Brain-derived neurotrophic factor (BDNF) has a critical role in stress response including neuropsychiatric disorders that are precipitated by stress, such as major depressive disorder (MDD). BDNF ...acts through its full-length BDNF receptor tyrosine kinase B (TrkB) to trigger a pro-plasticity effect. In contrast, the truncated isoform of the BDNF receptor (TrkB.t1) triggers an anti-plasticity effect. In stress outcomes, BDNF acting in the hippocampus has a stress resilience effect, and, inversely, in the nucleus accumbens (NAc), BDNF acts as a stress susceptible molecule. It is unknown if BDNF-TrkB acts on a specific NAc projection neuron, i.e., medium spiny neuron (MSN or spiny projection neuron), a subtype in stress outcomes. To determine this, we performed chronic social or vicarious witness defeat stress (CSDS or CWDS) in mice expressing TrkB.t1 in dopamine receptor 1 or 2 containing MSNs (D1- or D2-MSNs). Our results showed that TrkB.t1 overexpression in NAc D2-MSNs prevented the CSDS-induced social avoidance or other stress susceptible behaviors in male and female mice. We further showed that this overexpression in D2-MSNs blocked stress susceptible behavior induced by intra-NAc BDNF infusion. In contrast, our results demonstrate that overexpression of TrkB.t1 on NAc D1-MSNs facilitates the SDS susceptible behaviors. Our study provides enhanced details into the NAc cell subtype role of BDNF-TrkB signaling in stress outcomes.
•Social defeat stress to adolescent mice causes depressive-like behaviors.•Oligodendrogenesis is reduced by social defeat stress in adolescent mice.•Clemastine administration promotes ...oligodendrogenesis in socially defeated mice.•Clemastine treatment rescued depressive-like behaviors caused by social defeat stress during adolescence.
Strong stress related to adverse experiences during adolescence can cause mental disorders, as well as affecting brain structure and function. However, the underlying neurobiological mechanisms remain largely unknown. To investigate whether stress induced by adverse experience during adolescence affects oligodendrocyte (OL) remodeling, social defeat stress was applied to 6-week-old adolescent mice for 10 days, followed by behavioral tests and assessments of oligodendrogenesis. Socially defeated mice showed depressive-like behaviors in behavioral experiments. Stress led to a decrease in the number of newly born OLs in the anterior cortical region and the number of proteolipid protein-positive mature OLs in the corpus callosum and posterior cerebral cortex. Fewer bromodeoxyuridine-incorporated CC1-positive mature OLs were observed in these regions in socially defeated mice. To assess whether decreased oligodendrogenesis caused by social defeat stress is related to depressive-like symptoms under stress, clemastine, a drug that induces OL generation, was administered to socially defeated adolescent mice, resulting in the rescue of the behavioral abnormalities accompanied by increased oligodendrogenesis. These findings suggest that oligodendrogenesis in adverse environments during adolescence plays a role in psychiatric disorders, and clemastine may provide a potential therapeutic drug for adolescent mental disorders, targeting OLs.
Depression is one of the most prevalent mental illnesses in the world today, and the onset of depression is usually accompanied by neuroinflammation and impaired adult neurogenesis. As a new ...potential member of the endocannabinoid (eCB) system, G protein coupled receptor 55 (GPR55) has been associated with mood regulation. However, the role of GPR55 in the pathophysiology of depression remains poorly understood. Thus, a 10-day chronic social defeat stress (CSDS) paradigm was utilized as an animal model of depression to explore the potential role of GPR55 in depression. After CSDS, the protein level of GPR55 decreased significantly, but the mRNA expression did not change significantly, highlighting that although the GPR55 protein was involved in the progression of the depression- and anxiety-like phenotypes, its mRNA was not. Additionally, depression- and anxiety-like behaviors were also accompanied by neuroinflammation and impaired adult neurogenesis in the hippocampus. Interestingly, O-1602, a GPR55 agonist, remarkably prevented the development of depression- and anxiety-like behaviors as well as hippocampal neuroinflammation and neurogenesis deficits induced by CSDS. However, after electroacupuncture (EA) alleviated depression- and anxiety-like behaviors induced by CSDS, treatment with a GPR55 antagonist (CID16020046) reversed this effect. Our research demonstrated that downregulation of GPR55 expression in the hippocampus might mediate CSDS-induced depression- and anxiety-like phenotypes, and activation and upregulation of GPR55, which might be correlated with its anti-inflammatory and subsequent neuroprotective effects, could be a potential treatment for depression.
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•CSDS induces anxiodepression-like behaviors and decreases the protein level of GPR55 in hippocampus of mice.•Activation of GPR55 ameliorates anxiodepression-like behaviors, neuroinflammation and impaired neurogenesis.•Antagonism of GPR55 impedes the beneficial effects of electro-acupuncture on depression.
Exposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are ...resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD.
Thirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg).
IRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward.
Our findings help to characterize the nature of resilience to the effects of social stress during adolescence.
•Some mice are resilient to the effects of social defeats during early adolescence.•Low submission during defeats predicts resilience to depression-like behavior.•Low submission during defeats predicts resilience to potentiation of cocaine reward.•Resilience to depression-like behavior predicts resilience to acquire cocaine reward.
Background and Objectives: Infertility is one of the bitter experiences of life that causes many psychological problems for the individual and his family. The aim of this study was to investigate the ...role of infertility stress and defeat in predicting the quality of infertile womenchr(chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))39chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))s marital relationship. Methods: The present study was a descriptive correlational study. A sample of 120 infertile women using the available sampling method was selected from women who referred to the Infertility Center in Birjand in 2020. Research tools included Newton et al.chr(chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))39chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))s infertility stress scale, Gilbert and Allenchr(chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))39chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))s sense of failure, and the quality of the right marriage relationship with colleagues. To analyze the data, Pearson correlation coefficient and multiple regressions were used simultaneously using SPSS software version 22 at a significance level of 0.05. Results: The results showed that there was a direct relationship between infertility stress (r = 0.722) and feelings of failure (r = 0.651) and the quality of marital relationship (p <0.01). Also, the value of standardized regression coefficient (Beta) for infertility stress components including social dimension (p = 0.014, β = 0.135), sexual dimension (p = 0.035, β = 0.88), communication (p = 0.166, β = 0.260), lifestyle non-acceptance (p <0.001, β = 0.235), need for parenting (p <0.001, β = 0.219) and failure feeling component Included feelings of stagnation (p <0.001, β = 0.240), feeling of loss (p <0.001, β = 0.225) and feelings of satisfaction (p <0.001, β = 0.261). Conclusion: Based on the results of the study, it can be said that with increasing infertility stress and feelings of failure, the quality of the marital relationship of infertile women decreases. Thus, infertility stress and feelings of failure play a crucial role in the quality of infertile womenchr(chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))39chr(chr(chr('39')39chr('39'))39chr(chr('39')39chr('39')))s marital relationship.
•Metformin ameliorates SDS-induced depression-like behaviors.•Metformin enhances the antidepressant effect of fluoxetine.•Metformin exerts antidepressant effects by activating AMPK/CREB-mediated ...histone acetylation to increase BDNF expression.
Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated.
C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg−1), SDS + FLUOX (3 mg kg−1), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons.
The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CA1 pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB).
Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression.
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•Repeated social defeat stress model is ideal to investigate preventive and therapeutic measures for depressive-like behavior.•Partnership intervention prevents depressive-like ...behavior induced by repeated social defeat stress.•Single dose of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide treatment alleviates social avoidance behavior.
Persistent stress increases the probability for developing depression significantly thereafter. Repeated social defeat stress is a widely used model to investigate depressive-like behavior in preclinical models. Hence, the repeated social defeat stress model provided an ideal animal model, through which the hypotheses of prevention and treatment can be investigated. We have successfully induced depressive-like behavior for male C57BL/6J mice with this model. Here, we reported that certain level of during-stress social interactions with single female or multiple male peer(s) exerted a positive role in preventing the development of depressive-like behavior induced by repeated social defeat stress. Our data suggested that the stress-susceptible mice may benefit from positive social interaction, which reduces the chance for depressive-like behavior development. Since numerous studies indicate that the metabotropic glutamate receptor 5 (mGluR5) plays an important role in various cognitive functions, we further investigate the treatment effect of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) on the depressive-like behavior induced by repeated social defeat stress. Most importantly, robust anti-depressant effects have been achieved through modulating the mGluR5 function. We found that single oral dose administration of CDPPB (20 mg/kg), to some extent, alleviated the social avoidance behaviors for the stress-susceptible mice. Our data implies that the CDPPB, a positive allosteric modulator of mGluR5, is a promising anti-depressant candidate with limited side effect.
A number of very important challenges to the separation distress hypothesis of depression were discussed, clarified, and linked to various strands of existing literature. Foremost among those is the ...critical challenge to define a more comprehensive set of clinical precipitants, and the possibility that depression may have two prototype elicitors - social defeat and social loss, with hugely overlapping neurobiology, and currently inadequate differentiation in terms of biomarkers and fundamental neurobiology. The possibility of synergism versus exclusionary arguments around about various evolutionary and traditional psychiatric perspectives was advocated. Additional and relevant considerations around mammalian PLAY as an opponent process to depression, and the challenges posed by social constructivist views of emotion were also explored, as these were both neglected in the target article. Social constructivist views and prototype emotion theory are not incompatible; how cognition extensions of prototype 'elicitors,' as well as cognized versions of classic prototype affective behaviors might operate is also discussed. There is no way to defend social constructivist views of emotion in animals, and the enormous continuity - from subcortical architectures, neuromodulators and behavioral homologues - argues loudly against any assumption of a fundamental discontinuity between mammalian and human affective endowment.
Chronic social stress can increase susceptibility to chronic diseases such as depression. One of the most used models to study the physiological mechanisms and behavioral outcomes of this type of ...stress is chronic defeat stress (CDS) in male mice. OF1 male mice were subjected to a stress period lasting 18 days. During that time, non-stressed animals were housed in groups. The cluster analysis of the behavioral profile displayed during the first social interaction divided subjects into two groups: active/aggressive (AA) and passive/reactive (PR). The day after the end of the stress period, the following behavioral analyses were performed: the sucrose preference test (SPT) on day 19, the open field test (OFT) on day 20, and the forced swim test (FST) on day 21. Immediately after completing the last test, animals were weighed, and blood samples were obtained. Then, they were sacrificed, and their prefrontal cortices and hippocampi were removed and stored to analyze monoamine levels. Stressed animals displayed anhedonia, and solely the PR mice continued to show higher levels of immobility in the OFT and FST. All stressed animals, regardless of the coping strategy, presented higher plasma corticosterone levels. In addition, stressed mice showed lower levels of tyrosine, dopamine, DOPAC, MHPG, kynurenine, kynurenic acid, and 5-HIAA levels but higher serotonin levels in the prefrontal cortex, not in the hippocampus. In conclusion, our results show that CSD induces differences in monoamine levels between brain areas, and these differences did not respond to the coping strategy adopted.
The neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive ...and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT.
First, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior.
A single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses.
Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.
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