Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

David P Siderovski

Committee Co-Chair

Jefferson C Frisbee

Committee Member

Peter R Giacobbi

Committee Member

Kevin T Larkin

Committee Member

Paul J Marvar

Committee Member

Alexandre C d'Audiffret

Abstract

Chronic, irresolvable psychological stress, a major contributor of depressive disorders, has been identified as a key factor involved in the tightly linked 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 underlying 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 depression 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 reflects 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 mild exogenous stressors will ultimately lead to depressive disorders (Mineur et al., 2003). This model will be used to compare functional outcomes between males and females, as well as the effects of this chronic stress regimen in animals with pre-existing cardiovascular risk.;Initial experiments to investigate sex-specific differences in stress susceptibility and vascular dysfunction were performed using the BALB/cJ mouse. Experiments conducted for the rest of this dissertation utilized lean and obese Zucker rats (LZR and OZR) to allow for the use of a comorbid model of metabolic syndrome (MetS), as well as for female ovariectomy (OVX). The OZR is a model of MetS via a genetic mutation of a recessive leptin receptor; this mutation causes loss of satiety signaling in the hypothalamus, leading to chronic hyperphagia and the subsequent onset of obesity, hyperglycemia, insulin resistance, dyslipidemia, and moderate hypertension. MetS, which affects almost 25% of the US population and over 44% of adults 50 years or older, 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.;The OZR will also develop non-atherosclerotic peripheral vascular disease in addition to severe vascular impairments as it ages, and therefore represents a relevant model of underlying CVD risk. Research regarding the pathophysiological differences in clinical disease profiles between sexes has reported that women may have a greater endothelium-dependent vasodilatory capacity compared to men (Casey et al., 2013). There is extensive evidence for the vasoprotective actions of estrogen against oxidative and inflammatory stressors that reduce reactive oxygen species (ROS) and thereby increase nitric oxide (NO) bioavailability. This dissertation will address the effects of chronic stress on depressive-like behavioral outcomes and plasma levels of the hypothalamic pituitary adrenal (HPA) axis stress hormone, corticosterone, in male and female rodents. Additionally, sex-specific differences in the severity of impaired vascular reactivity to endothelial dependent vasodilator stimuli following exposure to chronic stress, as well as the specific mechanisms underlying stress- induced vascular dysfunction, will be investigated in both male and female rodents. Finally, these functional outcomes will be interrogated in OZR to determine the consequences of chronic stress/depressive symptoms on rodents with MetS, and the role of estrogen will be tested in both OVX obese and lean female animals subjected to conditions of UCMS.;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.

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