Corticotropin-releasing factor pathways facilitate hypervigilant behavioral and physiological responses to social stress in female rats

Abstract

<b>Abstract ID 28262</b> <b>Poster Board 469</b> Psychosocial stress is a common risk factor for comorbid anxiety and cardiovascular disease with women exhibiting increased susceptibility compared to men. Interestingly, this increased risk among women is confined between the onset of puberty and menopause, suggesting a role for cycling ovarian hormones. However, the underlying mechanism linking stress and ovarian hormones to the disproportionate risk of stress-related disorders among women remains unclear, making it difficult to develop targeted and effective pharmacotherapies. Using witness stress (WS), a social stress model in which a female rat observes an aggressive social defeat encounter between two male rats, we previously found that intact females are highly susceptible to this form of stress as evidenced by persistent hypervigilant behavioral and autonomic responses. Interestingly, ovariectomized (OVX) rats are resistant to WS-evoked behavioral and autonomic shifts, while 17-β estradiol (17-βE) replacement reinstates this hypervigilant phenotype. Therefore, interrogating systems regulated by stress and 17-βE may reveal novel pharmacological targets to treat stress-related hypervigilant disorders. The corticotropin-releasing factor (CRF)-rich central amygdala (CeA) is one stress- and estrogen-sensitive brain region that can regulate these responses. Specifically, the prominent CRF projections to the locus coeruleus (LC) facilitate burying behavior and increased sympathetic drive and vagal withdrawal, autonomic features of hypervigilance. Therefore, this study aimed to examine whether 17-βE regulates CRF expression in the CeA paired with the functional implications indicated by LC neuronal activity, hypervigilant behavior, and peripheral epinephrine (EPI) responses in the presence and absence of WS. Female rats, implanted with a catheter in the right jugular vein, were either left intact (sham) or OVX. One hour after injection (vehicle or 17-βE (10μg/rat, s.c.)), rats underwent WS or control handling (CON). Behavior was recorded during WS/CON (15 min) and blood was collected via i.v. catheter immediately following. Brains were collected 2 hours later, and immunohistochemistry was used to quantify CRF expression in the CeA and cfos expression in both the CeA and LC. WS-evoked burying behavior was blunted in OVX rats and reinstated by 17-βE, but 17-βE had no effect on rearing and freezing behavior. Accordingly, plasma EPI levels were also regulated by 17-βE as OVX blocked WS-evoked increases in EPI, and this response was reinstated by 17-βE replacement. In the brain, 17-βE selectively enhanced activation of CeA CRF+ neurons among WS rats. Further, OVX attenuated WS-evoked increases in LC cfos, but 17-βE reinstated this WS-evoked increase in LC activity. Taken together with evidence from clinical trials implicating the role of LC hyperactivity in stress-related disorders, these findings demonstrate that CRF and LC signaling in the brain may represent a novel therapeutic target for promoting stress resilience among women. This work was suported by RO1 grant MH113892 and VA Merit BX005661 (SKW) and American Heart Association Predoctoral Fellowship #915364 (BSP).