Prefrontal Cortical Regulation of Chronic Stress‐Induced Cardiovascular Susceptibility
Authors: Myers Brent , Schaeuble Derek , Packard Amy EB. , McKlveen Jessica M. , Morano Rachel L. , Fourman Sarah , Smith Brittany L. , Scheimann Jessie R. , Packard Ben A. , Wilson Steven P. , James Jeanne , Hui David Y. , Ulrich‐Lai Yvonne M. , Herman James P. 
Published: June 2021

The prefrontal cortex is necessary for appropriate appraisal and processing of stressful information and is a component of the central network coordinating visceral and behavioral functions. In addition, prolonged stress induces sympathetic predominance, suggesting that prefrontal circuitry may prevent chronic stress‐induced autonomic imbalance. We have previously identified a subregion of rodent prefrontal cortex, the infralimbic cortex (IL), as a key regulator of neuroendocrine responses to chronic stress. In the current study, we sought to determine how IL output may regulate hemodynamic, vascular, and cardiac responses to chronic stress. Viral genetic expression of an siRNA construct targeting vesicular glutamate transporter 1 (vGluT1) was employed to reduce the packaging and release of glutamate from IL presynaptic terminals. Rats were injected with either the vGluT1 siRNA‐expressing construct or a GFP control into the IL and then either remained as unstressed controls or were exposed to chronic variable stress (CVS). In animals instrumented with radiotelemetric devices, IL vGluT1 knockdown increased heart rate and arterial pressure reactivity to acute stress. A prior history of CVS further elevated heart rate and arterial pressure, while siRNA treatment differentially increased cumulative systolic and diastolic arterial pressures throughout the 14‐day course of CVS. In a separate cohort of rats, CVS and vGluT1 knockdown interacted to impair both endothelial‐dependent and endothelial‐independent vasoconstriction and vasorelaxation ex vivo. Diminished responses to vasodilatory and vasopressor agents were accounted for in part by inward remodeling of the vasculature. Specifically, siRNA‐treated animals that experienced CVS exhibited decreased luminal circumference, increased media thickness, and increased adventitial collagen. Further, analysis of cardiac parameters revealed that CVS increased heart weight and myocyte surface area in siRNA‐treated rats. Taken together, our data demonstrate interactions between IL glutamatergic outflow and both acute and chronic stress whereby hemodynamic reactivity was exaggerated, vascular function was impaired due to inward remodeling and fibrosis, and cardiac hypertrophy was manifest by increased myocyte size. As lentiviral‐mediated knockdown of glutamate packaging within IL synaptic terminals indicates that specific prefrontal cortical populations are necessary for preventing the enhanced sympathetic and endocrine responses to stress that promote susceptibility to cardiovascular pathophysiology, our findings provide evidence for a neurobiological mechanism that mediates the relationship between stress and poor cardiovascular health outcomes.

Support or Funding Information

K99/R00 HL122454 to B. Myers

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.