Donglou; Lv, Chuanfeng; Guo, Yujin; Yang, Ranyao; Zhu, Yungui; Jiang, Pei

    2016-02-01

    Exposure to chronic stress increases the likelihood of developing depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural development and function, and NRG1 has emerged as a novel modulator involved in the response of brain to stress, there is limited evidence concerning the effects of chronic stress exposure on NRG1/ErbB signaling. To fill this critical gap, we examined the protein expression of NRG1 and ErbB receptors in the brain of rats following chronic unpredictable mild stress (CUMS) exposure. After 6weeks of CUMS procedures, the rats were induced to a depression-like state. The stressed rats displayed elevated expression of NRG1 and phosphorylated ErbB4 (pErbB4) in the prefrontal cortex, whereas ErbB2 and pErbB2 were inhibited. In the hippocampus, CUMS also attenuated activation of the both ErbB receptors and suppressed the downstream Akt and ERK phosphorylation. Meanwhile, administration of sertraline enhanced NRG1/ErbB signaling and partly normalized the stress-induced behavioral changes and the disturbances of NRG1/ErbB system in CUMS rats. Combined, our data firstly showed the aberrant changes of NRG1/ErbB system in the brain of the animal model of depression, providing new evidence for the involvement of NRG1/ErbB pathway in the development and treatment of depression. PMID:26626816

  15. 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

  16. ER Stress-induced Aberrant Neuronal Maturation and Neurodevelopmental Disorders.

    PubMed

    Kawada, Koichi; Iekumo, Takaaki; Kaneko, Masayuki; Nomura, Yasuyuki; Okuma, Yasunobu

    2016-01-01

    Neurodevelopmental disorders, which include autism spectrum disorder, are congenital impairments in the growth and development of the central nervous system. They are mainly accentuated during infancy and childhood. Autism spectrum disorder may be caused by environmental factors, genomic imprinting of chromosome 15q11-q13 regions, and gene defects such as those in genes encoding neurexin and neuroligin, which are involved in synaptogenesis and synaptic signaling. However, regardless of the many reports on neurodevelopmental disorders, the pathogenic mechanism and treatment of neurodevelopmental disorders remain unclear. Conversely, it has been reported that endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases. ER stress is increased by environmental factors such as alcohol consumption and smoking. Here we show the recent results on ER stress-induced neurodevelopmental disorders. ER stress led to a decrease in the mRNA levels of the proneural factors Hes1/5 and Pax6, which maintain an undifferentiated state of the neural cells. This stress also led to a decrease in nestin expression and an increase in beta-III tubulin expression. In addition, dendrite length was shortened by ER stress in microtubule-associated protein-2 (MAP-2) positive cells. However, the ubiquitin ligase HRD1 expression was increased by ER stress. By suppressing HRD1 expression, the ER stress-induced decrease in nestin and MAP-2 expression and increase in beta-III tubulin returned to control levels. Therefore, we suggest that ER stress induces abnormalities in neuronal differentiation and maturation via HRD1 expression. These results suggest that targeting ER stress may facilitate quicker approaches toward the prevention and treatment of neurodevelopmental disorders. PMID:27252060

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  20. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.

    PubMed

    Lecca, Salvatore; Pelosi, Assunta; Tchenio, Anna; Moutkine, Imane; Lujan, Rafael; Hervé, Denis; Mameli, Manuel

    2016-03-01

    The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity. PMID:26808347

  1. Long-term ovariectomy enhances anxiety and depressive-like behaviors in mice submitted to chronic unpredictable stress.

    PubMed

    Lagunas, Natalia; Calmarza-Font, Isabel; Diz-Chaves, Yolanda; Garcia-Segura, Luis M

    2010-11-01

    Ovarian hormones exert anti-depressive and anxiolytic actions. In this study we have analyzed the effects of ovariectomy on the development of anxiety and depression-like behaviors and on cell proliferation in the hippocampus of mice submitted to chronic unpredictable stress. Animals submitted to stress 4 months after ovariectomy showed a significant increase in immobility behavior in the forced swimming test compared to animals submitted to stress 2 weeks after ovariectomy. In addition, long-term ovariectomy resulted in a significant decrease on the time spent in the open arms in the elevated plus-maze test compared to control animals. Stress did not significantly affect cell proliferation in the hilus of the dentate gyrus. However, ovariectomy resulted in a significant decrease in cell proliferation. These results indicate that long-term deprivation of ovarian hormones enhances the effect of chronic unpredictable stress on depressive- and anxiety-like behaviors in mice. Therefore, a prolonged deprivation of ovarian hormones may represent a risk factor for the development of depressive and anxiety symptoms after the exposure to stressful experiences. PMID:20691693

  2. Repeated, high-dose dextromethorphan treatment decreases neurogenesis and results in depression-like behavior in rats.

    PubMed

    Po, Kai Ting; Siu, Andrew Man-Hong; Lau, Benson Wui-Man; Chan, Jackie Ngai-Man; So, Kwok-Fai; Chan, Chetwyn C H

    2015-07-01

    Abuse of cough mixture is increasingly prevalent worldwide. Clinical studies showed that chronic consumption of cough mixture at high dosages may lead to psychiatric symptoms, especially affective disturbances, with the underlying mechanisms remain elusive. The present study aims at exploring the effect of repeated, high-dose dextromethorphan (DXM, a common active component of cough mixture) treatment on adult hippocampal neurogenesis, which is associated with pathophysiology of mood disturbances. After treatment with a high-dose of DXM (40 mg/kg/day) for 2 weeks, Sprague-Dawley rats showed increased depression-like behavior when compared to the control animals. Neurogenesis in the hippocampus was suppressed by DXM treatment, which was indicated by decreases in number of proliferative cells and doublecortin (an immature neuron marker)-positive new neurons. Furthermore, the dendritic complexity of the immature neurons was suppressed by DXM treatment. These findings suggest that DXM induces depression- and anxiety-like behavior and suppresses neurogenesis in rats. The current experimental paradigm may serve as an animal model for study on affective effect of cough mixture abuse, rehabilitation treatment options for abusers and the related neurological mechanisms. PMID:25939533

  3. Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats.

    PubMed

    Wulsin, Aynara C; Wick-Carlson, Dayna; Packard, Benjamin A; Morano, Rachel; Herman, James P

    2016-03-01

    Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45-58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood. PMID:26751968

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

    PubMed

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

    2015-01-01

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

  5. Mutation-related differences in exploratory, spatial, and depressive-like behavior in pcd and Lurcher cerebellar mutant mice.

    PubMed

    Tuma, Jan; Kolinko, Yaroslav; Vozeh, Frantisek; Cendelin, Jan

    2015-01-01

    The cerebellum is not only essential for motor coordination but is also involved in cognitive and affective processes. These functions of the cerebellum and mechanisms of their disorders in cerebellar injury are not completely understood. There is a wide spectrum of cerebellar mutant mice which are used as models of hereditary cerebellar degenerations. Nevertheless, they differ in pathogenesis of manifestation of the particular mutation and also in the strain background. The aim of this work was to compare spatial navigation, learning, and memory in pcd and Lurcher mice, two of the most frequently used cerebellar mutants. The mice were tested in the open field for exploration behavior, in the Morris water maze with visible as well as reversal hidden platform tasks and in the forced swimming test for motivation assessment. Lurcher mice showed different space exploration activity in the open field and a lower tendency to depressive-like behavior in the forced swimming test compared with pcd mice. Severe deficit of spatial navigation was shown in both cerebellar mutants. However, the overall performance of Lurcher mice was better than that of pcd mutants. Lurcher mice showed the ability of visual guidance despite difficulties with the direct swim toward a goal. In the probe trial test, Lurcher mice preferred the visible platform rather than the more recent localization of the hidden goal. PMID:26029065

  6. Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats

    PubMed Central

    Wulsin, Aynara C.; Wick-Carlson, Dayna; Packard, Benjamin A.; Morano, Rachel; Herman, James P.

    2016-01-01

    Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45–58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood. PMID:26751968

  7. Mutation-related differences in exploratory, spatial, and depressive-like behavior in pcd and Lurcher cerebellar mutant mice

    PubMed Central

    Tuma, Jan; Kolinko, Yaroslav; Vozeh, Frantisek; Cendelin, Jan

    2015-01-01

    The cerebellum is not only essential for motor coordination but is also involved in cognitive and affective processes. These functions of the cerebellum and mechanisms of their disorders in cerebellar injury are not completely understood. There is a wide spectrum of cerebellar mutant mice which are used as models of hereditary cerebellar degenerations. Nevertheless, they differ in pathogenesis of manifestation of the particular mutation and also in the strain background. The aim of this work was to compare spatial navigation, learning, and memory in pcd and Lurcher mice, two of the most frequently used cerebellar mutants. The mice were tested in the open field for exploration behavior, in the Morris water maze with visible as well as reversal hidden platform tasks and in the forced swimming test for motivation assessment. Lurcher mice showed different space exploration activity in the open field and a lower tendency to depressive-like behavior in the forced swimming test compared with pcd mice. Severe deficit of spatial navigation was shown in both cerebellar mutants. However, the overall performance of Lurcher mice was better than that of pcd mutants. Lurcher mice showed the ability of visual guidance despite difficulties with the direct swim toward a goal. In the probe trial test, Lurcher mice preferred the visible platform rather than the more recent localization of the hidden goal. PMID:26029065

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

    PubMed

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

    2016-07-01

    Specific growth factors induce formation and differentiation of excitatory and inhibitory synapses, and are essential for brain development and function. Fibroblast growth factor 22 (FGF22) is important for specifying excitatory synapses during development, including in the hippocampus. Mice with a genetic deletion of FGF22 (FGF22KO) during development subsequently have fewer hippocampal excitatory synapses in adulthood. As a result, FGF22KO mice are resistant to epileptic seizure induction. In addition to playing a key role in learning, the hippocampus is known to mediate mood and anxiety. Here, we explored whether loss of FGF22 alters affective, anxiety or social cognitive behaviors in mice. We found that relative to control mice, FGF22KO mice display longer duration of floating and decreased latency to float in the forced swim test, increased immobility in the tail suspension test, and decreased preference for sucrose in the sucrose preference test, which are all suggestive of a depressive-like phenotype. No differences were observed between control and FGF22KO mice in other behavioral assays, including motor, anxiety, or social cognitive tests. These results suggest a novel role for FGF22 specifically in affective behaviors. PMID:27036645

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2014-02-01

    Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. PMID:24485474