Postmortem studies of CRF-PACAP in human PTSD (Berretta)

总结：项目5（PACAP-CRF在人类PTSD/Berretta中的死后研究） 令人信服的证据表明，促皮质激素释放因子（CRF）和垂体腺苷酸环化酶激活 多肽（PACAP），以及它们之间的相互作用，对应激反应做出重要贡献， 焦虑、昼夜节律调节和创伤后应激障碍的病理生理机制 （PTSD）。涉及的潜在神经回路知之甚少，但重要的线索指向床 终纹核（BNST）、杏仁核（AMG）、扣带回背侧前回（dACG）和 下丘脑（HPTh）作为这些功能的关键调节器。目前的证据表明，CRF和PACAP 导致创伤后应激障碍的机制可能是性别特异性的，这增加了潜在的大脑 变化和潜在的治疗靶点在男性和女性中可能不同。目前和初步的数据表明， PACAP信号可能直接影响CRF表达细胞，PACAP及其受体的昼夜节律性表达， 同源受体PAC 1 R及其随后对CRF系统的调节可能在免疫过程中发生变化。 天这种变化可能潜在地导致与DSM定义的睡眠/觉醒周期相关联的睡眠/觉醒周期的中断。 包括创伤后应激障碍、重度抑郁症和焦虑症在内的疾病。令人惊讶的是，几乎没有任何信息 可用于人AMG、BNST、dACG和DACG中CRF和PACAP信号通路的细胞水平表达， HPTh，它们与昼夜节律的关系，以及CRF/PACAP相互作用在 PTSD的神经病理学我们的总体假设是，影响CRF/PACAP通路的异常， BNST、AMG、dACG和HPTh参与了PTSD的病理过程。在目标1中，我们解决了一个关键差距 了解CRF、PACAP的区域、性别和昼夜节律特异性表达和分布， 健康人脑中的受体。我们的假设是CRF、PACAP和 它们的受体是区域和性别特异性的;特别是，我们预测PACAP受体将显示细胞和 性别特异性和CRF阳性神经元的表达，支持PACAP调节这些神经元的假设。 神经元以性别依赖的方式。在目标2和3中，我们研究了蛋白质、基因表达， 并且在PTSD中dACG、AMG、BNST和HPTh中的细胞水平信号传导途径改变。我们的假设 与健康对照组相比，PTSD受试者的CRF和PACAP信号通路将发生改变， PACAP表达增加与CRF信号通路变化相关，在不同地区、性别和 昼夜节律的方式。我们预测PACAP阳性细胞和轴突的增加， 局部和来自下丘脑输入的PACAP表达增加，将伴随着表达改变 CRF阳性细胞中的PACAP受体和下游信号通路。项目5可确定通用报告格式， PACAP系统和回路在与压力相关的疾病（如PTSD）中发生了根本性的改变， 中心的关键联系，增强了其他（临床前，临床）要素，并被其他要素增强。

SUMMARY: PROJECT 5 (POSTMORTEM STUDIES OF PACAP-CRF IN HUMAN PTSD/BERRETTA) Compelling evidence indicates that corticotropic releasing factor (CRF) and pituitary adenylyl cyclase-activating polypeptide (PACAP), as well as their interactions together, make critical contributions to stress responses, anxiety, circadian rhythm regulation, and the pathophysiological mechanisms of post-traumatic stress disorder (PTSD). The underlying neural circuitry involved is poorly understood, but important clues point to the bed nucleus of the stria terminalis (BNST), amygdala (AMG), dorsal anterior cingulate gyrus (dACG), and the hypothalamus (HPTh) as critical regulators of these functions. Current evidence indicates that CRF and PACAP mechanisms that contribute to PTSD may be sex-specific, raising the possibility that the underlying brain changes and potential therapeutic targets may differ in males and females. Current and preliminary data suggest that PACAP signaling may directly affect CRF expressing cells and that circadian expression of PACAP and its cognate receptor PAC1R, and their subsequent regulation of CRF systems, may vary during the course of the day. Such variations may potentially contribute to disruptions of sleep/wake cycles associated with DSM-defined illnesses including PTSD, major depression, and anxiety disorders. Surprisingly, virtually no information is available on cell-level expression of CRF and PACAP signaling pathways in the human AMG, BNST, dACG and HPTh, their relationships to circadian rhythms, and the involvement of CRF/PACAP interactions in the neuropathology of PTSD. Our overarching hypothesis is that abnormalities affecting CRF/PACAP pathways in the BNST, AMG and dACG and HPTh contribute to the pathology of PTSD. In Aim 1, we address a critical gap of knowledge on the region-, sex- and circadian- specific expression and distribution of CRF, PACAP, and their receptors in healthy human brain. Our hypothesis is that protein and mRNA expression of CRF, PACAP, and their receptors are region- and sex-specific; in particular, we predict that PACAP receptors will show cell- and sex- specificity and expression in CRF-positive neurons, supporting the hypothesis that PACAP regulates these neurons in a sex dependent manner. In Aims 2 and 3, we examine whether—at the protein, gene expression, and cellular level—signaling pathways in the dACG, AMG, BNST and HPTh are altered in PTSD. Our hypothesis is that CRF and PACAP signaling pathways will be altered in subjects with PTSD, relative to healthy controls, with increased PACAP expression correlated with CRF signaling pathway changes, in a region-, sex-, and circadian rhythm-specific manner. We predict that increases of PACAP-positive cells and axons, reflecting increased PACAP expression locally and from hypothalamic inputs, will be accompanied by altered expression of PACAP receptors and down-stream signaling pathways in CRF-positive cells. Project 5 may identify CRF and PACAP systems and circuits as being fundamentally altered in stress-related illnesses such as PTSD, and is a key nexus of the Center that enhances, and is enhanced by, the other (preclinical, clinical) elements.