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.

Grant Number: 5F32HL172693-02
NIH Institute/Center: NIH
Principal Investigator: Courtney Bouchet