PACAP and the Response to Stressors: Neural Mechanisms

项目摘要 许多情感障碍是由于暴露在严重或反复的环境中而引起或加剧的 压力源。尽管应激源暴露在调节情绪方面起着重要作用，但 压力改变中枢情绪回路的机制仍不清楚。 大量证据表明，终纹的背侧前床核 (BNST)调节人和动物的焦虑样行为，很可能改变了BNST 功能是焦虑症的基础。我们已经证明，激活脑下垂体腺苷环化酶 多肽(PACAP)在BNST中的激活和释放介导了许多行为 反复应激对男性和女性的影响以及循环中PACAP水平和独特的 PAC1受体单核苷酸多态性预测创伤后应激障碍症状和诊断 女性，这表明PACAP系统。在非应激生物中，BNST PACAP释放 可能起源于臂旁外侧核(LPBn)；然而，我们认为如下 慢性应激，局部BNST PACAP的产生和释放与 PAC1受体介导的局部投射促肾上腺皮质激素释放因子的激活增加 (CRF)在BNST表达的神经元产生病理性焦虑。重要的是，不同 PAC1受体亚型可以通过多种机制发出信号，产生短持续时间和 对神经元兴奋性的持续影响。因此，cAMP在之后的激活 膜结合的PAC1受体激活腺酰环化酶(AC)可能导致 观察PACAP后BNSTov兴奋性的即刻变化。然而， 细胞外信号调节蛋白1/2(PERK)的磷酸化和活化 内体信号可能导致持续的焦虑性反应，而PERK信号可能 还支持营养作用，从而在更长时间内增强类似焦虑的行为反应 句号。本申请中的实验使用了分子、生理和 调查PACAP是否针对不同BNSTOV人群的行为方法 应激和非应激的男性和女性的神经元以及不同的PAC1受体 信号通路以不同的时间特征调节焦虑行为。 了解介导BNST效应的信号级联和细胞靶点 PACAP可以帮助更好地针对应激源暴露的不适应后果。

Project Summary Many affective disorders are caused or exacerbated by exposure to severe or repeated stressors. Despite the important role of stressor exposure in modulating emotion, the mechanisms by which central emotional circuits are altered by stress are still unknown. Substantial evidence has suggested that the dorsal anterior bed nucleus of the stria terminalis (BNST) mediates anxiety-like behavior in humans and animals, and it is likely that altered BNST function underlies anxiety disorders. We have shown that pituitary adenylate cyclase activating polypeptide (PACAP) activation and release in the BNST mediates many of the behavioral effects of repeated stress in males and females, and that circulating PACAP levels and a unique single nucleotide polymorphism in the PAC1 receptor predict PTSD symptoms and diagnosis in women, suggesting that PACAP systems. In non-stressed organisms, BNST PACAP release likely originates from the lateral parabrachial nucleus (LPBn); however, we argue that following chronic stress, local BNST PACAP production and release is increased concurrent to an increase in PAC1 receptor-mediated activation of locally-projecting corticotropin-releasing factor (CRF)-expressing neurons in the BNST to produce pathological anxiety. Importantly, different PAC1 receptor isoforms can signal via multiple mechanisms to produce short-duration and sustained effects on neuronal excitability. Hence, the activation of cAMP subsequent to membrane-bound PAC1 receptor activation of adenylyl cyclase (AC) likely leads to the immediate changes in BNSTov excitability observed following PACAP. However, the phosphorylation and activation of extracellular signal-regulated kinase 1/2 (pERK) via endosomal signaling likely leads to a sustained anxiogenic response, and pERK signaling may also support trophic actions to enhance anxiety-like behavioral responding for even longer periods. The experiments in this application use a combination of molecular, physiological and behavioral approaches to investigate whether PACAP targets different populations of BNSTov neurons in stress- and unstressed males and females, and whether different PAC1 receptor signaling pathways mediate anxiogenic behavior with different temporal characteristics. Understanding the signaling cascades and cellular targets that mediate the effects of BNST PACAP could help to better target the maladaptive consequences of stressor exposure.