DBS是中晚期帕金森病最有效的治疗手段。然而由于传统研究方法的局限性，DBS的治疗机制仍不清楚。随着在体光纤记录及遗传编码的荧光生物探针技术的发展，在DBS治疗过程中实时记录特定类型细胞的神经活动及递质释放已成为可能。课题组前期应用最新的光谱光纤技术检测DBS对局部神经核团及整个基底节环路神经元活动及递质释放的影响。研究结果显示，STN DBS对皮层和纹状体的活动仅有短暂影响，不足以解释其持续的治疗作用，而其却可引起STN区突触前神经元放电活动的持续增强及STN内Glu和GABA释放的减少，据此我们推测STN DBS的核心作用机制是引起突触前传入神经末梢高频放电，导致末梢神经递质耗竭，造成突触后神经元活动下降。在此基础上我们拟用腺相关病毒介导的化学遗传学方法来选择性的抑制投向STN的神经元的递质释放，以达到与DBS相同的疗效，最终开发出更易于病人接受的非植入性替代疗法。

Deep brain stimulation (DBS) of the subthalamic nucleus（STN）is currently the most effective treatment for advanced Parkinson’s disease (PD).However, owing to the limitations of traditional research methods, the mechanisms underlying the therapeutic effects of DBS remain elusive. With recent advances in the development of novel in vivo fiber photometry techniques and the genetically encoded fluorescent biosensors, it has now become possible to record the cell-type specific neural activity and neural transmitter release in freely moving animals during DBS treatment. Using these latest techniques, we have been able to measure the effects of DBS stimulation on the neuronal activity and neurotransmitter release locally in the STN and in the key nuclei of the cortico-basal ganglia circuit. Our preliminary results suggest that the effects of STN DBS in the cortex and striatum are transient, not sufficient to account for its sustained therapeutic effects in patients. However, STN DBS causes a sustained increase in the presynaptic neuronal activity, and at the same time, a sustained reduction in the local release of Glu and GABA in the STN. Based on these observations, we hypothesize that the central mechanism underlying the therapeutic effect of STN DBS is that the high-frequency discharge in the presynaptic afferent terminals caused by DBS leads to the depletion of presynaptic neurotransmitters, resulting in a decrease in the postsynaptic neuronal activity in the STN. To test this hypothesis, we plan to use the AAV-mediated chemogenetic approach to selectively inhibit the presynaptic neurotransmitter release in STN, and compare its effect on the motor symptoms in PD models with STN DBS. Our ultimate goal is to develop a less invasive, more affordable treatment to replace DBS.