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Cerebrovascular Dysfunction in Metabolic Syndrome and Depression: Mechanisms and Implications for Neurovascular Disease Steven D. Brooks Cerebrovascular diseases are any pathological conditions that are caused by disruptions or alterations in the blood supply to the brain. The brain, which is only 2% of body mass, constantly requires a minimum of 20% of cardiac output to meet its unique metabolic demands. Cerebral tissue relies on aerobic respiration and therefore requires a constant, steady supply of blood to provide oxygen and glucose to make ATP. Insufficient perfusion of the brain, which occurs as a result of reduced or obstructed blood flow, results in cerebral ischemia; ischemic neurons quickly deplete their available ATP and die if blood flow is not restored. Disruptions in the delivery of blood to the brain, either acutely or chronically, can lead to impairment of neurological function, neuronal cell death, and even death. Metabolic Syndrome (MetSyn) is the comorbid presence of three or more risk factors, including: central obesity, hypertriglyceridemia, high cholesterol, hypertension, and hyperglycemia. Data from the NHANES study reports that over 35% of all adults, and over 50% of adults over 60, are estimated to have MetSyn. MetSyn is a risk factor for almost every major cardiovascular disease, and causes well-defined impairments in the peripheral circulation. However, its effects on regulation of cerebral blood flow are not well understood. The primary aim of this dissertation is to study the functional and structural alterations cause by MetSyn in the cerebral circulation, utilizing the obese Zucker rat (OZR), a translationally relevant model for studying the vascular complications of MetSyn, and to interrogate how vascular and neurological outcomes to cerebrovascular disruptions are influenced by pre-existing cerebral vasculopathies associated with MetSyn in OZR. The specific aims are as follows: 1. Define and characterize structural and functional changes in vascular reactivity, vessel wall mechanics, and vascular remodeling in middle cerebral arteries (MCA) of OZR, and evaluate changes in microvascular density throughout the cerebral microcirculation. 2. Determine the contribution of each constituent pathology of MetSyn on the development of cerebrovascular impairments in OZR, and identify mechanisms through which these pathologies are progressing in the cerebral circulation. 3. Interrogate the mechanisms of stroke-induced vascular dysfunction in lean Zucker (LZR) and OZR, and determine how pre-existing vascular dysfunction in OZR changes outcomes and pathological mechanisms following ischemic stroke. 4. Investigate the effects of chronic stress/ depression on cerebrovascular function in LZR and OZR, assess efficacy of exercise as a prophylactic anti-depressant treatment, and evaluate mechanisms through which impairments, and exercise-based recovery, are occurring. The results of these studies have helped to establish the prominent driving mechanism of cerebrovascular dysfunction in MetSyn, and defined the functional impacts these impairments have on outcomes to ischemic stroke and stress-induced depression. By thoroughly interrogating these mechanisms and evaluating functional outcomes of relevant disease states, this dissertation hopes to lay the groundwork for a new approach to understanding the relationship between MetSyn, cerebrovascular dysfunction, and neurological outcomes.