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

项目4(Rosso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，其发病率是普通疾病的两倍 在女人身上和男人身上一样。除了女性，遗传因素也是创伤后应激障碍的危险因素。 此外，诊断需要暴露于至少一个高度创伤的应激源，这是独立的 与遗传脆弱性的协同作用会导致生物唤醒系统的长期扰动。一个 压力反应调节因子的数量可能会导致创伤后应激障碍，包括 女人。促肾上腺皮质激素释放因子和垂体腺苷环化酶激活功能的改变 多肽(PACAP)系统代表了性别相关的PTSD易感性调节的候选机制。 更高的血液PACAP水平和编码PAC1R受体的基因(ADCYAP1R1)的等位基因变异可以预测 患有创伤后应激障碍的女性出现更多的焦虑唤醒症状和总症状，以及更强的生理唤醒 在焦虑相关的范例中。CRF及其I型受体的变异也与两种疾病有关 创伤后应激障碍和抑郁，性别差异可能会在暴露于创伤后的女性中产生持续的生理唤醒 严重的压力。重要的是，CRF/PACAP的神经生物学关联与觉醒相关的大脑重叠 与创伤后应激障碍有关的回路，包括扩展的杏仁核(ExtAMG)和内侧前额叶皮质(MPFC)。 该项目旨在确定CRF-，PACAP-，CRF+PACAP-的主要中间表型 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)和纹状床核 由于有证据表明它们在恐惧中的部分分离作用，将对它们进行独立检查 与焦虑，以及他们对创伤后应激障碍的潜在不同贡献。Mpfc将成为一个区域的焦点。 这通过与AMG和BNST的相互联系来调节对威胁的唤醒反应。用血 从患有DSM-5创伤后应激障碍的成人样本中，我们将检测CRF和PACAP的变异(遗传、表观遗传、mRNA) 不同分析水平与高唤醒标志物的关系：(1)血液中PACAP和下丘脑的水平 作为CRF功能指标的垂体-肾上腺轴激素(ACTH和皮质醇)；(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 MPFC谷氨酸代谢和神经元完整性(N-乙酰天冬氨酸)的共振光谱； 恐惧条件反射和黑暗强化惊吓范式中唤醒的生理指标；(7)临床 过度唤醒的症状：焦虑性唤醒、烦躁不安的唤醒和睡眠中断(使用自我报告和 动作记录法)。项目4将加强我们对CRF/PACAP在人类中的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记物。BNST功能与谷氨酸代谢的神经成像 特别具有创新性，并可能促进针对个人的改进的诊断或治疗方法的开发 患有创伤后应激障碍。我们专注于与其他备用项目相同的多肽系统和大脑区域，我们 将使用整个中心的新发现来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.