PACAP and the Response to Stressors: Neural Mechanisms

项目摘要 许多情感障碍是由于暴露于严重或反复的 压力源尽管压力源暴露在调节情绪中起着重要作用， 中枢情绪回路被压力改变的机制仍然是未知的。 大量证据表明终纹背侧前床核 （BNST）介导人类和动物的焦虑样行为，并且改变的BNST可能 功能是焦虑症的基础我们已经证明垂体腺苷酸环化酶激活 BNST中的PACAP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PACAP水平和独特的 PAC 1受体单核苷酸多态性可预测创伤后应激障碍的症状和诊断 女性，这表明PACAP系统。在非强制降解微生物中，BNST PACAP释放 可能起源于外侧臂旁核（LPBn）;然而，我们认为， 慢性应激时，局部BNST PACAP的产生和释放增加， PAC 1受体介导的局部投射促肾上腺皮质激素释放因子活化增加 （CRF）表达神经元的BNST产生病理性焦虑。重要的是，不同 PAC 1受体亚型可以通过多种机制发出信号，产生短时间和短时间的信号。 对神经元兴奋性的持续影响。因此，cAMP的激活在 腺苷酸环化酶（AC）的膜结合PAC 1受体活化可能导致 PACAP后观察到BNSTov兴奋性的立即变化。但 细胞外信号调节激酶1/2（pERK）的磷酸化和活化 内体信号可能导致持续的焦虑反应，pERK信号可能 也支持营养行动，以增强焦虑样行为反应，甚至更长的时间 时期本申请中的实验使用分子、生理和生物学的组合。 行为学方法研究PACAP是否针对不同的BNSTov群体 神经元在应激和非应激的男性和女性，以及是否不同的PAC 1受体 信号通路介导具有不同时间特征的致焦虑行为。 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压力暴露的适应不良后果。

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.