THU118 Prefrontal-Medullary Circuit Is Necessary For Chronic Stress-Induced Neuroendocrine And Behavioral Outcomes

Disclosure: S.A. Pace: None. E. Lukinic: None. P. Barrette: None. T. Wallace: None. B. Myers: None. Chronic stress exposure is a major risk factor for psychiatric and cardiometabolic diseases. Although the pathologies associated with chronic stress are well-documented, the biological mechanisms underlying these physiological changes remain unknown. Human imaging studies indicate the prefrontal cortex is a key site for processing stress-related information. Within the rat prefrontal cortex, the infralimbic area (IL) is critical for regulating physiological stress reactivity in a sex-specific fashion. Here we examined the necessity of an IL downstream circuit for neurogenic regulation of neuroendocrine susceptibility after chronic stress. We focused on an IL to rostral ventrolateral medulla (RVLM) circuit due to the ability of the RVLM to initiate the sympatho-adrenomedullary stress responses and influence HPA axis activity. Critically, the IL-RVLM circuit is structurally positioned to underlie a crucial link between stress appraisal and sympathetic reactivity. To determine the role of the IL-RVLM circuit during chronic stress, an intersectional viral strategy was used to express a light-chain variant of Tetanus Toxin (TeLC) in RVLM-projecting IL neurons, thereby disrupting IL-RVLM signaling. TeLC-expressing IL neurons had less synaptobrevin-2 protein located on terminals and fewer synaptic appositions in the RVLM. This chronic circuit disruption approach was evaluated in the context of a 2-week chronic variable stress (CVS) paradigm in male and female rats. In males, CVS-exposed TeLC rats displayed decreased corticosterone levels in response to a novel stressor compared to control rats. CVS-naïve males showed no significant changes. In females, we similarly observed no differences in unstressed rats. However, CVS TeLC female rats had increased glycemic and corticosterone stress responses compared to CVS control animals. Additionally, female CVS TeLC rats had increased behavioral avoidance indicated by less time spent in the center of an open field arena compared to CVS control rats. This behavioral effect was not present in males. These results suggest that the IL-RVLM circuit is essential for preventing chronic stress outcomes in female rats, but not males. Further, this circuit regulation is necessary only after chronic stress exposure. Future studies will be aimed at determining sex differences in chronic stress effects on IL-RVLM signaling. Presentation: Thursday, June 15, 2023