Orexins contribute to sex differences in habituation to stress and cognitive function

 描述（由申请人提供）：与压力相关的精神疾病，如创伤后应激障碍（PTSD）和抑郁症，是严重的精神疾病，女性发生的频率是男性的两倍。尽管存在这种差异，但我们不了解这些性别差异的生物学基础。人类研究显示，与对照组相比，焦虑和抑郁患者的神经肽食欲素水平存在差异。此外，动物研究表明，食欲素有助于应激反应和焦虑样行为。我们已经获得的初步数据表明食欲素在雄性和雌性大鼠的大脑中的差异表达。与以前的研究一致，我们发现，雌性大鼠表现出更高的下丘脑垂体肾上腺轴的反应，重复的压力相比，男性。此外，女性表现出与压力有关的认知灵活性障碍，但男性没有。因此，我们假设食欲素表达的性别差异导致雌性大鼠的应激反应加剧和应激相关认知灵活性较差。这项研究旨在阐明食欲素如何在单细胞和行为水平上影响应激反应的性别差异。具体而言，本提案的目标1将使用体外电生理学来确定在应激前后食欲素神经元的膜和放电特性中是否观察到性别差异。还将使用Neurolucida神经元追踪软件检查雄性和雌性中食欲素神经元的形态。目的2将直接检验增食欲素表达介导更高的应激反应和更差的应激相关认知灵活性的假设。我们将使用DREADDS（Designer Receptor Exclusively Activated by Designer Drugs）技术来操纵压力期间的食欲素作用。我们预期，抑制女性食欲素神经元将减少应激反应并改善随后的认知功能。这些实验提供了第一个证据，将食欲素与压力和认知的性别差异联系起来，但这些结果也将对治疗产生直接影响。食欲素拮抗剂目前用于治疗失眠，因此我们了解这些神经肽在男性和女性之间的差异是至关重要的，因为未来可能需要制定性别特异性的剂量指南。此外，食欲素可以调节应激反应、食物摄入、自主反应和情绪记忆，从而导致各种精神症状。通过这种方式，靶向食欲素可以以性别特异性的方式治疗广泛的精神症状。

 DESCRIPTION (provided by applicant): 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. Human studies have revealed differences in the levels of the neuropeptides orexins in anxious and depressed patients compared to controls. Additionally, animal studies have revealed that orexins contribute to the stress response and to anxiety-like behavior. We have obtained preliminary data indicating orexins are differentially expressed in the brains of male and female rats. Consistent with previous research, we found that female rats exhibit a higher hypothalamic pituitary adrenal axis response to repeated stress compared with males. Furthermore, females exhibited a stress-related impairment in cognitive flexibility but males did not. Therefore, we hypothesize that this sex difference in orexin expression contributes to the exacerbated stress response and poorer stress-related cognitive flexibility in female rats. The proposed research aims to elucidate how orexins contribute to sex differences in the stress response at both a single cell and behavioral level. Specifically, Aim 1 of this proposal will use in vitro electrophysiology to determine if sex differences are observed i the membrane and firing properties of orexin neurons before and after stress. Morphology of orexin neurons in males and females will also be examined using Neurolucida neuron tracing software. Aim 2 will directly test the hypothesis that increased orexin expression mediates the higher stress response and poorer stress-related cognitive flexibility. We will use DREADDS (Designer Receptor Exclusively Activated by Designer Drugs) technology to manipulate orexin action during stress. We expect that inhibition of orexin neurons in females will decrease the stress response and improve subsequent cognitive function. These experiments provide the first evidence linking orexins to sex differences in stress and cognition, but these results will also have immediate implications for treatment. Orexin antagonists are currently used to treat insomnia, so it is crucial we understand how these neuropeptides differ between males and females, as there may be a future need to develop sex-specific guidelines in dosing. Moreover, orexins may 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.