Cortical-hypothalamic control of the cardiovascular consequences of stress

Project Summary Cardiovascular diseases are the leading cause of death globally and pathologies are exacerbated by chronic stress. Stress-cardiovascular comorbidities are more prevalent in females, however, the neurobiological mechanisms linking stress to cardiovascular outcomes are not well understood and could inform underlying cardiovascular susceptibility and resilience. The prefrontal cortex and hypothalamus are key regulators of stress and cardiovascular output; therefore, this proposal will test the hypothesis that cortical- hypothalamic neural circuitry mediates the sexually divergent cardiovascular consequences of chronic stress. Chronic psychosocial stress increases the incidence of cardiovascular diseases. The prefrontal cortex (PFC) is critical for stress appraisal, and both mood disorders and chronic stress are associated with altered PFC function. Recently, the sponsor’s lab reported that optogenetically activating the predominantly glutamatergic projection neurons from the rat infralimbic PFC (IL) produces sexually divergent effects on the stress response. However, the IL does not directly innervate neuroendocrine or preganglionic sympathetic neurons to mediate these effects; therefore, intermediate neurocircuitry must be involved in translating sex- specific cortical processing into sex-specific cardiovascular outcomes. The posterior hypothalamus (PH) is a major target of IL projection neurons and IL-PH projection neurons are stress-activated, however, neuroanatomical studies examining IL-PH circuitry have been performed exclusively in males. Pharmacological inactivation of the PH in vivo restrains acute stress responses while pharmacologically activating the PH exacerbates acute stress responses. PH activity also regulates cardiovascular function: pharmacologically activating the PH increases blood pressure and heart rate and pharmacological inactivation of the PH robustly blocks stress-induced increases in heart rate. The proposed experiments hypothesize that the PH is an intermediate synapse for sexually divergent outcomes and that stress-induced plasticity in this region mediates cardiovascular consequences of chronic stress. To test this hypothesis, I will learn viral-mediated circuit- and cell-type-specific slice electrophysiology to investigate synaptic plasticity within the IL-PH circuit after chronic variable stress in males and females. Additionally, I will learn pulse wave velocity and pressure myography to investigate vascular stiffness and reactivity in vivo and ex vivo, respectively, to determine the necessity of the IL-PH circuit for the detrimental consequences of chronic stress on vascular function. I have assembled a mentorship team with accomplished neurophysiologists and cardiovascular biologists to ensure the technical and career development training necessary for this project and, ultimately, starting my independent laboratory. These mentors will be critical for navigating my postdoctoral fellowship and preparing to run an independent research program studying unique dimensions of cardiovascular resilience.