Clinical studies of CRF-PACAP systems in human PTSD (Rosso)

项目4（罗索实验室）：总结 创伤后应激障碍（PTSD）是全球疾病负担的主要原因， 在女人和男人身上。除了女性，遗传因素也是PTSD的危险因素。 此外，诊断需要暴露于至少一种高度创伤性的应激源，其独立地 并与遗传脆弱性协同作用，导致生物唤醒系统的长期扰动。一 许多压力反应的调节因素可能导致PTSD，包括在 妇女促肾上腺皮质激素释放因子（CRF）和垂体腺苷酸环化酶激活因子的功能改变 PACAP系统代表了PTSD易感性的性别依赖性调节的候选机制。 较高的血液PACAP水平和编码PAC 1 R受体的基因（ADCYAP 1 R1）的等位基因变异预测 PTSD女性患者的焦虑唤醒症状和总症状更强， 在焦虑相关的范例中。CRF及其I型受体的变异也与这两种疾病有关。 创伤后应激障碍和抑郁症，以及性别差异可能会产生持续的生理唤醒妇女暴露于 严重的压力重要的是，CRF/PACAP的神经生物学相关性与觉醒相关的大脑重叠， 与PTSD有关的电路，包括扩展杏仁核（extAMG）和内侧前额叶皮层（mPFC）。 本项目旨在鉴定CRF-、PACAP-、CRF+ PACAP占优势的中间表型， 患有创伤后应激障碍的女性和男性extAMG的两个亚区，杏仁核（AMG）和纹状体床核 终末（BNST），将被独立审查，由于其部分分离的恐惧作用的证据， 与焦虑的对比，以及它们对创伤后应激障碍的潜在贡献。作为一个区域， 通过与AMG和BNST的相互联系来调节对威胁的唤醒反应。使用血液 从患有DSM-5 PTSD的成人样本中，我们将检查CRF和PACAP变异（遗传，表观遗传，mRNA） 关于跨分析水平的过度觉醒的标志物：（1）PACAP和下丘脑的血液水平 垂体肾上腺轴激素（ACTH和皮质醇）作为CRF功能的指标;（2）静息状态功能 extAMG-mPFC的磁共振成像;（4）extAMG-mPFC的扩散张量成像;（5）磁共振成像 mPFC谷氨酸代谢和神经元完整性的共振光谱（N-乙酰天冬氨酸）;（6） 在恐惧条件反射和黑暗增强惊吓范例期间唤醒的生理学指标;和（7）临床 过度觉醒的症状：焦虑性觉醒、焦虑性觉醒和睡眠中断（使用自我报告和 活动记录法）。项目4将加强我们对人类CRF/PACAP生物行为机制的理解， 有可能发现新的创伤后应激障碍生物标志物。BNST功能和谷氨酸代谢的神经影像学研究 并且可以促进用于个体的改进的诊断或治疗的发展 创伤后应激障碍我们专注于与其他SPARED项目相同的肽系统和大脑区域，我们 我们将利用整个中心的新发现，不断完善和优化我们的目标。

PROJECT 4 (ROSSO LAB): SUMMARY Post-Traumatic Stress Disorder (PTSD) is a leading cause of global disease burden, and it is twice as common in women as in men. In addition to female sex, genetic factors are established risk factors for PTSD. Furthermore, the diagnosis requires exposure to at least one highly traumatizing stressor, which independently and synergistically with genetic vulnerability leads to long-lasting perturbations in biological arousal systems. A number of moderators of stress responsiveness may contribute to PTSD, including the differential risk seen in women. Altered function of corticotropin releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP) systems represent candidate mechanisms of sex-dependent moderation of PTSD liability. Higher blood PACAP levels and allelic variation in the gene (ADCYAP1R1) encoding the PAC1R receptor predict greater anxious arousal symptoms and total symptoms in women with PTSD, and greater physiological arousal during anxiety-related paradigms. Variation in CRF and its Type-I receptor have also been associated with both PTSD and depression, and sex differences may produce persistent physiological arousal in women exposed to severe stress. Importantly, the neurobiological correlates of CRF/PACAP overlap with arousal-related brain circuitry that is implicated in PTSD, including extended amygdala (extAMG) and medial prefrontal cortex (mPFC). This project is designed to identify CRF-, PACAP-, CRF+PACAP-predominant intermediate phenotypes in women and men with PTSD. Two subregions of the extAMG, the amygdala (AMG) and bed nucleus of the stria terminalis (BNST), will be independently examined, due to evidence of their partially separable roles in fear versus anxiety, and their potentially differential contributions to PTSD. The mPFC will be a focus as a region that modulates arousal responses to threat via reciprocal connections with the AMG and BNST. Using blood samples from adults with DSM-5 PTSD, we will examine CRF and PACAP variation (genetic, epigenetic, mRNA) in relation to markers of hyperarousal across levels of analysis: (1) blood levels of PACAP and hypothalamic pituitary adrenal axis hormones (ACTH and cortisol) as indices of CRF function; (2) resting state functional magnetic resonance imaging of extAMG-mPFC; (4) diffusion tensor imaging of extAMG-mPFC; (5) magnetic resonance spectroscopy of mPFC glutamate metabolism and neuronal integrity (N-acetylaspartate); (6) physiological indices of arousal during fear conditioning and dark enhanced startle paradigms; and (7) clinical symptoms of hyperarousal: anxious arousal, dysphoric arousal, and sleep disruption (using self-report and actigraphy). Project 4 will enhance our understanding of biobehavioral mechanisms of CRF/PACAP in humans, with the potential to identify new PTSD biomarkers. Neuroimaging of BNST function and glutamate metabolism is particularly innovative and may facilitate development of improved diagnostics or therapeutics for individuals with PTSD. We focus on the same peptide systems and brain regions as the other SPARED Projects, and we will use new discoveries from across the Center to continuously refine and optimize our objectives.