Sex differences in cortical-hypothalamic control of stress reactivity and cardiovascular susceptibility
Date
2023
Authors
Schaeuble, Derek, author
Myers, Brent, advisor
Chicco, Adam, committee member
Gentile, Chris, committee member
Tobet, Stu, committee member
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Abstract
Major depressive disorder (MDD) is characterized by prolonged sadness and a loss of interest, and it impacts an estimated 21 million adults in the United States. The onset of MDD is multifactorial and rates of MDD have increased due to the psychosocial and economic factors associated COVID-19 pandemic. This poses a substantial threat to population health as MDD is projected to be the leading cause of disability by 2030. Even throughout the pandemic, cardiovascular disease (CVD) is still the highest mortality rate of any disease worldwide average of 17.9 million deaths per year. More importantly, MDD and CVD have devastating comorbidity that is poorly understood. MDD doubles the risk of developing cardiovascular disease and significantly increases the chance of morbidity following cardiovascular events. Thus, we need to address mental health disabilities and cardiovascular disease susceptibility. Interestingly, both diseases are exacerbated by chronic life stressors, which increase the prevalence of mood disorders and can alter sympathetic nervous activity increasing heart rate and blood pressure. Studying how stress affects the brain may yield important information on how to treat these two diseases. In this series of experiments, I examine how the ventral medial prefrontal cortex (vmPFC) alters stress responding through its downstream connections to provide a mechanism for MDD and cardiovascular disease comorbidity. I will provide a brief background of the structure and function of the vmPFC and describe how neurons from this region can alter stress responding through synapses in the hypothalamus. Chapter 2 is the first of a series of experiments where I show decreased activity of the vmPFC interacts with chronic stress to predispose male rats to cardiovascular disease susceptibility. Because mood disorders are more common in women and cardiovascular disease is more prevalent in post-menopausal women compared to men, chapter 3 examines whether activating vmPFC projection neurons is sufficient to influence behavior, stress responding, and cardiovascular activity in both sexes of rats. This work uncovered that output of vmPFC glutamate neurons has sexually divergent outcomes on neuroendocrine and autonomic cardiovascular responses to stress. Furthermore, it became evident that altered vmPFC activity predisposes males but not females to cardiovascular disease susceptibility. The vmPFC does not directly project to autonomic or neuroendocrine effector regions, so chapter 4 investigates whether the vmPFC is sufficient to control stress autonomic and neuroendocrine responding through downstream intermediary synapses. The intermediate region of interest is the posterior hypothalamus (PH) which can regulate endocrine and cardiovascular activity and receives dense innervation from the vmPFC. In chapter 5, I am exploring the necessity of this vmPFC-PH circuit to regulate cardiovascular activity and stress reactivity following chronic stress exposure. Altogether these data identify novel neurocircuitry linking stress exposure to cardiovascular disease risk.
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Subject
neuroscience
prefrontal cortex
cardiovascular
stress
posterior hypothalamus