持续性神经炎症是影响各类脑病进展的重要发病机制，小胶质细胞在维持神经元周围微环境的稳定和调节神经炎症方面发挥着“双刃剑”的作用。研究发现，激活奖赏系统VTA多巴胺神经元可以强化固有免疫和适应性免疫功能，但VTA多巴胺神经元是否通过调节小胶质细胞免疫功能参与神经炎症并不清楚。我们的预实验结果显示，炎症微环境下增加多巴胺的浓度，可诱导小胶质细胞多巴胺受体Drd2表达上调，激活Drd2可促进下游Cryab蛋白的表达增加。基于这一发现，我们提出VTA多巴胺神经元激活小胶质细胞Drd2，上调下游Cryab蛋白的表达并促进Cryab发生磷酸化，增强小胶质细胞吞噬能力，从而改善神经炎症。本项目将应用光遗传、DREADD、病毒转染、RNAi、免疫微球荧光计数等技术验证上述科学假说，完善多巴胺神经元 “奖赏”小胶质细胞改变免疫功能的理论，为寻找改善神经炎症的合适靶点及推进各类退行性疾病的治疗提供新思路。

Persistent neuroinflammation is an important pathogenesis affecting the progression of various types of encephalopathy. Microglia plays a "double-edged sword" effect in regulating neuroinflammation and maintaining the stability of neuronal microenvironment. Activation of the ventral tegmental area (VTA) dopaminergic neurons can boost both innate and adaptive immune function, however, whether VTA dopaminergic neurons participate in neuroinflammation via regulating microglia immune function is still unknown. Our preliminary results show that increasing dopamine concentration in the inflammatory microenvironment can induce up-regulation of dopamine receptor D2 (Drd2) expression in microglia, and activation of Drd2 can promote the expression of downstream Cryab protein. Based on this, we propose that VTA dopaminergic neurons activate microglia Drd2, up-regulate the expression of downstream Cryab protein and promote the phosphorylation of Cryab, enhance the phagocytic ability of microglia, and thus relieve neuroinflammation. Techniques such as optogenetics, DREADD, viral transfection, RNAi, and immunomicrosphere fluorescent technique will be used to verify the above scientific hypothesis and improve the theory that dopaminergic neurons "reward" microglia to change immune function. This study may provide insight and new ideas for finding potential targets for improving neuroinflammation and promoting the treatment of various neurodegenerative diseases.