The Effects of Cytokine Receptor Antagonism in the Locus Coeruleus on Stress-related Behaviors in Females

Abstract ID 99689 Poster Board 112 It is estimated that 8 million deaths/year worldwide are due to mental health disorders. While this is problematic to society as a whole, women are disproportionally affected with over twice the rate of post-traumatic stress disorder (PTSD) compared to males, presenting as social avoidance and hypervigilance, being easily startled and feeling constantly "on edge". A mechanism responsible for this heightened susceptibility in women may be the higher neuroimmune response to stress which is associated with worsening mood symptoms in females but not in males. One brain region impacted by stress is the locus coeruleus (LC), where proinflammatory cytokines signaling through the IL-1 receptor activate LC neurons to release norepinephrine (NE). Subsequently, LC-NE projections to forebrain regions promote the hyperarousal observed in PTSD patients. Importantly, females exhibit a higher neuronal density within the LC and these cells display greater dendritic extension and morphological complexity. The variations in neuroimmune signaling and LC physiology between sexes raise the question: are cytokine receptor targets in the LC-NE system a viable therapeutic for stress disorders in females? These experiments addressed this question using IL-1Ra, a selective IL-1 receptor antagonist that inhibits IL-1R activation for <96 hours after central administration, to block the robust inflammatory repercussions of psychosocial stress. Rats were exposed to witness stress (WS, 15 min/day for 5 days), a preclinical model of psychosocial stress whereby females were placed behind a clear perforated partition in the cage of an aggressive retired breeder male with a smaller intruder male introduced for social defeat. WS is a potent neuroimmune stimulus that produces a hypervigilant phenotype as defined by stress-evoked burying behavior and increased acoustic startle. A dose-response study was conducted (0ng, 1ng, and 30ng IL-1Ra) and determined that 30ng intra-LC IL-1Ra prevented WS-induced hypervigilant burying behavior and reduced LC neuronal activity. Therefore, adult female Sprague Dawley rats received bilateral microinjection cannulae aimed at the LC and were placed into pre-stress behavioral testing to measure a baseline acoustic startle response (ASR). Subsequently, 1 μL of either vehicle (0.1% BSA in PBS) or 30 ng/μL IL-1Ra was delivered into the LC the day prior to WS/control exposure and on the 2nd/4th days. Post-stress behavioral testing consisted of ASR and a social interaction task to determine whether intra-LC IL-1Ra had a therapeutic effect on stress-evoked hypervigilance and social avoidance. A final behavioral measure of hypervigilance was assessed in which females were placed back into the aggressive males9 cage with their paired intruder for exposure to the cues and environment in which they originally experienced stress. Brain tissue was collected following this test for the analysis of neuronal activity in LC projection regions to determine how a history of stress ± cytokine antagonism impacts LC-NE signaling. Rats exposed to WS exhibited increased startle amplitude and decreased social interaction time, and IL-1Ra prevented the exaggerated startle response observed in WS rats. Overall, the further analysis of additional hypervigilant/social behaviors and the examination of LC-NE alterations will allow us to determine the role of neuroimmune signaling within this region in the susceptibility to stress in females. R01 MH113892 & VA Merit BX005661 (SKW)