Sex-specific prefrontal-hypothalamic control of behavior and stress responding

Depression and cardiovascular disease are both augmented by daily life stress. Yet, the biological mechanisms that translate psychological stress into affective and physiological outcomes are unknown. Previously, we demonstrated that stimulation of the ventromedial prefrontal cortex (vmPFC) has sexually divergent outcomes on behavior and physiology. Importantly, the vmPFC does not innervate the brain regions that initiate autonomic or neuroendocrine stress responses; thus, we hypothesized that intermediate synapses integrate cortical information to regulate stress responding. The posterior hypothalamus (PH) directly innervates stress-effector regions and receives substantial innervation from the vmPFC. In the current studies, circuit-specific approaches examined whether vmPFC synapses in the PH coordinate stress responding. Here we tested the effects of optogenetic vmPFC-PH circuit stimulation in male and female rats on social and motivational behaviors as well as physiological stress responses. Additionally, an intersectional genetic approach was used to knock down synaptobrevin in PH-projecting vmPFC neurons. Our collective results indicate that male vmPFC-PH circuitry promotes positive motivational valence and is both sufficient and necessary to reduce sympathetic-mediated stress responses. In females, the vmPFC-PH circuit does not affect social or preference behaviors but is sufficient and necessary to elevate neuroendocrine stress responses. Altogether, these data suggest cortical regulation of stress reactivity and behavior is mediated, in part, by projections to the hypothalamus that function in a sex-specific manner.