中脑多巴胺神经元对慢性痛相关焦虑症状的调控机制研究

慢性痛及其导致的负性情绪是人类主要的健康问题之一。焦虑和抑郁是慢性痛的重要伴发症状且可加剧患者疼痛反应，但其中枢环路调控机制尚不清楚。申请人长期从事慢性痛中枢机制研究（J Neurosci, 2018，2017；Mol Pain, 2015），前期研究中发现，单侧神经损伤（SNI）模型鼠产生明显的痛敏和焦虑样行为反应，且对侧腹侧被盖（VTA）区多巴胺神经元活性降低，VTA下游投射区NAc中多巴胺分泌明显降低，化学激活VTA多巴胺神经元能明显缓解焦虑反应。提示多巴胺神经元异常参与调节慢性痛负性情绪的产生。然而其中枢环路调节机制却不清楚。本项目拟借助电生理膜片钳、电化学、行为学、光遗传、在体荧光成像及分子生化等实验室特色技术，明确前扣带回皮层（ACC）-VTA环路多巴胺神经元对慢性痛焦虑情绪调控作用与机制，有望对慢性痛情绪调节神经环路的内在分子调控机制增加新的认识和补充，为其临床转化奠定基础。

Chronic pain and the related negative emotions are one of the major health problems in humans. Anxiety and depression are the major concomitant symptoms of chronic pain. This negative emotion can aggravate the pain response of patients. But the central nerve circuits and the regulation mechanism of it are still unclear. In the research of the mechanism of chronic pain (J Neurosci, 2018, 2017; Mol Pain, 2015)，our previous study found that the selective nerve injury (SNI) mice model have shown mechanical and thermal allodynia in the ipsilateral hindpaw of mice, and shown anxiety-like behavioral response in SNI model. We also found that the activity of dopamine neuron was decreased in the contralateral ventral tegmental area (VTA), also the DA level was reduced in the contralateral NAc.The anxiety-like response was alleviatesd by chemical activated the dopamine neuron in VTA. The result suggest that the dopamine neurons participate the regulating of chronic pain related negative emotions. However, the regulation mechanism of it is still unclear. This project intends to use the electrophysiological whole cell patch-clamp recording, electrochemical recording, behavioral, optogenetic, in vivo fluorescence imaging and molecular biochemistry to conduct this research. We intend to clarify the effect and mechanism of anterior cingulate cortex (ACC)-VTA dopamine circuits on chronic pain related anxiety. This expected to add new insights and supplements to the intrinsic molecular regulation mechanisms of the neural circuits that regulate chronic pain, and the synaptic transmission and occurrence and development of chronic pain. Regulatory mechanisms provide new clues and lay the foundation for clinical transformation studies.