Investigating the mechanism by which orexins contribute to sex differences in cognitive flexibility after stress

Project Summary and Abstract Stress-related psychiatric disorders, such as post-traumatic stress disorder (PTSD) and depression, are serious mental illnesses that occur twice as frequently in women compared to men. Despite this disparity, we do not understand the biological basis of these sex differences. A key

feature of stress-related disorders such as PTSD is hyperarousal, which contributes to cognitive flexibility deficits. The neuropeptides orexins, known to promote arousal and the stress response, are altered in PTSD patients; increased orexin expression has been reported in women compared to men in postmortem clinical populations. My previous research demonstrates that female rats exhibit higher

levels of orexins compared with male rats, contributing to impaired habituation to repeated stress and subsequent cognitive flexibility deficits. However, the brain areas and specific receptors that orexins target to cause sex-specific cognitive deficits after stress are unclear. Importantly, the orbitofrontal

cortex (OFC) is known to play a role in cognitive flexibility, and both the orexin 1 and 2 receptors (Ox1R and Ox2R) are present in this brain area. Another important question that remains unanswered is the mechanism by which orexins are upregulated in females compared with males. The gonadal hormone estrogen is a likely candidate, as our previous data indicate that estrogen and orexin levels

are positively correlated and females in proestrus (when estrogen levels peak) show higher orexin system activity and cognitive deficits after stress. Thus, the proposed research aims to understand how orexins contribute to sex-specific cognitive deficits after stress and the mechanism behind sex differences in the orexin system. Specifically, Aim 1 of this proposal will use a newly developed orexin

sensor paired with fiber photometry to examine real time orexin binding in the OFC to understand how orexins lead to sex-specific cognitive deficits after stress. Aim 2 will examine the mechanism behind sex differences in the orexin system by manipulating estrogen levels and assaying orexin measures

and cognitively flexibility after stress. We will also test whether estrogen exerts its actions via the G protein coupled estrogen receptor (GPER), which is highly expressed in orexin neurons. These findings will have immediate implications for treatment, as orexin antagonists are currently used to treat insomnia, so it is crucial we understand how this neuropeptide system differs between males and

females, as there may be a future need to develop sex-specific guidelines in dosing. Moreover, orexins regulate stress responses, food intake, autonomic responses, and emotional memory and thereby contribute to a variety of psychiatric symptoms. In this way, targeting orexins may treat a broad range of psychiatric symptoms in a sex-specific manner.