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

CRF-PACAP 在人类 PTSD 中的尸检研究 (Berretta)

• 批准号: 10356108
• 负责人: Sabina Berretta
• 金额: $ 33.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356108
• 关键词: Address; Adenylate Cyclase; Affect; Amygdaloid structure; Anterior; Anxiety; Anxiety Disorders; Autopsy; Axon; Biological Rhythm; Brain; Brain region; Cells; Cessation of life; Circadian Rhythms; Clinical; DNA Methylation; Data; Detection; Disease; Diurnal Rhythm; Dorsal; Education; Elements; Female; Functional disorder; Gene Expression; Hormones; Hospitals; Human; Hypothalamic structure; Image; Individual; Knowledge; Link; Major Depressive Disorder; Messenger RNA; MicroRNAs; Multiomic Data; Mus; Neurons; Pathology; Pathway interactions; Peptides; Periodicity; Phenotype; Pituitary Gland; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Proxy; Publishing; RNA; Regulation; Research; Research Domain Criteria; Sampling; Sex Differences; Signal Pathway; Signal Transduction; Signaling Molecule; Signs and Symptoms; Sleep; Sleep Wake Cycle; Sleep disturbances; Specificity; Stress; Structure of terminal stria nuclei of preoptic region; System; Testing; Time; Transcript; Variant; Work; biological adaptation to stress; cingulate gyrus; circadian; cohort; design; experimental study; human data; in vivo; mRNA Expression; male; mouse model; neural circuit; neuropathology; parabrachial nucleus; polypeptide; pre-clinical; protein expression; receptor; release factor; sex; symptomatology; therapeutic target; virtual

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.

摘要：项目5（人为PTSD/Berretta中PACAP-CRF的验尸研究） 令人信服的证据表明，皮质释放因子（CRF）和垂直腺苷酸环化酶激活 多肽（PACAP）及其相互作用一起为压力反应做出了重要的贡献， 焦虑，昼夜节律调节以及创伤后应激障碍的病理生理机制 （PTSD）。涉及的基本神经回路尚不清楚，但重要的线索指向床 质末端（BNST），杏仁核（AMG）的核，背扣带回回（DACG）和 下丘脑（HPTH）作为这些功能的关键调节剂。当前的证据表明CRF和PACAP 促进PTSD的机制可能是特定于性别的，这增加了潜在的大脑 男性和女性的变化和潜在的治疗靶标可能会有所不同。当前和初步数据建议 PACAP信号传导可能直接影响CRF表达细胞，而PACAP的昼夜节律表达及 同源受体PAC1R及其随后对CRF系统的调节，在过程中可能会有所不同 天。这种变化可能有可能导致与DSM定义相关的睡眠/唤醒周期的中断 包括PTSD，严重抑郁症和焦虑症在内的疾病。令人惊讶的是，几乎没有任何信息是 可在人类AMG，BNST，DACG和 HPTH，他们与昼夜节律的关系以及CRF/PACAP互动的参与 PTSD的神经病理学。我们的总体假设是影响CRF/PACAP途径的异常 BNST，AMG和DACG和HPTH有助于PTSD的病理。在AIM 1中，我们解决了一个关键的差距 关于CRF，PACAP及其的区域，性别和昼夜节律表达和分布的知识 健康人脑中的受体。我们的假设是CRF，PACAP和 他们的受体是区域和性别特定的；特别是，我们预测PACAP受体将显示细胞和 CRF阳性神经元中的性别特异性和表达，支持PACAP调节这些假设 神经元以性依赖性方式。在目标2和3中，我们检查了 - 在蛋白质，基因表达中，是否是否 和细胞水平 - DACG，AMG，BNST和HPTH中的信号途径在PTSD中发生了变化。我们的假设 与健康对照组相对于PTSD受试者的CRF和PACAP信号通路将改变 随着PACAP表达的增加，与CRF信号通路的变化相关，区域，性别和 昼夜节律特定方式。我们预测PACAP阳性细胞和轴突的增加，反映 PACAP表达在本地和下丘脑输入中增加，将伴随着表达的改变 CRF阳性细胞中的PACAP受体和下游信号通路。项目5可以确定CRF和 PACAP系统和电路在与压力有关的疾病（如PTSD）中从根本上改变了，并且是一种 另一个（临床前，临床）元素增强并增强的中心的关键联系。