Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility

Abstract

Key Points• Knockdown of glutamate release from infralimbic cortex increases heart rate and arterial pressure reactivity • Reduced infralimbic glutamate release increases cumulative arterial pressure during chronic variable stress • Decreased infralimbic glutamate output leads to vascular dysfunction after chronic stress• These functional changes associate with histological indicators of cardiac hypertrophy, as well as vascular hypertrophy and fibrosis. Running TitleCortical regulation of cardiovascular responses to stress AbstractThe medial prefrontal cortex (mPFC) is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes.However, prolonged stress impairs mPFC function and prefrontal-dependent behaviors.Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associated with autonomic imbalance. Previous studies identified a subregion of rodent prefrontal cortex, infralimbic cortex (IL), as a key regulator of neuroendocrine-autonomic integration after chronic stress, suggesting that IL output may prevent chronic stress-induced autonomic imbalance. In the current study, we tested the hypothesis that the IL regulates hemodynamic, vascular, and cardiac responses to chronic stress. To address this hypothesis, a viral-packaged siRNA construct was used to knockdown vesicular glutamate transporter 1 (vGluT1) and reduce glutamate packaging and release from IL projection neurons. Male rats were injected with a vGluT1 siRNA-expressing construct or GFP control into the IL and then remained as unstressed controls or were exposed to chronic variable stress (CVS). IL vGluT1 knockdown increased heart rate and mean arterial pressure (MAP) reactivity, while CVS increased chronic MAP only in siRNA-treated rats. In a separate cohort, CVS and vGluT1 knockdown interacted to impair both endothelial-dependent and endothelial-independent vasoreactivity ex vivo. Furthermore, vGluT1 knockdown and CVS increased histological markers of fibrosis and hypertrophy. Thus, knockdown of glutamate release from IL projection neurons indicates that these cells are necessary to prevent the enhanced sympathetic responses to stress that promote susceptibility to cardiovascular pathophysiology. These findings provide evidence for a neurobiological mechanism mediating the relationship between stress and poor cardiovascular health outcomes.

α2δ-1–Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension

“…In our study, a significant increase in the MAP occurred after 4 weeks of CUMS in normotensive WKY rats. Others have shown that chronic mild stress for 3 weeks does not significantly increase the MAP in normotensive rats (Grippo et al, 2002;Schaeuble et al, 2019). To date, brain regions involved in CUMS-induced chronic hypertension have not been specifically identified.…”

Sex‐specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice

“…The rise in coronary tone in females is relevant to increased risk of mental stress‐related infarction (Vaccarino et al, 2014, 2018), which is thought to involve coronary microvascular abnormalities (Almuwaqqat et al, 2019). Chronic stress has recently been shown to impair endothelial‐dependent dilation in ex vivo aortic segments, a response mitigated by cortical glutamate signaling (Schaeuble et al, 2019). Such a pathway may similarly influence coronary microvascular control, and potentially impair vascular reactivity more widely, including within hepatic and cerebral circulations.…”

Cortical-brainstem circuitry attenuates physiological stress reactivity

“…Additionally, stressrelated disorders such as depression and post-traumatic stress disorder associate with altered structure and function of the vmPFC (Drevets et al, 1997;Drevets et al, 2008;Hamani et al, 2011;Liotti et al, 2000). In rodents, male vmPFC glutamate neurons promote socio-motivational behaviors and reduce physiological stress responses including hyperglycemia, tachycardia, and corticosterone release (Myers et al, 2017;Schaeuble et al, 2019;Wallace et al, 2021). Notably, vmPFC neurons do not directly project to neurosecretory cells or preganglionic sympathetic neurons, requiring intervening effector(s) to modulate physiological responses (Ulrich-Lai & Herman, 2009).…”