新型神经肽Spexin通过纹状体尾壳核DA/DRD5抗抑郁的分子机制研究

抑郁症对患者和社会造成的负担即将位居各类疾病榜首，开发新型抗抑郁药物迫在眉睫。Spexin是新发现的内源性神经肽，广泛分布于人及动物中枢神经系统。前期实验发现抑郁症患者血液中spexin mRNA水平显著降低；小鼠侧脑室注射Spexin有明显抗抑郁作用，且纹状体尾壳核多巴胺（DA）和多巴胺受体D5（DRD5）含量增加，但具体机制不清楚。本项目拟结合临床抑郁症患者血液样本分析，采用经典的强迫游泳实验和悬尾实验模型检测小鼠的抑郁样行为变化，用膜片钳、DRD5-shRNA慢病毒敲减、免疫电镜、脑微透析等技术研究中枢Spexin通过GALR3/AC/cAMP信号通路增强DA能神经元的兴奋性，提高纹状体尾壳核神经细胞外DA浓度，继而激活DRD5及其下游PLC信号通路，揭示神经肽Spexin抗抑郁的分子机制。研究结果可为潜在抗抑郁新药Spexin的研发和临床应用提供理论依据。

The burden caused by depression on patients and society will soon top among the various diseases. Discovering novel targets for depression treatment is urgent. Spexin, identified as a novel endogenous neuropeptide, is widely distributed in central nervous system in human and rodents. Our previous work demonstrates that the spexin mRNA level in whole blood of the patients with depression is lower than the healthy subjects. Intracerebroventricular (i.c.v.) administration with Spexin obviously produced antidepressant effect in mice, and the content of dopamine (DA) and dopamine receptor D5 (DRD5) were increased in the caudate putamen (CPu). However, its mechanism was still unknown. The present proposal is designed to evaluate the depression-like behavior using the classical models of depression, the forced swimming test (FST) and tail suspension test (TST). Whether i.c.v. Spexin could improve the excitability of dopaminergic neurons via the GALR3/AC/cAMP signal pathway, increase the content of extracellular DA in the CPu, and subsequently activate the DRD5 and its downstream signal pathway PLC will be identified, using the methods, such as patch-clamp recording technique, DRD5-shRNA lentivirus knockdown, immunoelectron microscopy, microdialysis, etc. The molecular mechanism of the antidepressant effect of Spexin will be revealed. The results could provide theoretical basis for the clinical application of Spexin, a potential antidepressant novel drugs.