Sex differences in cortical-hypothalamic circuitry mediating cardiovascular disease risk.

Endocrine and autonomic stress responses adapt the body to real or perceived threats by engaging physiological pathways to maintain homeostasis. Unfortunately, the burden of prolonged stress contributes to maladaptive stress responding, increasing risk for pathologies including cardiometabolic disorders. However, the circuit mechanisms integrating endocrine and autonomic stress responses have yet to be defined. Our previous studies found that glutamate neurons of the infralimbic cortex (IL) have sex-specific effects on endocrine and cardiovascular stress reactivity. While the IL is important for coordinating behavioral and physiological responses to stress, these cortical cells do not directly innervate the secretory or pre-autonomic cells that initiate endocrine and autonomic stress responses. However, we previously found that the posterior hypothalamus (PH) receives dense stress-activated inputs from the IL. Thus, the current study tests the hypothesis that IL glutamate release in the PH mediates sex-specific effects on stress integration. To test this hypothesis, adult male and female Sprague-Dawley rats received stereotaxic injections in the IL of a viral-packaged construct expressing channelrhodopsin-2 and bilateral fiber optics targeting the PH to stimulate IL synapses in the PH. After recovery and acclimatization to handling, rats were tested in the real-time place preference paradigm to examine behavioral preference or aversion for circuit stimulation. These data indicate that IL-PH signaling is preferred by males and that females have neither preference nor aversion for IL-PH stimulation. Additionally, acute restraint was used to examine glucose and corticosterone responses to stress. Results found that IL synapses in the PH decrease stress-induced glucose mobilization without affecting corticosterone in male rats. In contrast, IL-PH stimulation in females increases corticosterone responses to restraint but does not affect glucose mobilization. Furthermore, non-invasive assessment of hemodynamics indicate that IL-PH stimulation increases heart rate in females but not males. Thus, the IL-PH circuit increases place preference and reduces glucose responses to stress in males, while increasing corticosterone stress responses and heart rate in females. Taken together, these data suggest that the PH represents a key node for sex-specific integration of descending cortical signals with endocrine and autonomic stress reactivity. Ultimately, sex-specific delineation of stress-regulatory neurocircuitry may provide insight into the differential impact of stress pathologies in men and women.