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

项目摘要 长期暴露在紧张的经历中会导致适应不良的情感状态，从而产生行为 啮齿动物的紊乱和人类的应激相关的情绪障碍。在过去的十年里，神经回路 在这些不适应效应的背后，压力已经得到了更好的定义。一个重要的领域是床 终纹核(BNST)是连接杏仁中央核和大脑皮质的主要输出通路。 下丘脑的腹内侧核，也接受来自其他边缘区域的直接投射。 因此，BNST可能是边缘信息和价态监测的综合中心。心理和心理 生理压力对男性和女性的影响是不同的。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，因为芳香酶和 两种雌激素受体(ER)在男性和女性BNST中有所不同。卵圆内神经元的直接激活 BNST核(OvBNST)增加了雄性啮齿动物焦虑相关的负价行为，并且 我们的初步数据表明，C57BL/6J雄性小鼠暴露于慢性温和可变应激(CVMS)。 结果促肾上腺皮质激素释放激素(CRH/CRF)信号增强，mEPSC幅度增加，改变 静息膜电位，降低OVBNST神经元的M-电流。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纽带，许多问题仍然没有答案。 我们的总体假设是CRH表达的ovBNST神经元是慢性应激的关键介质 BNST中的性二型性是男性不同的慢性应激反应的基础 和雌性。提出的具体目标将直接回答这些问题，并增加我们的理解 关于ovBNST如何调节慢性应激的不良适应效应。在目标1中，我们将确定细胞群体 受慢性应激源(CVMS，慢性非歧视性社会失败应激[CNSDS])和 雄性和雌性小鼠的神经生理学后果。在目标2中，我们将评估慢性压力如何影响 BNST中的ER信号以及ER阳性的BNST神经元的光遗传调制是否模仿和/或 逆转慢性压力对行为的影响。在目标3中，我们将确定 OvBNST神经元CRH信号介导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.