Global Neuropeptidome Profiling in Response to Predator Stress in Rat: Implications for Post-Traumatic Stress Disorder

Traumatic stress triggers or exacerbates multiple psychiatric illnesses, including post-traumatic stress disorder (PTSD). Nevertheless, the neurophysiological mechanisms underlying stress-induced pathology remain unclear, in part due to the limited understanding of neuronal signaling molecules, such as neuropeptides, in this process. Here, we developed mass spectrometry (MS)-based qualitative and quantitative analytical strategies to profile neuropeptides in rats exposed to predator odor (an ethologically relevant analogue of trauma-like stress) versus control subjects (no odor) to determine peptidomic alterations induced by trauma. In total, 628 unique neuropeptides were identified across 5 fear-circuitry-related brain regions. Brain-region-specific changes of several neuropeptide families, including granin, ProSAAS, opioids, cholecystokinin, and tachykinin, were also observed in the stressed group. Neuropeptides from the same protein precursor were found to vary across different brain regions, indicating the site-specific effects of predator stress. This study reveals for the first time the interaction between neuropeptides and traumatic stress, providing insights into the molecular mechanisms of stress-induced psychopathology and suggesting putative novel therapeutic strategies for disorders such as PTSD.创伤性应激可诱发或加重多种精神疾病，包括创伤后应激障碍（post-traumatic stress disorder, PTSD）。然而，应激诱导病理的神经生理机制仍未阐明，这在一定程度上源于学界对该过程中神经肽（neuropeptides）这类神经元信号分子的认知不足。本研究构建了基于质谱法（mass spectrometry, MS）的定性与定量分析策略，用于表征暴露于捕食者气味（一种符合行为生态学范式的创伤样应激模型）与对照组（无气味暴露）大鼠体内的神经肽表达谱，以解析创伤诱导的肽组学改变。本研究在5个与恐惧环路相关的脑区中，共鉴定得到628种独特的神经肽。应激组大鼠还呈现出多个神经肽家族的脑区特异性表达变化，涉及颗粒蛋白（granin）、ProSAAS、阿片类（opioids）、胆囊收缩素（cholecystokinin）与速激肽（tachykinin）。来自同一蛋白质前体的神经肽在不同脑区中的表达水平存在差异，这表明捕食者应激具有脑区特异性效应。本研究首次揭示了神经肽与创伤性应激之间的相互作用，为应激诱导精神病理的分子机制提供了全新视角，并为创伤后应激障碍（PTSD）等精神疾病的潜在新型治疗策略提供了理论依据。