Sexually‐Divergent Effects of Infralimbic Cortex Stimulation on Endocrine and Cardiovascular Stress Reactivity

Abstract

Stress, defined as a real or perceived threat to homeostasis, promotes adaptive physiological responses. Unfortunately, the burden of prolonged stress contributes to a variety of pathologies including cardiometabolic disorders. While the impact of stress on cardiovascular disease is well‐documented, mechanisms have yet to be defined. Our previous studies found that inhibition of glutamate release from the infralimbic cortex (IL), a subregion of prefrontal cortex, leads to impaired vascular function after chronic stress. This led to the hypothesis that IL activity may be sufficient to restrain cardiovascular and endocrine responses to stress. Furthermore, we hypothesized that IL activity may mitigate chronic variable stress (CVS) effects on cardiac function and structure. In the current study, we utilized optogenetics to stimulate glutamatergic IL neurons in male and female rats exposed to stress. Briefly, male and female rats received intra‐IL injections of adeno‐associated virus containing a construct coding for the light‐sensitive cation channel, channelrhodopsin‐2, or a control construct expressing yellow fluorescent protein. Both constructs were expressed under the calcium/calmodulin‐dependent protein kinase IIa promoter, permitting the activation of IL glutamate neurons via targeted blue light stimulation. After recovery from injection and optic implantation, rats were exposed to restraint and novel environment stressors to examine acute reactivity. During optic stimulation, rats exposed to restraint stress had blood collected to examine stress‐induced corticosterone and glucose responses. Animals were also implanted with radiotelemeters to measure blood pressure and heart rate reactivity, as well as autonomic balance, during exposure to a novel environment. Following acute stress, rats were subject to 14‐day CVS which consisted of twice‐daily and overnight psychological stressors. All animals underwent echocardiographic assessment of cardiac structure and function before and after CVS. In males, activation of IL glutamate outflow reduced corticosterone and glucose responses to restraint. In contrast, females did not have altered corticosterone secretion but exhibited enhanced glucose responses. When placed in a novel environment, IL activation reduced male heart rate and blood pressure reactivity, while increasing female heart rate. Analysis of the autonomic components of heart rate variability during acute stress indicated that IL stimulation reduced net sympathetic drive in males but not females. Likewise, throughout CVS, males but not females showed a decrease in circadian net sympathetic drive. Furthermore, IL activation in males prevented increased left ventricular wall thickness and fractional shortening after CVS. Together, these data suggest IL glutamate neurons are critical for integrating physiological responses to stress. These findings also provide a sex‐specific mechanism linking stress and cardiovascular health outcomes.Support or Funding InformationNIH grant R00 HL122454 to B. Myers