Sex differences in CRH signaling in the ovBNST underlie effects of chronic stressors

项目摘要 长期暴露于压力体验会导致适应不良的情感状态， 啮齿类动物的精神障碍和人类与压力有关的情绪障碍。在过去的十年里， 压力的这些适应不良影响的基础已经得到更好的定义。一个重要的区域是床 终纹核（BNST），这是一个主要的输出途径，连接中央杏仁核到 下丘脑的腹内侧核，也接受来自边缘系统其他区域的直接投射。 因此，BNST可能是一个整合的边缘信息和效价监测中心。心理和 生理压力对男性和女性的影响不同。BNST是一种性二态结构， 可能导致男性和女性不同的慢性应激反应，因为芳香化酶和 雌激素受体（ER）在雄性和雌性BNST中均不同。直接激活卵圆内的神经元 BNST核（ovBNST）增加雄性啮齿动物中焦虑相关的负价行为， 我们的初步数据表明，C57 BL/6 J雄性小鼠暴露于慢性可变轻度应激（CVMS） 导致促肾上腺皮质激素释放激素（CRH/CRF）信号传导增加，mEPSC振幅增加， ovBNST神经元静息膜电位和M电流减少。虽然这些数据表明， ovBNST可能是慢性应激对情感状态影响的一个联系，许多问题仍然没有答案。 我们的总体假设是表达CRH的ovBNST神经元是慢性应激的关键介质， BNST中的性二态性是在男性中发现的不同慢性应激反应的基础 和女性。提出的具体目标将直接回答这些问题，并增加我们的理解 ovBNST如何调节慢性压力的适应不良效应。在目标1中，我们将识别细胞群 受慢性压力源（CVMS，慢性非歧视性社会失败压力[CNSDS]）和 在雄性和雌性小鼠中的神经生理学后果。在目标2中，我们将评估慢性压力如何影响 BNST中的ER β信号传导以及ER β阳性BNST神经元的光遗传学调节是否模拟和/或 逆转慢性压力对行为的影响。在目标3中，我们将确定以下方面的必要性和充分性： ovBNST神经元中CRH信号传导介导CVMS和CNSDS的行为效应。

Project Summary Chronic exposure to stressful experiences can result in maladaptive affective states that yield behavioral disturbances in rodents and stress-related mood disorders in humans. Over the last decade, the neural circuits underlying these maladaptive effects of stress have become better defined. One region of importance is the bed nucleus of the stria terminalis (BNST), which is a major output pathway connecting the central amygdala to the ventromedial nucleus of the hypothalamus that also receives direct projections from other limbic areas. Therefore, BNST may be an integrative center for limbic information and valence monitoring. Psychological and physiological stressors affect males and females differently. The BNST is a sexually dimorphic structure that may contribute to distinct chronic stress responses in males and females because expression of aromatase and both estrogen receptors (ER)  differs in male and female BNST. Direct activation of neurons within the oval nucleus of the BNST (ovBNST) increases anxiety-associated negative valence behaviors in male rodents, and our preliminary data demonstrates that exposure of C57BL/6J male mice to chronic variable mild stress (CVMS) results in increased corticotropin releasing hormone (CRH/CRF) signaling, increased mEPSC amplitude, altered resting membrane potential, and diminished M-currents in ovBNST neurons. While these data suggest that ovBNST may be a nexus for the effects of chronic stress on affective states, many questions remain unanswered. Our overall hypothesis is that CRH-expressing ovBNST neurons are critical mediators of the chronic stress response and that sexual dimorphism in the BNST underlies the distinct chronic stress responses found in males and females. The proposed specific aims will directly answer these questions and increase our understanding of how ovBNST mediates the maladaptive effects of chronic stress. In Aim 1, we will identify the cell populations that are impacted by chronic stressors (CVMS, chronic nondiscriminatory social defeat stress [CNSDS]) and the neurophysiological consequences in male and female mice. In Aim 2, we will assess how chronic stress affects ER signaling in BNST and whether optogenetic modulation of ER-positive BNST neurons mimics and/or reverses the effects of chronic stress on behavior. In Aim 3, we will determine the necessity and sufficiency of CRH-signaling in ovBNST neurons in mediating the behavioral effects of CVMS and CNSDS.