Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, 221004, China.
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, 221004, China.
Biochem Biophys Res Commun. 2021 Dec 31;585:139-145. doi: 10.1016/j.bbrc.2021.11.048. Epub 2021 Nov 14.
The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.
创伤后应激障碍（PTSD）的发病机制在很大程度上尚不清楚。大量证据表明，5-羟色胺（5-HT）的异常水平与 PTSD 的发病密切相关。有几项报道表明，一氧化氮（NO）会影响大脑各个区域细胞外 5-HT 水平，但没有发现一致的变化方向，其潜在机制尚不清楚。中缝背核（DRN）中的大部分 5-羟色胺能神经元共同表达神经元型一氧化氮合酶（nNOS），这是一种在中枢神经系统中衍生的一氧化氮（NO）合成酶。在这里，我们发现 nNOS 的过度表达，从而导致的高浓度一氧化氮接着是单一延长压力（SPS）导致 DRN 5-HT 神经元活性受到抑制，引发 PTSD 样表型，包括焦虑样行为增加、情景恐惧记忆增强和恐惧泛化。我们的研究揭示了 DRN nNOS-NO 通路在 PTSD 病理中的重要作用，这可能有助于对 PTSD 分子机制的新理解。
