Vasiliki Michopoulos, Ph.D. - US grants

DESCRIPTION (provided by applicant): The incidence of mood disorders, such as anxiety and depression, in women is twice that in men. Moreover, women are susceptible to a distinct group of mood disorders that are associated with fluctuations in ovarian hormone levels, including premenstrual dysphoric disorder, postpartum depression, and hormone replacement therapy induced negative mood. A precipitating factor in these disorders may be chronic exposure to psychosocial stressors and increased activation of the body?s primary stress axis. The occurrence of these mood disorders in women is complicated by the presence of other adverse health outcomes. Notably, eating disorders, such as emotional eating and obesity, are highly co-morbid with affective disorders, having similar disruptions in neurobiological systems present within individuals diagnosed with mood disorders. The long-term objective of the proposal is to elucidate the mechanisms by which progestagens modulate the disruption of stress axis and the serotonergic (5HT) system, both of which have been implicated in the etiology of mood and eating disorders in women. The central goal of this proposal is to implicate the disruption of allopregnanolone (ALLO), a specific progesterone, levels as a critical player in the disruption of systems associated with increased emotional and stress axis reactivity characteristic of affective disorders. The first aim is to evaluate how progestagens modulate socially induced changes in emotional reactivity and appetite. The second aim is to determine whether changes in ALLO and associated behavioral phenotypes are due to stress-induced activity. We will make use of an ethologically relevant model of psychosocial stress, employing hormonal and pharmacological means to assess emotional behavior and preference for a high calorie diet. PUBLIC HEALTH RELEVANCE: Women are twice as susceptible as men to mood and eating disorders, including anxiety, depression, obesity, and emotional eating. Studying the mechanisms by which psychosocial stress disrupts the actions of ovarian hormones will speak to the development of anxiety-based psychopathology in women.

Project Summary The social environment has a clear and profound impact on human health and well being. Chronic social stress and reduced access to social support are strongly linked to major diseases of aging; as a result, social adversity is highly predictive of life expectancy itself. Recent evidence suggests that, while some of this relationship is explained by correlated factors such as smoking, obesity, and health care access, social stressors also have a direct impact on physiological function. Indeed, work in animal models has clearly demonstrated that the experience of social subordination alone can alter the function of the immune system, in part by altering gene regulation in immune cells. The goal of the proposed research is to address a key outstanding question that arises from these findings: when, and for whom, are chronic social stress effects on immune function most important? To do so, it will take advantage of dominance rank in female rhesus macaques as a model for chronic social stressor exposure in humans. Rhesus macaque females are excellent models for human social stress because they naturally organize into dominance rank hierarchies in which low ranking individuals experience increased rates of harassment, reduced social affiliation, and physiological markers of rank-related stress. Importantly, dominance rank assignments, and thus an individual's exposure to social stressors, can be manipulated in this species by manipulating group membership. Such manipulations yield a powerful experimental model for investigating the consequences of socially induced stress?an approach that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this model to investigate how differential exposure to dominance rank-induced social stress causally influences gene expression in the immune system. Specifically, it will use an in vitro approach to efficiently screen for condition-specific social stress effects on gene expression levels across 30 physiologically relevant environmental conditions (e.g., pathogen exposure, steroid hormone signaling). It will complement the in vitro screen with an in vivo test of the gene regulatory and antibody response to influenza vaccination, a medical procedure in which variable responses are of particular concern as individuals age. Finally, it will test whether age, social behavior, and genotype can be used to predict interindividual variation in the strength of social stressor effects on immune regulation, and hence which individuals are most vulnerable. Together, the proposed analyses will provide much-needed insight into the factors that explain when and why individuals differ in their response to the same social stressors, as well as the potential consequences of these differences for medical treatment. The project's results will therefore have direct translational application to both identifying the most susceptible members of our aging population and suggesting tailored strategies for intervention.

SUMMARY The cumulative rate of repeated trauma exposure is greater in African American (AA) communities of urban, low socioeconomic status. This cumulative trauma exposure is associated with increased depressive and posttraumatic symptoms (PTS), and dysregulated fear responses. While traumatized women are more at risk for depression and anxiety compared to men, the factors that increase vulnerability to hormone-induced alterations in affect remain unclear. This is especially true for pregnant women, who have received minimal focus in trauma research even though there is evidence that suggests that PTS are altered during pregnancy. However, the specific nature of the effect of pregnancy on PTS has been equivocal. Because pregnant AA women experience disproportionately higher rates of cumulative trauma exposure and PTS, understanding how hormonal fluctuations and DNA methylation changes during pregnancy in traumatized AA women influence PTS and fear psychophysiology is critical for the mother's wellbeing both before and after delivery. The proposed longitudinal study is well positioned to address this gap in knowledge given our recruitment of pregnant AA women from a high trauma risk population. The proposed research will combine clinical interviews and fear physiology methods to examine how changes in estrogen, progesterone, cortisol and DNA methylation during each trimester of pregnancy and 1-month postpartum period influence PTS and fear inhibition deficits. Furthermore, because studies implicate prenatal stress exposure with increased fetal cortisol exposure and increased risk for adverse birth outcomes (i.e. low birth weight) and negative physical and mental health outcomes in adulthood, we will determine how cumulative maternal trauma prior to pregnancy and PTS during pregnancy are transmitted to offspring to impact vulnerability to adverse outcomes by assessing placental DNA methylation and fetal exposure to glucocorticoids via the umbilical cord.

PROJECT 1: ABSTRACT Sex hormones are influential in setting the tone of immune responses and estradiol exhibits a particularly strong influence that varies across the life cycle in women. Although largely anti-inflammatory and protective, estradiol can have divergent effects. In addition, the influence and availability of estradiol changes with aging, most notably with the menopause transition. Furthermore, exposure to stressors can impact the functions of sex hormones, including estradiol. Women living with HIV (WLH) may be more vulnerable to the effects of stress and trauma exposure on hormone function and precipitated changes may manifest as enhanced inflammatory signaling. The proposed studies will further our understanding of the biology of aging, and specifically the prognosis of WLH, and characterize the link between immunosenescence and endocrinesenescence. The planned research will define estrogen deficiency at both the systemic and receptor level and evaluate the extent to which global variation in these parameters predicts pro-inflammatory pathways in WLH. We will conduct clinical interviews to assess trauma exposure and trauma-related hyperarousal to examine how these factors interact with HIV to exacerbate estrogen deficiency and inflammation. Furthermore, we will characterize the influence of trauma exposure and estrogen receptor function on inflammation at the molecular level in WLH. Overall, the data generated from this proposal will provide critical information about the influence of estradiol signaling on inflammation in WLH and provide mechanistic insight more broadly into the influence of estradiol receptor function on inflammation. Because trauma exposure and its related adverse mental health outcomes (i.e. posttraumatic stress disorder; PTSD) are poorly controlled in WLH, and PTSD has dangerous implications for HIV pathogenesis and transmission, it is of critical importance to identify the effects of trauma and PTSD comorbidity with HIV in order to titrate the most effective treatment approaches for this complex comorbidity.

PROJECT SUMMARY In most mammalian species, social interactions among individuals of the same species are governed by dominance relationships. These hierarchical relationships are established and maintained by agonistic behaviors, including aggression. Importantly, recent data indicate that the neural mechanisms underlying aggression and attaining dominance produce a phenotype that is resistant to social stress while the mechanisms underlying subordinate status produce a social stress-susceptible phenotype that may result in a number of adverse behavioral and physiological outcomes. Despite the relationship between social status and stress, the neurochemical mechanisms that underlie dominance have received only limited attention in males and almost no attention in females. This project will fill this critical gap in our knowledge by testing an integrated series of hypotheses using Syrian hamsters and rhesus monkeys. This project will critically test the overarching hypothesis that the agonistic behaviors responsible for the formation and maintenance of dominance relationships are regulated in dramatically different ways by vasopressin (AVP) and serotonin (5- HT) in males and females. Specifically, we propose that activation of AVP and inhibition of 5-HT promotes dominant status and a stress resistant phenotype in MALES while producing subordinate status and a stress susceptible phenotype in FEMALES. In contrast, inhibition of AVP and activation of 5-HT promotes dominance and a stress resistant phenotype in FEMALES while producing subordinate status and a stress susceptible phenotype in MALES. Together, these data will significantly expand our knowledge of sex differences in the neurochemical mechanisms that define social phenotypes and will provide innovative gender specific strategies for promoting resistance to social stress. The data obtained in this project could have an almost immediate clinical impact by guiding drug treatments for stress reduction in men and women as well as guiding drug development by emphasizing the role of AVP-targeted drugs in males and 5-HT- targeted drugs in females.

Project Summary The social environment has a clear and profound impact on human health and well being. Chronic social stress and reduced access to social support are strongly linked to major diseases of aging; as a result, social adversity is highly predictive of life expectancy itself. Recent evidence suggests that, while some of this relationship is explained by correlated factors such as smoking, obesity, and health care access, social stressors also have a direct impact on physiological function. Indeed, work in animal models has clearly demonstrated that the experience of social subordination alone can alter the function of the immune system, in part by altering gene regulation in immune cells. The goal of the proposed research is to address a key outstanding question that arises from these findings: when, and for whom, are chronic social stress effects on immune function most important? To do so, it will take advantage of dominance rank in female rhesus macaques as a model for chronic social stressor exposure in humans. Rhesus macaque females are excellent models for human social stress because they naturally organize into dominance rank hierarchies in which low ranking individuals experience increased rates of harassment, reduced social affiliation, and physiological markers of rank-related stress. Importantly, dominance rank assignments, and thus an individual's exposure to social stressors, can be manipulated in this species by manipulating group membership. Such manipulations yield a powerful experimental model for investigating the consequences of socially induced stress?an approach that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this model to investigate how differential exposure to dominance rank-induced social stress causally influences gene expression in the immune system. Specifically, it will use an in vitro approach to efficiently screen for condition-specific social stress effects on gene expression levels across 30 physiologically relevant environmental conditions (e.g., pathogen exposure, steroid hormone signaling). It will complement the in vitro screen with an in vivo test of the gene regulatory and antibody response to influenza vaccination, a medical procedure in which variable responses are of particular concern as individuals age. Finally, it will test whether age, social behavior, and genotype can be used to predict interindividual variation in the strength of social stressor effects on immune regulation, and hence which individuals are most vulnerable. Together, the proposed analyses will provide much-needed insight into the factors that explain when and why individuals differ in their response to the same social stressors, as well as the potential consequences of these differences for medical treatment. The project's results will therefore have direct translational application to both identifying the most susceptible members of our aging population and suggesting tailored strategies for intervention.