Evaluation and test of the reliability and validity of the Chinese defeat scale in the elite athletes of Chinese universities.

To test the reliability and validity of the "Defeat Scale" and explore whether the scale is suitable for use in surveys of college athletes. A total of 226 athletes from five universities in China were selected for evaluation using the defeat scale. Factor analysis and correlation analysis were used to explore the reliability and validity of the defeat scale. Exploratory factor analysis showed that two factors could be extracted from this scale, namely a sense of decadence and a sense of low achievement. Confirmatory factor analysis showed that the model fit of the two factors was excellent (X2/DF = 2.809, RMSEA = 0.092, SRMR = 0.054, NFI = 0.891, IFI = 0.927, CFI = 0.926, GFI = 0.919, TLI = 0.910) . The convergent validity AVE values are 0.579 and 0.505 respectively, AVE > 0.5, and the combined reliability is 0.946 and 0.746 respectively. Both > 0.7 indicate good convergence effect. The arithmetic square roots of AVE, 0.760 and 0.710, are both higher than the absolute value of the correlation coefficient between the two dimensions, 0.30, indicating good discriminant validity; and the Cronbach's alpha coefficient of defeat is 0.931, and the Spearman-Brown coefficient is 0.888. The defeat scale has good reliability and validity among college athletes.

Chronic social defeat stress gives rise to social avoidance through fear learning.

Chronic social defeat stress (CSDS), a widely used rodent model of stress, reliably leads to decreased social interaction in stress susceptible animals. Here, we investigate a role for fear learning in this response using male 129 Sv/Ev mice, a strain that is more vulnerable to CSDS than the commonly used C57BL/6 strain. We first demonstrate that defeated 129 Sv/Ev mice avoid a CD-1 mouse, but not a conspecific, indicating that motivation to socialize is intact in this strain. CD-1 avoidance is characterized by approach behavior that results in running in the opposite direction, activity that is consistent with a threat response. We next test whether CD-1 avoidance is subject to the same behavioral changes found in traditional models of Pavlovian fear conditioning. We find that associative learning occurs across 10 days CSDS, with defeated mice learning to associate the color of the CD-1 coat with threat. This leads to the gradual acquisition of avoidance behavior, a conditioned response that can be extinguished with 7 days of repeated social interaction testing (5 tests/day). Pairing a CD-1 with a tone leads to second-order conditioning, resulting in avoidance of an enclosure without a social target. Finally, we show that social interaction with a conspecific is a highly variable response in defeated mice that may reflect individual differences in generalization of fear to other social targets. Our data indicate that fear conditioning to a social target is a key component of CSDS, implicating the involvement of fear circuits in social avoidance.

Christensenella minuta mitigates behavioral and cardiometabolic hallmarks of social defeat stress.

Psychological stress during early development and adolescence may increase the risk of psychiatric and cardiometabolic comorbidities in adulthood. The gut microbiota has been associated with mental health problems such as depression and anxiety and with cardiometabolic disease, but the potential role of the gut microbiota in their comorbidity is not well understood. We investigated the effects and mode of action of the intestinal bacterium Christensenella minuta DSM 32891 on stress-induced mental health and cardiometabolic disturbances in a mouse model of social defeat stress. We demonstrate that administered C. minuta alleviates chronic stress-induced depressive, anxiogenic and antisocial behavior. These effects are attributed to the bacterium's ability to modulate the hypothalamic-pituitary-adrenal axis, which mediates the stress response. This included the oversecretion of corticosterone and the overexpression of its receptors, as well as the metabolism of dopamine (DA) and the expression of its receptors (D1, D2L and D2S). Additionally, C. minuta administration reduced chronically induced inflammation in plasma, spleen and some brain areas, which likely contribute to the recovery of physical and behavioral function. Furthermore, C. minuta administration prevented chronic stress-induced cardiovascular damage by regulating key enzymes mediating liver fibrosis and oxidative stress. Finally, C. minuta increased the abundance of bacteria associated with mental health. Overall, our study highlights the potential of microbiota-directed interventions to alleviate both the physical and mental effects of chronic stress.

Psychosis risk for lesbian, gay, and bisexual individuals: systematic review and meta-analysis.

The social defeat hypothesis posits that low status and repeated humiliation increase the risk for psychotic disorders (PDs) and psychotic experiences (PEs). The purpose of this paper was to provide a systematic review of studies on risk of PDs and PEs among lesbian, gay, or bisexual (LGB) people and a quantitative synthesis of any difference in risk. PubMed, PsycINFO, Embase, and Web of Science were searched from database inception until January 30, 2024. Two independent reviewers assessed the eligibility and quality of studies, extracted effect sizes, and noted the results of mediation analyses. Using a random effects model we computed pooled odds ratios (ORs). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The search identified seven studies of PDs and six of PEs. As for PDs, the unadjusted (2.13; 95% confidence interval 0.72-6.34) and covariate-adjusted pooled OR (2.24; 1.72-3.53) were not significantly increased for LGB individuals. After exclusion of a study of limited quality, both the unadjusted pooled OR (2.77; 1.21-6.32) and the covariate-adjusted pooled OR (2.67; 1.53-4.66) were significantly increased. The pooled ORs were increased for PEs: unadjusted, pooled OR = 1.97 (1.47-2.63), covariate-adjusted, pooled OR = 1.85 (1.50-2.28). Studies of PE that examined the mediating role of several variables reported that the contribution of drug abuse was small compared to that of psychosocial stressors. The results of a study in adolescents suggested a protective effect of parental support. These findings suggest an increased psychosis risk for LGB people and support the social defeat hypothesis.

Effects of chronic social defeat stress on social behavior and cognitive flexibility for early and late adolescent.

This study investigated the risk to social behavior and cognitive flexibility induced by chronic social defeat stress (CSDS) during early and late adolescence (EA and LA). Utilizing the "resident-intruder" stress paradigm, adolescent male Sprague-Dawley rats were exposed to CSDS during either EA (postnatal days 29-38) or LA (postnatal days 39-48) to explore how social defeat at different stages of adolescence affects behavioral and cognitive symptoms commonly associated with psychiatric disorders. After stress exposure, the rats were assessed for anxiety-like behavior in the elevated plus maze, social interaction, and cognitive flexibility through set-shifting and reversal-learning tasks under immediate and delayed reward conditions. The results showed that CSDS during EA, but not LA, led to impaired cognitive flexibility in adulthood, as evidenced by increased perseverative and regressive errors in the set-shifting and reversal-learning tasks, particularly under the delayed reward condition. This suggests that the timing of stress exposure during development has a significant impact on the long-term consequences for behavioral and cognitive function. The findings highlight the vulnerability of the prefrontal cortex, which undergoes critical maturation during early adolescence, to the effects of social stress. Overall, this study demonstrates that the timing of social stressors during adolescence can differentially shape the developmental trajectory of cognitive flexibility, with important implications for understanding the link between childhood/adolescent adversity and the emergence of psychiatric disorders.

Amyloban, extracted from Hericium erinaceus, ameliorates social deficits and suppresses the enhanced dopaminergic system in social defeat stress mice.

Social dysfunctions are common in various psychiatric disorders, including depression, schizophrenia, and autism, and are long-lasting and difficult to treat. The development of treatments for social impairment is critical for the treatment of several psychiatric disorders. "Amyloban 3399," a product extracted from the mushroom Hericium erinaceus, markedly improves social dysfunctions in patients with treatment-resistant schizophrenia and depression. However, the molecular mechanism(s) through which amyloban ameliorates social impairment remains unclear. To clarify this mechanism, in this study, we aimed to establish a mouse model of social defeat stress (SDS) and investigate the effects of amyloban on social deficits. Amyloban administration ameliorated social deficits and the dopamine system activity in SDS mice. These findings suggest that there is a possibility that amyloban may improve social deficits by suppressing the hyperactivation of the dopaminergic system. Amyloban may be an effective treatment for social dysfunctions associated with various psychiatric disorders.

Preventing social defeat stress-induced behavioural and neurochemical alterations by repeated treatment with a mix of Centella asiatica, Echinacea purpurea and Zingiber officinale standardized extracts.

Background: Prolonged exposure to stress is a risk factor for the onset of several disorders. Modern life is burdened by a pervasive prevalence of stress, which represents a major societal challenge requiring new therapeutic strategies. In this context, botanical drug-based therapies can have a paramount importance. Methods: Here we studied the preventive effects of a repeated treatment (p.o. daily, 3 weeks) with a combination of Centella asiatica (200 mg/kg), Echinacea purpurea (20 mg/kg) and Zingiber officinale (150 mg/kg) standardized extracts, on the chronic social defeat stress (CSDS) deleterious outcomes. After 10 days of CSDS exposure, male mice' performances were evaluated in paradigms relevant for social (social interaction test), emotional (tail suspension test), cognitive (novel object recognition) domains as well as for pain perception (cold plate and von Frey tests) and motor skills (rotarod). Mice were then sacrificed, the spinal cords, hippocampi and frontal cortices dissected and processed for RT-PCR analysis. Results: Extracts mix treatment prevented stress-induced social aversion, memory impairment, mechanical and thermal allodynia and reduced behavioural despair independently of stress exposure. The treatment stimulated hippocampal and cortical BDNF and TrkB mRNA levels and counteracted stress-induced alterations in pro- (TNF-α, IL-1ß and IL-6) and anti-inflammatory (IL4, IL10) cytokines expression in the same areas. It also modulated expression of pain related genes (GFAP and Slc1a3) in the spinal cord. Conclusion: The treatment with the extracts mix obtained from C. asiatica, E. purpurea and Z. officinale may represent a promising strategy to promote resilience and prevent the deleterious effects induced by extended exposure to psychosocial stress.

A prospective examination of sleep chronotype and future suicide intent among adults in the United Kingdom: A test of the integrated motivational volitional model of suicide.

OBJECTIVES/BACKGROUND: Prior research identified a connection between evening chronotype and suicidality, but the mechanism underlying that connection is not well understood. The Integrated Motivational Volitional (IMV) Model of Suicide may provide a theoretical explanation for this link. The current project includes a three-time point longitudinal survey to examine whether 1) suicide intent likelihood varies across time, 2) chronotype affects suicide intent likelihood prospectively, and 3) defeat and entrapment explain the association between chronotype and suicide intent likelihood. PATIENTS/METHODS: Participants (n = 187 UK adults) completed a baseline survey (demographics, chronotype (morning-eveningness; MEQ), defeat and entrapment, and perceived intent to make a future suicide attempt), and follow-up surveys (MEQ and suicide intent likelihood) 3 and 6 months later. RESULTS: Results indicated that suicidal intent at 6-month follow-up was lower than baseline or 3-month follow-up. It was also found that strong evening chronotype at baseline is associated with increased suicidal intent 6 months later, and that defeat mediates this relationship. CONCLUSION: Our theoretically informed findings shed light on the psychological mechanisms linking chronotype (i.e., eveningness) and future suicide intent by highlighting the role of defeat and entrapment. We propose that feelings of defeat might be derived from evening types' experiences of social jetlag (resulting from conflict between biologically driven sleep schedules and externally dictated social schedules), which consequently drives entrapment and greater future suicide intent. Within this context, defeat and entrapment may be good transdiagnostic and modifiable target variables for future intervention development.

New Insights into Contradictory Changes in Brain-Derived Neurotrophic Factor (BDNF) in Rodent Models of Posttraumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that may develop after experiencing traumatic events. Preclinical studies use various methods to induce PTSD-like models such as fear-conditioning, single-prolonged stress (SPS), restraint stress, and social defeat. Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophin in mood regulation. Evidence shows BDNF changes in different neuropsychiatric disorders particularly PTSD. This review examined BDNF alterations in preclinical rodent models of PTSD where we demonstrated a wide range of paradoxical changes in BDNF. We found that the fear-conditioning model produced the most inconsistent alterations in BDNF, and suggest that conclusions drawn from these changes be approached with caution. We suggest that BDNF maladaptive changes in social defeat and restraint stress models may be related to the duration of stress, while the SPS model appears to have more consistent results. Ultimately, we propose that evaluating BDNF alterations in the process of treating PTSD symptoms may not be a reliable factor.

An Examination of Hate-Motivated Behavior Among Adults in Scotland and Associations with Risk Factors for Self-Directed Violence.

Hate-motivated behavior (HMB) ranges from microaggressions to criminal acts and is a public health concern with consequences for the physical and mental well-being of individuals, families, and communities. The Hate-Motivated Behavior Checklist (HMBC) was developed with the goal of advancing the measurement of HMB perpetration. To provide insights into perpetration and victimization across the HMB continuum in Scotland, the present study sought to examine the factor structure of both the original HMBC and our adapted victimization version in a sample of adults currently living in Scotland. It also aimed to test associations between HMB and cognitions, which are related to self-directed violence (defeat and entrapment). Participants (n = 447) completed an online cross-sectional survey assessing demographic factors, HMB (perpetration and victimization), and perceptions of defeat and entrapment. Confirmatory factor analysis was used to examine the factor structure of the HMBC and the adapted victimization version of this checklist and path analyses were implemented to provide insights into potential links between HMB, defeat, and entrapment. In line with previous work, results provided support for interpreting the HMB Checklist as a single-factor total score. This was also true for the victimization version of the checklist. Results indicated that HMB victimization (but not perpetration) was associated with increased perceptions of defeat and entrapment. These findings suggest that the HMBC (for assessing both perpetration and victimization) represents potentially useful tools for HMB research and supports their applicability outside of an American context. Furthermore, by examining HMB through the lens of a contemporary model of suicidal behavior, our findings also provide insights into potential psychological mechanisms linking interpersonal and self-directed violence. Future research should implement prospective research designs and integrate measures of self-directed violence outcomes alongside HMB, defeat, and entrapment, to further advance understanding of this association.

Inhibition of Nitric Oxide Synthesis Prevents the Effects of Intermittent Social Defeat on Cocaine-Induced Conditioned Place Preference in Male Mice.

We have previously observed that mice exposed to social defeat stress are more sensitive to cocaine in the conditioned place preference (CPP) paradigm. In this context, it has been suggested that the nitric oxide (NO) pathway plays a role in the effects of stress. The present study evaluates the role of a neuronal NO synthase (nNOS) inhibitor (7-nitroindazole, 7-NI) in the short- and long-term behavioural effects of intermittent social defeat (ISD). Four groups of mice were employed for the study: a control group and three stressed groups, one treated with vehicle and two treated with 7-NI (7.25 or 12.5 mg/kg). After the last episode of defeat, mice were tested in the elevated plus maze (EPM), social interaction, object recognition and tail suspension tests. Three weeks later, mice were conditioned with cocaine (1 mg/kg). Stressed mice, irrespective of the treatment received, showed anxiety in the EPM, presented a deficit of social interaction and spent less time immobile in the tail suspension test. However, only stressed mice treated with vehicle developed CPP. Thus, although 7-NI did not modify the short-term behavioural effects of ISD, it prevented ISD-induced potentiation of the rewarding properties of cocaine in adulthood. These results support a specific role of nNOS in the effects of social stress on drug reward.

Hippocampal HDAC5-mediated histone acetylation underlies stress susceptibility in mice exposed to chronic social defeat stress.

Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals.

Effects of social dominance and acute social stress on morphology of microglia and structural integrity of the medial prefrontal cortex.

Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.

Social defeat stress impairs systemic iron metabolism by activating the hepcidin-ferroportin axis.

Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin-ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron-refractory anemia.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

Relationship between marital satisfaction and defeat in IVF-ET: based on actor-partner interdependence model approach.

OBJECTIVE: A person's marital satisfaction is a strong predictor of their own mental health outcomes. However, marital satisfaction results from both spouses' experiences, so a partner's marital satisfaction also affects his or her mental health outcomes. This study adopted the actor-partner interdependence model approach (APIM) to evaluate the relationship between marital satisfaction and sense of defeat in vitro fertilization-embryo transfer (IVF-ET) couples. METHODS AND MEASURES: In this cross-sectional study, 181 infertile couples undergoing IVF-ET treatment were recruited using the Marital Satisfaction Scale of the ENRICH Marital Quality Questionnaire and Defeat Scale. Through APIM and Pearson analysis, the path relationship between marital satisfaction and defeat was analyzed. RESULTS: The varying degrees of defeat in IVF-ET couples, are closely related to actors' and partners' marital satisfaction. In terms of actor effects, the Marital Satisfaction of both husbands (ß = -0.71, p < 0.001) and wives (ß = -0.46, p = 0.001) have a significant effect on individual Defeat. With regard to partner effects, husbands' Marital Satisfaction (ß = -0.23, p = 0.038) has a significant impact on wives' Defeat and the wives' Marital Satisfaction (ß = -0.45, p = -0.005) has a significant impact on husbands' Defeat. CONCLUSION: IVF-ET couples must be looked at as a whole, and it is critical to include couples and not just men or women when studying infertility. The importance of their interaction is essential to improve the psychosocial adaptation of infertile couples in IVF-ET treatment.

Childhood trauma and suicide risk: Investigating the role of adult attachment.

BACKGROUND: Suicide is a leading cause of death globally and a serious public health concern. Childhood trauma has been found to be associated with adult suicide vulnerability. Recent research has turned attention to investigating the role of attachment in the context of the childhood trauma-adult suicide relationship. The current study investigated for the first time whether attachment influences and moderates the childhood trauma-suicidality relationship, using a daily diary design, in the general population. METHODS: 481 participants completed questionnaires assessing experiences of childhood trauma, attachment patterns, and history of suicidality. 243 participants continued to a daily diary phase where measures of daily stress, defeat and entrapment were completed for 7 consecutive days. RESULTS: Higher levels of childhood trauma were associated with a history of suicide ideation and attempt and also higher levels of daily defeat, entrapment and stress during the 7 day study. Similarly, higher levels of attachment anxiety and avoidance were associated with a history of suicide ideation and attempt together with higher levels of daily defeat, entrapment and stress. However, the effects of childhood trauma on suicide history and on daily suicide vulnerability factors were not moderated by attachment anxiety or avoidance. LIMITATIONS: The measure of childhood trauma was a retrospective self-report tool that may be influenced by memory biases. CONCLUSIONS: Childhood trauma and insecure attachment are implicated in adult suicide risk. Interventions aimed at mitigating the negative effects of childhood trauma and insecure attachment should also incorporate components that target modifiable risk factors such as defeat, entrapment and stress.

MiR-184-3p in the paraventricular nucleus participates in the neurobiology of depression via regulation of the hypothalamus-pituitary-adrenal axis.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants.

Chronic Social Defeat Stress Induces Pathway-Specific Adaptations at Lateral Habenula Neuronal Outputs.

The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing, and ex vivo whole-cell patch-clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression at the DRN and VTA neurons, respectively, receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole-cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.

Acute social defeat during adolescence promotes long-lasting aggression through activation of the medial amygdala.

Traumatic stress, particularly during critical developmental periods such as adolescence, has been strongly linked to an increased propensity and severity of aggression. Existing literature underscores that being a victim of abuse can exacerbate aggressive behaviors, with the amygdala playing a pivotal role in mediating these effects. Historically, animal models have demonstrated that traumatic stressors can increase attack behavior, implicating various amygdala nuclei. Building on this foundation, our previous work has highlighted how traumatic stress invokes long-lasting aggression via an excitatory pathway within the posterior ventral medial amygdala (MeApv). In the current study, we sought to further delineate this mechanism by examining the effects of acute social defeat during adolescence on aggressive behaviors and neural activation in mice. Using a common social defeat paradigm, we first established that acute social defeat during late adolescence indeed promotes long-lasting aggression, measured as attack behavior 7 days after the defeat session. Immunolabeling with c-Fos demonstrated that acute social defeat activates the MeApv and ventrolateral aspect of the ventromedial hypothalamus (VmHvl), consistent with our previous studies that used foot shock as an acute stressor. Finally, chemogenetically inhibiting excitatory MeApv neurons during social defeat significantly mitigated the aggression increase without affecting non-aggressive social behavior. These results strongly suggest that the MeApv plays a critical role in the onset of aggression following traumatic social experience, and offer the MeA as a potential target for therapeutic interventions.