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This study investigated relationships between self-reported experiences of social defeat and individual dimensions of self-reported schizotypy. 1632 adults aged between 18 and 79 participated across two non-clinical samples (n = 920, n = 712). Multiple regression analyses tested the relationships between dimensions of schizotypy and social defeat. The analyses demonstrated evidence of relationships between increased overall schizotypy and increased social defeat, with schizotypal suspiciousness and disorganised or constrained thought and speech consistently emerging as the two most important individual predictors. These results suggest that increased schizotypy is associated with increased social defeat, although the specific relationships may depend on the specific aspects of social defeat and schizotypy being measured. Future research should investigate whether social defeat plays a role in the manifestation of specific schizotypy traits. [ABSTRACT FROM AUTHOR]

Mood disorders, including depressive and bipolar disorders, are the group of psychiatric disorders with the highest prevalence and disease burden. However, their pathophysiology remains poorly understood. Animal models are an extremely useful tool for the investigation of molecular mechanisms underlying these disorders. For psychiatric symptom assessment in animals, a meaningful behavioral phenotype is needed. Social behaviors constitute naturally occurring complex behaviors in rodents and can therefore serve as such a phenotype, contributing to insights into disorder related molecular changes. In this narrative review, we give a fundamental overview of social behaviors in laboratory rodents, as well as their underlying neuronal mechanisms and their assessment. Relevant behavioral and molecular changes in models for mood disorders are presented and an outlook on promising future directions is given. [ABSTRACT FROM AUTHOR]

Stress‐related illnesses are linked to the onset and progression of renal diseases and depressive disorders. To investigate stress‐induced changes in the renal transcriptome associated with the development of depressive behaviors, we generated here a chronic social defeat stress (CSDS) model of C57 BL/6 male mice and then performed RNA sequencing of the kidneys to obtain an inflammation‐related transcriptome. Administration of the antidepressant drug fluoxetine (10 mg·kg−1·day−1) during CSDS induction could partially alleviate renal inflammation and reverse CSDS‐induced depression‐like behaviors. Moreover, fluoxetine also modulated gene expression of stress‐related hormone receptors, including prolactin and melanin‐concentrating hormone. These results suggest that CSDS can induce gene expression changes associated with inflammation in the kidney of C57 BL/6 male mice, and this inflammation can be treated effectively by fluoxetine. [ABSTRACT FROM AUTHOR]

Women are more likely to suffer from stress-related affective disorders than men, but the underlying mechanisms of sex differences remain unclear. Previous works show that microRNA (miRNA) profiles are altered in stressed animals and patients with depression and anxiety disorders. In this study, we investigated how miRNA expression in the anterior bed nucleus of stria terminalis (BNST) was affected by social defeat stress in female and male California mice (Peromyscus californicus). We performed sequencing to identify miRNA transcripts in the whole brain and anterior BNST followed by qPCR analysis to compare miRNA expression between control and stressed animals. The results showed that social defeat stress induced sex-specific miRNA expression changes in the anterior BNST. Let-7a, let-7f and miR-181a-5p were upregulated in stressed female but not male mice. Our study provided evidence that social stress produces distinct molecular responses in the BNST of males and females.

Social interactions play a key role in modulating the impact of stressful experiences. In some cases, social interactions can result in social buffering, the process in which the presence of one individual reduces the physiological and behavioral impact of stress in another individual. On the other hand, there is growing evidence that a key initiating factor of social buffering behaviors is the initiation of an anxiogenic state in the individual that was not directly exposed to the stress. This is referred to as stress contagion (a form of emotion contagion). Both processes involve the transmission of social information, suggesting that contagion and buffering could share similar neural mechanisms. In general, mechanistic studies of contagion and buffering are considered separately, even though behavioral studies show that a degree of contagion is usually necessary for social buffering behaviors to occur. Here we consider the extent to which the neuropeptides corticotropin releasing hormone and oxytocin are involved in contagion and stress buffering. We also assess the importance that frontal cortical areas such as the anterior cingulate cortex and infralimbic cortex play in these behavioral processes. We suggest that further work that directly compares neural mechanisms during stress contagion and stress buffering will be important for identifying what appear to be distinct but overlapping circuits mediating these processes.

Basic research on avoidance by Murray Sidman laid the foundation for advances in the classification, conceptualization and treatment of avoidance in psychological disorders. Contemporary avoidance research is explicitly translational and increasingly focused on how competing appetitive and aversive contingencies influence avoidance. In this laboratory investigation, we examined the effects of escalating social-evaluative threat and threat of social aggression on avoidance of social interactions. During social-defeat learning, 38 adults learned to associate 9 virtual peers with an increasing probability of receiving negative evaluations. Additionally, 1 virtual peer was associated with positive evaluations. Next, in an approach-avoidance task with social-evaluative threat, 1 peer associated with negative evaluations was presented alongside the peer associated with positive evaluations. Approaching peers produced a positive or a probabilistic negative evaluation, while avoiding peers prevented a negative evaluation (and forfeited a positive evaluation). In an approach-avoidance task with social aggression, virtual peers gave and took money away from participants. Escalating social-evaluative threat and aggression increased avoidance, ratings of feeling threatened and threat expectancy and decreased ratings of peer favorableness. These findings underscore the potential of coupling social defeat and approach-avoidance paradigms for translational research on the neurobehavioral mechanisms of social approach-avoidance decision-making and anxiety.

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines IL-1β has been proposed to be a key mediator in the pathophysiology of mood-related disorders. However, the IL-1 receptor antagonist (IL-1ra) is a natural antagonist of IL-1 and plays a key role in the regulation of IL-1-mediated inflammation, the effects of IL-1ra in stress-induced depression has not been well elucidated. Chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) were used to investigate the effects of IL-1ra. ELISA kit and qPCR were used to detect IL-1ra levels. Golgi staining and electrophysiological recordings were used to investigate glutamatergic neurotransmission in the hippocampus. Immunofluorescence and western blotting were used to analyze CREB-BDNF pathway and synaptic proteins. Serum levels of IL-1ra increased significantly in two animal models of depression, and there was a significant correlation between serum IL-1ra levels and depression-like behaviors. Both CSDS and LPS induced the imbalance of IL-1ra and IL-1β in the hippocampus. Furthermore, chronic intracerebroventricular (i.c.v.) infusion of IL-1ra not only blocked CSDS-induced depression-like behaviors, but also alleviated CSDS-induced decrease in dendritic spine density and impairments in AMPARs-mediated neurotransmission. Finally, IL-1ra treatment produces antidepressant-like effects through the activation of CREB-BDNF in the hippocampus. Further studies need to investigate the effect of IL-1ra in the periphery in CSDS-induced depression. Our study suggests that the imbalance of IL-1ra and IL-1β reduces the expression of the CREB-BDNF pathway in the hippocampus, which dysregulates AMPARs-mediated neurotransmission, ultimately leading to depression-like behaviors. IL-1ra could be a new potential candidate for the treatment of mood disorders. Schematic of effects of IL-1ra on CSDS-induced depression-like behaviors and glutamatergic dysregulation in the hippocampus. Chronic stress induces the imbalance of IL-1ra and IL-1β in the hippocampus, subsequently decreases the phosphorylation of CREB in the Ser133 and BDNF levels. This will result in glutamatergic dysregulation, such as reduction in spine density, LTP and mEPSCs amplitude, and phosphorylation of GluA1 at Ser831 and Ser845. These events lead to depression-like behaviors in mice. Chronic i.c.v. infusion of IL-1ra prevents CSDS-induced depression-like behaviors and glutamatergic dysregulation in the hippocampus. [Display omitted] • CSDS and LPS increase the expression of IL-1β and IL-1ra in the hippocampus. • CSDS impairs hippocampal AMPARs-dependent long-term potentiation (LTP) via inducing the imbalance of IL-1ra and IL-1β. • IL-1ra treatment prevents CSDS-induced depression-like behavior and glutamatergic dysfunction in the hippocampus. • IL-1ra treatment alleviates stress-induced attenuation of BDNF-CREB pathway in the hippocampus. [ABSTRACT FROM AUTHOR]

Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive‐like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)‐dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)‐induced depression‐like behavior. Further analysis exhibits that inhibition of gamma‐aminobutyric acidergic neurons in MS projecting to the DG (MSGABA+‐DG) increases the expression of platelet‐derived growth factor‐BB (PDGF‐BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant‐like effects. Overexpression of the PDGF‐BB or exogenous administration of PDGF‐BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult‐born hippocampal neurons, as well as on depressive‐like behaviors. Conversely, knockdown of PDGF‐BB facilitates CSDS‐induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet‐derived growth factor receptor beta (PDGFRβ) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF‐BB. These results delineate a previously unidentified PDGF‐BB/PDGFRβ signaling in regulating depressive‐like behaviors and identify a novel mechanism by which the MSGABA+‐DG pathway regulates the expression of PDGF‐BB in SOM‐positive interneurons. [ABSTRACT FROM AUTHOR]

The conditions of stress contagion are induced in bystanders without direct experiences of stressful events. This study determined the effects of stress contagion on masseter muscle nociception in mice. Stress contagion was developed in the bystanders after cohabitating with a conspecific mouse subjected to social defeat stress for 10 days. On Day 11, stress contagion increased anxiety‐ and orofacial inflammatory pain‐like behaviors. The c‐Fos and FosB immunoreactivities evoked by masseter muscle stimulation were increased in the upper cervical spinal cord, while c‐Fos expressions were increased in the rostral ventromedial medulla, including the lateral paragigantocellular reticular nucleus and nucleus raphe magnus in stress contagion mice. The level of serotonin in the rostral ventromedial medulla was increased under stress contagion, while the number of serotonin positive cells was increased in the lateral paragigantocellular reticular nucleus. Stress contagion increased c‐Fos and FosB expressions in the anterior cingulate cortex and insular cortex, both of which were positively correlated with orofacial inflammatory pain‐like behaviors. The level of brain‐derived neurotrophic factor was increased in the insular cortex under stress contagion. These results indicate that stress contagion can cause neural changes in the brain, resulting in increased masseter muscle nociception, as seen in social defeat stress mice. [ABSTRACT FROM AUTHOR]

Rationale: The management of depression continues to be challenging despite the variety of available antidepressants. Herbal medicines are used in many cultures but lack stringent testing to understand their efficacy and mechanism of action. Isoalantolactone (LAT) from Elecampane (Inula helenium) improved the chronic social defeat stress (CSDS)-induced anhedonia-like phenotype in mice comparable to fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Objectives: Compare the effects of LAT and fluoxetine on depression-like behaviors in mice exposed to CSDS. Result: The CSDS-induced decrease in protein expression of postsynaptic density (PSD95), brain derived neurotrophic factor (BDNF), and glutamate receptor subunit-1 (GluA1) in the prefrontal cortex was restored by LAT. LAT showed robust anti-inflammatory activity and can lessen the increase in IL-6 and TNF-α caused by CSDS. CSDS altered the gut microbiota at the taxonomic level, resulting in significant changes in α- and β-diversity. LAT treatment reestablished the bacterial abundance and diversity and increased the production of butyric acid in the gut that was inhibited by CSDS. The levels of butyric acid were negatively correlated with the abundance of Bacteroidetes, and positively correlated with those of Proteobacteria and Firmicutes across all treatment groups. Conclusions: The current data suggest that, similar to fluoxetine, LAT show antidepressant-like effects in mice exposed to CSDS through the modulation of the gut-brain axis. [ABSTRACT FROM AUTHOR]

Severe stress exposure increases the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and behavioral changes. Current markerless pose estimation tools allow for more complex and naturalistic behavioral tests. Here, we introduce the open-source tool DeepOF to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut-annotated pose estimation data. Applying this tool to chronic social defeat in male mice, the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter and fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. Moreover, DeepOF aims to facilitate reproducibility and unification of behavioral classification by providing an open-source tool, which can advance the study of rodent individual and social behavior, thereby enabling biological insights and, for example, subsequent drug development for psychiatric disorders. Accurate phenotyping is key to deciphering behavior. Here, authors show the utility of the software package DeepOF in supervised and unsupervised identification of distinct individual and social behavioral patterns following chronic social stress. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory—e.g., the amygdala and hippocampus—are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing β-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects. [ABSTRACT FROM AUTHOR]

Inflammation has been associated with depression, and innate immune receptors, such as the Toll-like receptor (TLR) 2/4 in the medial prefrontal cortex (mPFC), are crucial for chronic stress-induced depression-related behaviors in mice. HMGB1, a putative ligand for TLR2/4, has been suggested to promote depression-related behaviors under acute stress. However, the roles of endogenous HMGB1 under chronic stress remain to be investigated. Here, we found that the cerebroventricular infusion of HMGB1 proteins blocked stress-induced social avoidance and that HMGB1-neutralizing antibodies augmented repeated social defeat stress-induced social avoidance in mice, suggesting the antidepressive-like effect of HMGB1 in the brain. By contrast, the infusion of HMGB1-neutralizing antibodies to the mPFC and HMGB1 knockout in α-CaMKII-positive forebrain neurons attenuated the social avoidance, suggesting the pro-depressive-like effect of HMGB1 released from prefrontal neurons under chronic stress. In addition, repeated social defeat stress induced HMGB1 nuclear export selectively in mPFC neurons, which was abolished in the mice lacking RAGE, one of HMGB1 receptors, suggesting the positive feedback loop of HMGB1-RAGE signaling under chronic stress. These findings pave the way for identifying multiple roles of HMGB1 in the brain for chronic stress and depression. [ABSTRACT FROM AUTHOR]

Introduction: Accumulating evidence indicates that abnormalities in the composition of gastrointestinal (GI) microbiota play a vital role in stress-related disorders. Both human beings and animals perceive stressful events differently, i.e., resilience or susceptibility. However, the role of GI microbiota in stress resilience/susceptibility and the underlying mechanisms remain largely unknown. Methods and Results: Sixty male C57BL/6J mice were exposed to 10-day chronic social defeat stress (CSDS), and 28 were found to be resilient to CSDS. We next analyzed microbiota compositions in the cecum using 16S rDNA gene sequencing, which revealed a significant increase in the relative abundance of Lactobacillus at the genus level in the resilient mice. In subsequent experiments, we found that oral administration of a strain of Lactobacillus (Lactobacillus murinus) for 2 weeks attenuated the increased levels of stress-induced corticosterone and anxiety-like behavior in stress-susceptible mice. The mRNA expression of tryptophan hydroxylase 2 (a rate-limiting enzyme in serotonin [5-HT] synthesis) was also significantly increased in the dorsal raphe nucleus (DR) of stress-susceptible mice. Conclusions:Lactobacillus contributes to stress resilience, and the DR 5-HT system may play an important role during this process. The above results suggest that certain organisms in the GI tract may play an essential role in stress response and be useful in the prevention and treatment of some stress-related psychiatric disorders, such as depression. [ABSTRACT FROM AUTHOR]

Aims: The aim was to investigate the effect of mood disorders on parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced motor disability, substantia nigra pars compacta (SNc) dopaminergic (DA) neurons loss. Also, the neural circuit mechanism was elucidated. Methods: The depression‐like (physical stress, PS) and anxiety‐like (emotional stress, ES) mouse models were established by the three‐chamber social defeat stress (SDS). The features of Parkinson's disease were reproduced by MPTP injection. Viral‐based whole‐brain mapping was utilized to resolve the stress‐induced global changes in direct inputs onto SNc DA neurons. Calcium imaging and chemogenetic techniques were applied to verify the function of the related neural pathway. Results: We found that PS mice, but not ES mice, showed worse movement performance and more SNc DA neuronal loss than control mice after MPTP administration. The projection from the central amygdala (CeA) to the SNcDA was significantly increased in PS mice. The activity of SNc‐projected CeA neurons was enhanced in PS mice. Activating or inhibiting the CeA‐SNcDA pathway could mimic or block PS‐induced vulnerability to MPTP. Conclusions: These results indicated that projections from CeA to SNc DA neurons contribute to SDS‐induced vulnerability to MPTP in mice. [ABSTRACT FROM AUTHOR]

Background Paranoia is higher in minority group individuals, especially those reporting intersecting aspects of difference. High negative and low positive self and other beliefs, and low social rank, are predictive of paranoia overtime; however, data are typically from majority group participants. This study examined whether social defeat or healthy cultural mistrust best characterizes paranoia in minority groups. Study Design Using cross-sectional, survey design, with a large (n = 2510) international sample, moderation analyses (PROCESS) examined whether self and other beliefs, and perceived social rank, operate similarly or differently in minority vs majority group participants. Specifically, we tested whether beliefs moderated the influence of minority group, and intersecting aspects of difference, on paranoia. Study Results Paranoia was consistently higher in participants from minority vs majority groups and level of paranoid thinking was significantly higher at each level of the intersectionality index. Negative self/other beliefs were associated with elevated paranoia in all participants. However, in support of the notion of healthy cultural mistrust, low social rank, and low positive self/other beliefs were significantly associated with paranoia in majority group participants but unrelated to paranoia in respective minority group members. Conclusions Although mixed, our findings signal the need to consider healthy cultural mistrust when examining paranoia in minority groups and bring into question whether "paranoia" accurately describes the experiences of marginalized individuals, at least at low levels of severity. Further research on paranoia in minority groups is crucial to developing culturally appropriate ways of understanding people's experiences in the context of victimization, discrimination, and difference. [ABSTRACT FROM AUTHOR]

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA sequencing. Using this isolation technique, we found an enrichment in BVAC populations, including distinct subsets of endothelial and microglial cells. In CSD compared to non-stress, home-cage control, differential gene expression patterns disclosed biological pathways involving vascular dysfunction, vascular healing, and immune system activation. Overall, our work demonstrates a unique technique to study BVAC populations from fresh brain tissue and suggests that neurovascular dysfunction is a key driver of psychosocial stress-induced brain pathology. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is mainly expressed in neurons, and its receptor CD200R1 is primarily in microglia. Although the CD200–CD200R1 pathway is necessary for microglial activation, its role in the pathophysiology of depression remains unknown. Methods: The chronic social defeat stress (CSDS) with behavioral tests were performed to investigate the effect of CD200 on the depressive-like behaviors. Viral vectors were used to overexpress or knockdown of CD200. The levels of CD200 and inflammatory cytokines were tested with molecular biological techniques. The status of microglia, the expression of BDNF and neurogenesis were detected with immunofluorescence imaging. Results: We found that the expression of CD200 was decreased in the dentate gyrus (DG) region of mice experienced CSDS. Overexpression of CD200 alleviated the depressive-like behaviors of stressed mice and inhibition of CD200 facilitated the susceptibility to stress. When CD200R1 receptors on microglia were knocked down, CD200 was unable to exert its role in alleviating depressive-like behavior. Microglia in the DG brain region were morphologically activated after exposure to CSDS. In contrast, exogenous administration of CD200 inhibited microglia hyperactivation, alleviated neuroinflammatory response in hippocampus, and increased the expression of BDNF, which in turn ameliorated adult hippocampal neurogenesis impairment in the DG induced by CSDS. Conclusions: Taken together, these results suggest that CD200-mediated alleviation of microglia hyperactivation contributes to the antidepressant effect of neurogenesis in dentate gyrus in mice. [ABSTRACT FROM AUTHOR]

Introduction: Chronic exposure to social defeat stress (SDS) has been used to investigate the neurobiology of depressive- and anxiety-like responses and mnemonic processes. We hypothesized that these affective, emotional, and cognitive consequences induced by SDS are regulated via glutamatergic neurons located in the bed nucleus of the stria terminalis (BNST), amygdaloid complex, and hippocampus in mice. Methods: Here, we investigated the influence of chronic SDS on (i) the avoidance behavior assessed in the social interaction test, (ii) the anxiety-like behavior (e.g., elevated plus-maze, and open field tests) (iii) depressive-like behaviors (e.g., coat state, sucrose splash, nesting building, and novel object exploration tests), (iv) the short-term memory (object recognition test), (v) ΔFosB, CaMKII as well as ΔFosB + CaMKII labeling in neurons located in the BNST, amygdaloid complex, dorsal (dHPC) and the ventral (vHPC) hippocampus. Results: The main results showed that the exposure of mice to SDS (a) increased defensive and anxiety-like behaviors and led to memory impairment without eliciting clear depressive-like or anhedonic effects; (b) increased ΔFosB + CaMKII labeling in BNST and amygdala, suggesting that both areas are strongly involved in the modulation of this type of stress; and produced opposite effects on neuronal activation in the vHPC and dHPC, i.e., increasing and decreasing, respectively, ΔFosB labeling. The effects of SDS on the hippocampus suggest that the vHPC is likely related to the increase of defensive- and anxiety-related behaviors, whereas the dHPC seems to modulate the memory impairment. Discussion: Present findings add to a growing body of evidence indicating the involvement of glutamatergic neurotransmission in the circuits that modulate emotional and cognitive consequences induced by social defeat stress. [ABSTRACT FROM AUTHOR]

Anxiety disorders are the most prevalent co‐morbidity factor associated with the core domains of autism spectrum disorders (ASD). Investigations on potential common neuronal mechanisms that may explain the co‐occurrence of ASD and anxiety disorders are still poorly explored. One of the key questions that remained unsolved is the role of Shank3 protein in anxiety behaviours. Firstly, we characterize the developmental trajectories of locomotor, social behaviour and anxiety traits in a mouse model of ASD. We highlight that the anxiety phenotype is a late‐onset emerging phenotype in mice with a Shank3Δe4‐22 mutation. Consequently, we used an shRNA strategy to model Shank3 insufficiency in the bed nucleus of the stria terminalis (BNST), a brain region exerting a powerful control on anxiety level. We found that Shank3 downregulation in the anteromedial BNST (amBNST) induced anxiogenic effects and enhanced social avoidance after aversive social defeat. Associated with these behavioural defects, we showed alteration of glutamatergic synaptic functions in the amBNST induced by Shank3 insufficiency during adolescence. Our data strongly support the role of Shank3 in the maturation of amBNST, and its key role in anxiety control. Our results may further help to pave the road on a better understanding of the neuronal mechanisms underlying anxiety disorders implicated in ASDs. [ABSTRACT FROM AUTHOR]

Anxiety is an evolutionarily conserved response that is essential for survival. Pathological anxiety, however, is a maladaptive response to nonthreatening situations and greatly affects quality of life. The recent COVID-19 pandemic has increased the prevalence of anxiety symptoms and highlighted the urge to identify the molecular events that initiate pathological anxiety. To this aim, we investigated the extent of similarity of brain region-specific gene expression patterns associated with innate and stress-induced anxiety-like behavior. We compared the cortico-frontal (FCx) and hippocampal (Hpc) gene expression patterns of five inbred mouse strains with high or low levels of innate anxietylike behavior with gene expression patterns of mice subjected to chronic social defeat stress. We found significantly large overlap of the Hpc but small overlap of the FCx gene expression patterns in innate and stress-induced anxiety, that however, converged onto common inflammation and immune system canonical pathways. Comparing the gene expression data with drug-gene interaction datasets revealed drug candidates, including medrysone, simvastatin, captopril, and sulpiride, that produced gene expression changes opposite to those observed in innate or stress-induced anxiety-like behavior. Together, our data provide a comprehensive overview of FCx and Hpc gene expression differences between innate and stress-induced anxiety and support the role of inflammation and immune system in anxiety-like behavior. [ABSTRACT FROM AUTHOR]

An absence of reward in chronic stress may impair the reward circuit in the brain, resulting in major depressive disorder (MDD). In a part of chronically stressed individuals, MDD is not present, i.e., there is resilience, implying endogenous anti-depressive mechanisms in the brain. We studied social defeat model mice and analyzed the mRNA maps of the hippocampus from a control group and social defeat (SD)-susceptible and SD-resilient mice using high-throughput sequencing techniques. It was found that the immune response was associated with depression. Existing studies have proven that microglia play an important role in the brain immune response, and their activation level increases after chronic social defeat stress (CSDS). In our study, minocycline inhibited the activation of microglia, thereby improving the depressive state of CSDS mice. In addition, minocycline combined with fluoxetine enhanced the efficacy of fluoxetine. Thus, our results propose the most probable mechanism underlying different responses to CSDS and indicate the potential of a combination of anti-inflammatory drugs and antidepressants in treating refractory depression. [ABSTRACT FROM AUTHOR]

(b and c) The ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the mouse brain regions from social defeat stress (susceptible) mice and control (unsusceptible) mice. Graph: Figure 1p-EphA4/EphA4 and p-ephexin1/ephexin1 ratios in the brain regions of mice with the depression-like phenotype and the postmortem brains of depressed patients. [Extracted from the article]

Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of chronic stress on tissue levels of corticosterone (CORT), progesterone (PROG), 11-deoxycorticosterone (11DOC) and 11-dehydrocorticosterone (11DHC) and on gut microbiota, which may reshape the stress response. Male BALB/c mice, liquid chromatography-tandem mass spectrometry and 16S RNA gene sequencing were used to screen steroid levels and fecal microbiome, respectively. Stress induced greater increase of CORT in the brain, liver, and kidney than in the colon and lymphoid organs, whereas 11DHC was the highest in the colon, liver and kidney and much lower in the brain and lymphoid organs. The CORT/11DHC ratio in plasma was similar to the brain but much lower in other organs. Stress also altered tissue levels of PROG and 11DOC and the PROG/11DOC ratio was much higher in lymphoid organs that in plasma and other organs. Stress impacted the β- but not the α-diversity of the gut microbiota and LEfSe analysis revealed several biomarkers associated with stress treatment. Our data indicate that social defeat stress modulates gut microbiota diversity and induces tissue-dependent changes in local levels of corticosteroids, which often do not reflect their systemic levels. [ABSTRACT FROM AUTHOR]

(1) Background: there is an urgent clinical need for rapid and effective antidepressants. (2) Methods: We employed proteomics to profile proteins in two animal models (n = 48) of Chronic Unpredictable Stress and Chronic Social Defeat Stress. Additionally, partial least squares projection to latent structure discriminant analysis and machine learning were used to distinguish the models and the healthy control, extract and select protein features and build biomarker panels for the identification of different mouse models of depression. (3) Results: The two depression models were significantly different from the healthy control, and there were common changes in proteins in the depression-related brain regions of the two models; i.e., SRCN1 was down-regulated in the dorsal raphe nucleus in both models of depression. Additionally, SYIM was up-regulated in the medial prefrontal cortex in the two depression models. Bioinformatics analysis suggested that perturbed proteins are involved in energy metabolism, nerve projection, etc. Further examination confirmed that the trends of feature proteins were consistent with mRNA expression levels. (4) Conclusions: To the best of our knowledge, this is the first study to probe new targets of depression in multiple brain regions of two typical models of depression, which could be targets worthy of study. [ABSTRACT FROM AUTHOR]

Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A + neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility. [ABSTRACT FROM AUTHOR]

Consumer-resource population models drive progress in predicting and understanding predation. However, they are often built by averaging the foraging outcomes of individuals to estimate per capita functional responses (functions that describe predation rate). Reliance on per-capita functional responses rests on the assumption that that individuals forage independently without affecting each other. Undermining this assumption, extensive behavioral neuroscience research has made clear that facilitative and antagonistic interactions among conspecifics frequently alter foraging through interference competition and persistent neurophysiological changes. For example, repeated social defeats dysregulates rodent hypothalamic signaling, modulating appetite. In behavioral ecology, similar mechanisms are studied under the concept of dominance hierarchies. Neurological and behavioral changes in response to conspecifics undoubtedly play some sort of role in the foraging of populations, but modern predator-prey theory does not explicitly include them. Here we describe how some modern approaches to population modeling might account for this. Further, we propose that spatial predator-prey models can be modified to describe plastic changes in foraging behavior driven by intraspecific interaction, namely individuals switching between patches or plastic strategies to avoid competition. Extensive neurological and behavioral ecology research suggests that interactions among conspecifics help shape populations’ functional responses. Modeling interdependent functional responses woven together by behavioral and neurological mechanisms may thus be indispensable in predicting the outcome of consumer–resource interactions across systems. [ABSTRACT FROM AUTHOR]

Social hierarchies exert a powerful influence on behavior, but the neurobiological mechanisms that detect and regulate hierarchical interactions are not well understood, especially at the level of neural circuits. Here, we use fiber photometry and chemogenetic tools to record and manipulate the activity of nucleus accumbens-projecting cells in the ventromedial prefrontal cortex (vmPFC-NAcSh) during tube test social competitions. We show that vmPFC-NAcSh projections signal learned hierarchical relationships, and are selectively recruited by subordinate mice when they initiate effortful social dominance behavior during encounters with a dominant competitor from an established hierarchy. After repeated bouts of social defeat stress, this circuit is preferentially activated during social interactions initiated by stress resilient individuals, and plays a necessary role in supporting social approach behavior in subordinated mice. These results define a necessary role for vmPFC-NAcSh cells in the adaptive regulation of social interaction behavior based on prior hierarchical interactions. Here, the authors identify a frontostriatal circuit that is involved in regulating social interactions based on learned hierarchical relationships. [ABSTRACT FROM AUTHOR]

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in cognitive impairment and is often accompanied by anxiety. In this study, we investigated whether the activation of VTAVgat neurons could reduce anxiety in APP/PS1 mice. We hypothesized that acute social defeat stress (SDS) would lead to anxiety in APP/PS1 mice, and that the activation of VTAVgat neurons would alleviate this anxiety. Methods: We exposed APP/PS1 mice to acute SDS and assessed anxiety using the open field test and elevated plus-arm test. Activated VTAVgat neurons was tested by cfos staining. Sleep quality was detected using electroencephalogram after SDS or non-SDS procedure. Sleep duration, sleep latency, and non-rapid eye movement (NREM) percentage were analyzed. VTAVgat neurons were chemogenetically activated by deschloroclozapine. Results: Our results showed that acute SDS led to anxiety in APP/PS1 mice, as evidenced by increased anxiety-related behaviors in the open field and elevated plus-arm tests. Activation of VTAVgat neurons by SDS led to an increase in sleep duration, primarily due to a decrease in sleep latency and an increase in NREMs. However, the quality of sleep was poor. Chemogenetical activation of VTAVgat neurons improved sleep quality and relieved SDS-induced anxiety. Furthermore, the anxiety state correlated negatively with sleep duration and NREM percentage and correlated positively with theta power density in APP/PS1 mice. Discussion: Our study provides evidence that the activation of VTAVgat neurons alleviates SDS-induced anxiety in APP/PS1 mice, suggesting that poor sleep quality may exacerbate anxiety in AD. These findings may have important implications for the treatment of anxiety in AD, as targeting VTAVgat neurons could be a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

The ventral hippocampus (vHC) is a core brain region for emotional memory. Here, we examined how the vHC regulates stress susceptibility from the level of gene expression to neuronal population dynamics in male mice. Transcriptome analysis of samples from stress-naïve mice revealed that intrinsic calbindin (Calb1) expression in the vHC is associated with susceptibility to social defeat stress. Mice with Calb1 gene knockdown in the vHC exhibited increased stress resilience and failed to show the increase in the poststress ventral hippocampal sharp wave ripple (SWR) rate. Poststress vHC SWRs triggered synchronous reactivation of stress memory-encoding neuronal ensembles and facilitated information transfer to the amygdala. Suppression of poststress vHC SWRs by real-time feedback stimulation or walking prevented social behavior deficits. Taken together, our results demonstrate that internal reactivation of memories of negative stressful episodes supported by ventral hippocampal SWRs serves as a crucial neurophysiological substrate for determining stress susceptibility. Stressful memories are a possible factor to induce psychiatric symptoms. Here, the authors demonstrate that stress susceptibility is related to memory consolidation mechanisms in the ventral hippocampus. [ABSTRACT FROM AUTHOR]

Inflammatory microglia and P2X7R are involved in the development of stress-induced depression. Endoplasmic reticulum (ER) stress and mitochondrial damage play an important role in depression and microglial activation. Bullatine A (BLA) has anti-inflammatory and anti-rheumatic effects, and can be used as a P2X7R antagonist. We found that Bullatine A can effectively inhibit the calcium overload of mitochondria and the increase of ER and mitochondrial colocalization caused by eATP (extracellular ATP) in BV2-cells. Bullatine A can also inhibit the activation of PERK-elF-2α unfolded protein response (UPR), lysosome production and the increase of NLRP3 inflammasome protein expression in BV2-cells Both intragastric administration and intra-hippocampal microinjection of Bullatine A can significantly improve the despair behavior but not anhedonia of Chronic chronic social defeat stress (CSDS) mice. Bullatine A may have a beneficial therapeutic effect in treating diseases related to stress stimulation, such as depression. [Display omitted] • The concentration of 50 μM Bullatine A can effectively mitigate the effect of extracellular ATP on BV-2 cells. • Bullatine A can effectively inhibit the increase of ER and mitochondrial colocalization caused by extracellular ATP. • Bullatine A can also inhibit the increase of NLRP3 inflammasome protein expression. • Bullatine A can significantly improve the despair behavior of CSDS mice. [ABSTRACT FROM AUTHOR]

Whole-transcriptome data were used to study the changes in expression of genes coding proteins involved in the calcium regulation processes in the hippocampus of male mice with symptoms of depression caused by chronic social defeat stress. Cacna1g, Cacnb3, Camk1g, Camk2d, Camk2n2, Caly, Caln1, S100a16, and Slc24a4 genes were upregulated in the hippocampus of depressed mice compared to a control, while C-acna2d1, Cacng5, Grin2a, and Calm2 were downregulated. The greatest number of significant correlations was observed between the expression level of Calm2, which showed the highest transcriptional activity, and other differentially expressed genes. Calcium signaling in the hippocampus was assumed to be disrupted in mice exposed to chronic social defeat stress. The involvement of Calm2, Сamk1g, Camk2d, and Camk2n2 genes in the process is discussed. [ABSTRACT FROM AUTHOR]

Introduction: Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early-life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). Methods: During the first 2 weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. There were four groups (n = 10/group): Std-Con, MS-Con, Std-CSDS, and MS-CSDS. Results: Early and/or adult life adversity reduced β-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of β-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content, respectively, in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets' insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. Conclusion: MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced β-cell number and islets' insulin secretion under CSDS. The decreased muscular FKBP51 content might be a homeostatic response to slow down insulin resistance development under chronic stress. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depressionlike behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression. [ABSTRACT FROM AUTHOR]

β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms. [ABSTRACT FROM AUTHOR]

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease. [ABSTRACT FROM AUTHOR]

Abnormal amino acid metabolism in neural cells is involved in the occurrence and development of major depressive disorder. Taurine is an important amino acid required for brain development. Here, microdialysis combined with metabonomic analysis revealed that the level of taurine in the extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. Therefore, taurine supplementation may be usable an intervention for depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice. Moreover, taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and the proportions of different types of spines. The expression of N-methyl d-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation. These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits. [ABSTRACT FROM AUTHOR]

Rationale: Stress may contribute to relapse to alcohol use in part by enhancing reactivity to cues previously paired with alcohol. Yet, standard models of stress-induced reinstatement generally use contingent presentations of alcohol-paired cues to reinforce instrumental behaviors, making it difficult to isolate the ability of cues to invigorate alcohol-seeking. Objective: Here we sought to test the impact of stress on behavioral responses to alcohol-paired cues, using a model of stress-induced reinstatement of Pavlovian conditioned approach, inspired by Nadia Chaudhri's work on context-induced reinstatement. Methods: Long Evans rats were trained to associate one auditory cue with delivery of alcohol or sucrose and an alternative auditory cue with no reward. Following extinction training, rats were exposed to a stressor prior to being re-exposed to the cues under extinction conditions. We assessed the effects of yohimbine, intermittent footshock and olfactory cues paired with social defeat on responses to alcohol-paired cues and the effects of yohimbine on responses to sucrose-paired cues. Results: The pharmacological stressor, yohimbine, enhanced alcohol seeking in a Pavlovian setting, but not in a cue-selective manner. Intermittent footshock and social defeat cues did not enhance alcohol seeking in this paradigm. Conclusions: While yohimbine elicited reinstatement of reward-seeking in a Pavlovian setting, these effects may be unrelated to activation of stress systems or to interactions with specific cues. [ABSTRACT FROM AUTHOR]

Different types of stress produce different effects on social relationships between partners. Chronic social defeat has been found to alter the emotional and social behaviours, whether it affects partner preference remains unclear. Using monogamous mandarin voles (Microtus mandarinus), the present study found that 14 days of social defeat to male vole could increase social avoidance in sociality test, and reduced attacking, intimate, sniffing and exploratory behaviours, but increased avoidance defensive, immobile behaviours in social interaction test. In addition, this treatment significantly reduced side-by-side contact with partner throughout cohabitation period, and reduced the attacking behaviour to strangers after 11 days' cohabitation. Furthermore, in mandarin vole with chronic social defeat, partner preference was abolished on 5 and 7 days' cohabitation indicating that pair bonding stability was impaired by chronic social defeat. Moreover, although mandarin voles spent longer time rescuing partner than stranger in both groups, chronic social defeat did not affect rescuing significantly. Impairment of pair bonding may be due to abnormalities in social interaction induced by chronic social defeat. This finding provides some insights into mechanisms underlying effects of prolong social stress on social relationships between partners. [ABSTRACT FROM AUTHOR]

• Intra-LC LPS augments behavioral and physiological responses to social stress. • Mannosylated liposomal clodronate site-specifically reduces microglial expression. • Microglia within the locus coeruleus regulate stress-evoked behavior in female rats. Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 μg/side, n = 5–6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 μg/side, n = 13–14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1β (IL-1β). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1β. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chronic stress induces depressive-like behaviors and cortical synapse loss in mice. • Microglia-mediated aberrant excitatory synaptic pruning leads to synaptic loss. • The elevated C3 is required for excessive microglia phagocytosis during the stress. • Chronic stress-induced cortical hypo-connectivity can be rescued by knockout of C3. Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality. [ABSTRACT FROM AUTHOR]

Alexander Bogdanov (1873–1928) was a Russian social theorist and revolutionary activist whose 'universal organizational science', or Tektology, is increasingly being recognized as offering stronger foundations for the systems approach than the later 'general system theory' of Ludwig von Bertalanffy. Had his thinking not been suppressed by Stalin, the course of Soviet history might have been different. Stafford Beer (1926–2002) was a British management scientist and consultant who was a pioneer in the development of 'organizational cybernetics'. His best‐known engagement was with the government of Salvador Allende, in Chile, seeking to use his 'viable system model' to create a socialist society that did not rest on a command economy. This experiment was cut short by the Pinochet coup d'etat. I have found no evidence that Beer was familiar with the work of Bogdanov, and this makes the similarities in their thinking particularly striking. This paper explores the ideas they shared in common. The work of other writers who have drawn on the work of Bogdanov and Beer, in formulating contemporary visions of post‐capitalism, is highlighted. [ABSTRACT FROM AUTHOR]

The article exploring the connectivity and communication between the Basolateral Amygdala (BLA) and the Mediodorsal Thalamic Nucleus (MD), essential in governing responsivity to stress and fear. It discusses that the study reveals that the BLA sends both GABAergic and glutamatergic projections to the MDm; shedding light on the complex dynamics; and mechanisms regulating neural circuits involved in stress-induced psychopathologies.

The article discusses the role of the rostral ventromedial medulla (RVM) in stress-induced depression and pain. The RVM is known to modulate spinal sensory transmission and can contribute to both facilitation and inhibition of pain. Chronic pain and emotional stress are interconnected, and the RVM is closely linked to brain structures associated with pain and stress. The study found that activating the RVM during stress ameliorated stress outcomes, while inhibiting the RVM facilitated pain. The RVM may be involved in the regulation of chronic stress-related pain and depression. Further research is needed to understand the mechanisms and connections involved in stress-induced comorbidities. [Extracted from the article]

Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depression-like behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression.

Our previous variable-light intensity lighting program studies indicate the light intensity preference behavior of broilers for their daily activity including eating and resting. To evaluate the effects of variable-light intensity lighting program on performance and welfare of broilers, four commercial trials were conducted for looking at behaviors, mortality, leg-health, performance, and brain welfare indicator genes including tryptophan hydroxylase 2 and tyrosine hydroxylase (TH), glucocorticoid receptor (GR), brain-derived neurotropic factor (BDNF), and melanopsin (Opn4) gene expression. One-day-old broilers were housed in four commercial broiler houses. Each quadrant (section) of the house was placed with 4,800 chicks. A total of four lighting programs began on day 7 with 5 lux (lx), 20 lx, natural light (NL, 480 lx), and variable light (2--5/40 lx) using LED lights on a 16L:8D photoperiod. In the variable-light house, the number of dustbathing holes was significantly higher than that in natural-light houses and 5-lx and 20-lx houses. Daily physical activities, footpad condition, fear response to novel objects, body weight, feed conversion ratio, and the number of leg-problem induced culled birds were affected by the variable-light intensity lighting program. Expression of tryptophan hydroxylase 2 in the DRN and VTA of variable-light treated birds was lower than that of 5-lx- and 20-lx-treated birds on day 42 (p < 0.05). Higher expression of VTA-TH in 5-lx-treated birds than that in 20-lx-, NL-, and variable-light-treated birds suggests the high stress-susceptibility of 5-lx treated birds. Lower VTA-GR expression in 20-lx- and variable-light-treated birds indicates lower stress than that in NL- and 5-lx-treated birds (p < 0.05). The VTA-BDNF expression of NL-treated birds was 2.5 fold higher than that of 5- lx-, 20-lx-, and variable-light-treated birds (p < 0.05), and variable-light-treated birds showed the lowest level of BDNF expression (p < 0.05), suggesting the chronic social defeat stress in NL-treated birds. The result of VTA-Opn4 expression on day 42 suggests the possible role of VTA-Opn4 in broiler welfare through central light perception. Taken together, the variable-light intensity lighting program increased volunteer natural behaviors and physical activity, which may improve footpad condition and leg health of birds, consequently. Performance data including the increased daily weight gain and the lowered feed conversion ratio and results of brain welfare indicator gene expression showed the beneficial effect of the variable-light intensity lighting program on the performance and welfare of commercial broilers. [ABSTRACT FROM AUTHOR]