Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats.

Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.

Sex-specific behavioral, cardiac, and neuroendocrine responses to repeated witness social stress in adult rats.

In humans, sex disparities exist in the prevalence of social stress-related disorders, yet our understanding of the predisposing factors and underlying mechanisms is still elusive. Also at the preclinical level, the investigation of sex differences in social stress responses is limited. In this study, adult male and female wild-type Groningen rats were repeatedly exposed to witness social defeat stress (WS) to assess sex-specific behavioral, neuroendocrine, and cardiac responses to the same social stress paradigm. Male and female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control (CTR) procedure. Stress-related parameters were assessed in correspondence to the first and last WS/CTR exposure and also during subsequent exposure to the stress context alone in the absence of social defeat. During WS, rats of both sexes displayed larger amounts of burying behavior and smaller amounts of rearing and grooming behaviors, but with a greater extent in female witnesses. Cardiac autonomic responses to WS were similar between the sexes, yet only females displayed higher plasma corticosterone levels after the first WS exposure compared to CTRs, and had a larger corticosterone increase than male witnesses upon repeated WS. Exposure to the stress context alone (i.e., without the presence of the aggressive resident rat) elicited greater amount of burying behavior and more pronounced and persistent tachycardic responses in females than males with a history of WS. Our findings suggest sex-disparities in the response of adult rats to WS at multiple behavioral, cardiac, and neuroendocrine levels, highlighting the utility of this social stress paradigm for investigating predisposing factors and pathophysiological mechanisms underlying sex-specific vulnerabilities to stress-related pathologies.

Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERß) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERß is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERß activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERß and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERß antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERß was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERß in the CeA during WS prevented the development of depressive-, anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERß signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.

Vicarious social defeat stress: Bridging the gap between physical and emotional stress.

BACKGROUND: Animal models capable of differentiating the neurobiological intricacies between physical and emotional stress are scarce. Current models rely primarily on physical stressors (e.g., chronic unpredictable or mild stress, social defeat, learned helplessness), and neglect the impact of psychological stress alone. This is surprising given extensive evidence that a traumatic event needs not be directly experienced to produce enduring perturbations on an individual's health and psychological well-being. Post-traumatic stress disorder (PTSD), a highly debilitating neuropsychiatric disorder characterized by intense fear of trauma-related stimuli, often occurs in individuals that have only witnessed a traumatic event. NEW METHOD: By modifying the chronic social defeat stress (CSDS) paradigm to include a witness component (witnessing the social defeat of another mouse), we demonstrate a novel behavioral paradigm capable of inducing a robust behavioral syndrome reminiscent of PTSD in emotionally stressed adult mice. RESULTS: We describe the vicarious social defeat stress (VSDS) model that is capable of inducing a host of behavioral deficits that include social avoidance and other depressive- and anxiety-like phenotypes in adult male mice. VSDS exposure induces weight loss and spike in serum corticosterone (CORT) levels. A month after stress, these mice retain the social avoidant phenotype and have an increased CORT response when exposed to subsequent stress. COMPARISON WITH EXISTING METHOD(S): The VSDS is a novel paradigm capable of inducing emotional stress by isolating physical stress/confrontation in mice. CONCLUSIONS: The VSDS model can be used to study the short- and long-term neurobiological consequences of exposure to emotional stress in mice.