缺血性脑卒中后抑郁发生关键脑区的神经环路解析

Post-stroke depression was extremely common mood disorder in cerebrovascular disease patients that gave great threat to their recovery. Drug remission was not as satisfied as expected due to the poor and ignoring in understanding the neuronal mechanism in PSD morbidity. Hence, systematic and deep study about neuronal circuitry involved in PSD was necessary. Previous study demonstrated abnormality neuron activity in PSD mice model with some of the brain nuclei showed intensive activity and others were highly suppressed, which showed a highly coincide with neuronal circuitry mechanism. Here, we hypothesis that there exit specific neuronal circuitry in the PSD, in the meanwhile, the abnormal activity of the excitatory and inhibitory neurons were important during the PSD processing, however, we speculated that the manipulate the activity of these abnormal neurons may ease or relief depression behavior in PSD mice. In this proposal, we intended to use deep brain calcium signal collection system, neuronal tracing technology, optogenetic and DREADD to study the neuronal circuitry of PSD, based on what to figure out the mechanism and importance of the circuitry in PSD. This study of great importance for better understanding of the neuronal mechanism of PSD in the future. Hopefully, this study can supply new ideal to treat PSD.

卒中后抑郁是脑血管病患者高发的情绪障碍疾病，严重危害患者的康复。但因发病的具体神经机制尚不清楚，所以目前药物治疗的缓解率并不理想。因此，对卒中后抑郁的神经机制进行系统而深入的研究尤为重要。研究表明，卒中后抑郁小鼠的神经活动发生了异常，伴随着神经放电在部分脑区加强，另一部分脑区减弱，呈现出典型的神经环路机制。因此我们认为卒中后抑郁在关键脑区具有特异的神经环路，而且该环路中兴奋性和抑制性神经元及其电活动的异常对脑卒中后抑郁的发病具有重要作用，同时反向调控这些活动异常的神经元能够实现对脑卒中后抑郁小鼠抑郁行为的有效缓解。项目拟利用深脑钙信号采集、神经环路示踪、光遗传和化学遗传等技术对卒中后抑郁的神经环路进行研究，在此基础上探索卒中后抑郁的发病机制。本项目的研究有助于为卒中后抑郁发病机制研究提供理论依据，同时也有很大可能性为治疗提供新的更高效的靶点。

为了阐明微RNA和mRNA在PSD模型中的差异表达，本研究通过向小鼠内侧前额叶皮质（mPFC）注射血管收缩剂ET-1（血管内皮素-1）构建PSD小鼠模型。动物随后进行了高架十字迷宫试验、旷场试验、悬尾试验和强迫游泳试验。并进行了转录组测序分析差异表达的mRNA和microRNA。结果表明，PSD小鼠在开臂次数和时间明显减少。模型组小鼠进入中心的次数明显减少。模型组小鼠climb时间明显缩短。PSD小鼠的行为表现出明显的变化，行为测试的一些指标显著低于对照组。转录组测序分析显示，模型组的1206个基因和21个microRNA的表达显著上调，而2113个基因和32个microRNA的表达显著下调。GO分析表明，差异表达基因主要参与单个多细胞生物过程、发育过程、细胞外周、质膜和神经元投射的调控途径。同时，KEGG分析结果表明，差异表达基因主要参与神经活性配体-受体相互作用、钙信号通路和细胞因子-细胞因子-受体相互作用的信号通路。以上研究结果为进一步研究PSD的早期识别、预防和治疗提供了理论基础和新的见解。