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Chronic Stress, Depressive Symptoms and Peripheral Vascular Dysfunction: Fundamentals, Mechanisms, Sex Disparities, and Determinants of Integrated Outcomes Shyla Christine Stanley Chronic, irresolvable psychological stress, a major contributor of depressive disorders, has been identified as a key factor involved in the association between the prevalence/severity of depressive symptoms and the concurrent development of cardiovascular disease (CVD). Furthermore, there are marked differences in the incidence and pathology of these diseases between males and females, although the mechanisms involved are unclear. The purpose of this dissertation is to investigate the effects of chronic stress/depression on behavioral and vascular function in rodents in order to elucidate the underlying mechanisms linking depressive symptom severity with cardiovascular development/outcome. The unpredictable chronic mild stress (UCMS) model is well recognized in behavioral studies as a translationally appropriate animal model for generating depressive symptoms in rodents that accurately reflect human clinical characteristics, including learned helplessness and anhedonia (Willner et al., 1997; Yalcin et al., 2008). This model is based on the fundamental concept that chronic exposure to uncontrollable exogenous stressors will ultimately lead to depressive disorders (Mineur et al., 2003). This model will be used to compare functional outcomes (relative to behavior and CVD risk) between males and females, as well as the effects of this chronic stress regimen in animals with pre-existing cardiovascular risk. The differential effects of UCMS on depressive symptom severity and vascular function on male and female rodents were initially performed using the BALB/cJ mouse (Chapter 1 of this dissertation). The following experiments (Chapters 2 and 3) utilized male and female lean and obese Zucker rats (LZR and OZR) as a comorbid animal model of metabolic syndrome (MetS). Furthermore, ovariectomized (OVX) female LZR and OZR were utilized in order to further investigate sex specific mechanisms involved in cardiovascular and behavioral outcomes to UCMS. The OZR develop similar symptoms of MetS observed in humans due to a genetic mutation in the leptin receptor gene that causes loss of satiety signaling, thus leading to chronic hyperphagia and the subsequent onset of obesity, hyperglycemia, insulin resistance, dyslipidemia, and moderate hypertension. MetS, which affects 34% of adults (≥ 20 years of age) in the United States, is generally defined by the presence of a constellation of comorbid factors (abdominal obesity, insulin resistance, atherogenic dyslipidemia, pro-inflammatory/pro-thrombotic state) that are significantly associated with increased CVD risk (American Heart Association, 2014). The OZR also progressively develop non-atherosclerotic peripheral vascular disease in addition to severe vascular impairments, and therefore represents a relevant model of underlying CVD risk. This dissertation addresses the differential sex-specific effects of UCMS-induced chronic stress on depressive-like behavioral severity and the severity of impaired vascular responsivity to endothelial dependent vasodilator stimuli, as well as the specific mechanisms underlying stressinduced vascular dysfunction, between male and female rodents. These functional outcomes were interrogated in male and female OZR (versus lean rodents, LZR) to determine the consequences of UCMS-induced chronic stress/depressive symptoms on rodents with pre-existing MetS. Finally, the effects of UCMS were investigated in OVX LZR and OZR to determine the implications of loss of female sex hormones on behavior and cardiovascular function in both healthy and obese female rodents. Specific Aims: Aim 1: To determine the impact of UCMS on vascular reactivity in mice of both sexes. It is hypothesized that UCMS will result in a more severe development of depressive symptoms in female mice (vs. males), but vascular function will be superior to that of males. Aim 2: To determine if the protective effect against UCMS-induced vasculopathy in females is altered in rats with pre-existing cardiovascular disease risk factors and/or following OVX. It is hypothesized that vascular function in female animals will no longer be protected from UCMS-induced impairments in animals with comorbid CVD risk factors or in animals having undergone OVX. Aim 3: To determine the impact of pharmacological interventions on chronic stress/depressive symptoms and vascular function in male animals with pre-existing cardiovascular disease risk factors. It is predicted that improving CVD risk and vascular function with drugs will improve behavioral symptoms/corticosterone levels.

Chronic Stress, Depressive Symptoms and Peripheral Vascular Dysfunction: Fundamentals, Mechanisms, Sex Disparities, and Determinants of Integrated Outcomes