基于对前额叶皮层生物钟基因Bmal1的调控研究电针抗抑郁的作用机制

针灸抗抑郁疗效明确，但作用机制不明。有研究表明抑郁症患者的前额叶皮层（PFC）等脑区的生物钟基因表达异常，而生物钟基因又能影响突触和神经元活动。我们前期应用抑郁动物模型给予电针百会、印堂干预，发现电针能提高兴奋性突触活动并改善抑郁样行为；同时对相关脑区进行转录组学测序分析，发现电针能明显调节由应激导致的PFC生物钟核心基因Bmal1的表达异常。由此提出：电针可能通过调节PFC脑区Bmal1基因，进而改善神经活动和抑郁样行为的科学假说。本项目将综合运用条件性基因打靶、脑片膜片钳、在体多通道电生理和单细胞测序等技术，首先观察电针对抑郁小鼠PFC神经活动和Bmal1节律性表达的影响，其次探究PFC不同细胞上的Bmal1对神经活动的调节，最后挖掘与针灸抗抑郁相关的Bmal1分子调控网络。本项目完成不仅为针灸抗抑郁提供具体分子-细胞-神经网络调控机制，还能为抑郁症的治疗提供新的靶点和思路。

Acupuncture has an affirmative clinical efficacy in anti-depression, however the mechanism remains unclear. Previous studies have shown that clock genes were abnormally expressed in the prefrontal cortex (PFC) and other brain regions of depressive patients, and clock genes can affect synaptic and neuronal activities. By giving electroacupuncture (EA) interventions to the depression model animals at acupoints of Baihui (GV 20) and Yintang (GV 29) in our previous study, we found that EA significantly increased the excitatory synaptic activities and ameliorated the depression-like behaviors. Also, we analyzed the related cerebral regions by applying high throughput transcriptomics sequencing, and found that EA can obviously regulate stress-induced abnormal expression of Bmal 1 gene, which was the core gene of biological clock. Therefore, we proposed a scientific hypothesis that EA may improve neural activities and ameliorate depression-like behaviors by regulating the expression of biological clock core gene Bmal1 in PFC area. This program will apply various new neurobiological techniques including conditional gene targeting, large-scale neural ensemble in vivo recording technology, cerebral slice patch clamp recording and single-cell sequencing to specify the effects of EA on rhythmic expression of Bmal1 and neural activities. Furthermore, we will clarify the mechanism of Bmal1 participating in neuronal activities by investigating the regulation of Bmal1 gene in different cells of PFC on nerve activity. Finally, we will excavate the molecular regulatory network of Bmal1 related to the antidepressant effect of acupuncture. The program will not only offer specific molecular-cellular-neural circuit mechanism for EA treating depression, but also provide new targets and ideas for the clinical treatment of depression.