皮层边缘脑区小胶质细胞调控慢性痛诱发焦虑/抑郁的机制研究

临床上，慢性痛继发焦虑和抑郁的现象相当普遍，但迄今为止对这种共病的机制还了解甚少。皮层边缘脑区 (如前扣带皮层、内侧前额叶、海马、杏仁核等) 在学习记忆、情感动机、行为决策、以及慢性痛和痛相关情绪中发挥重要作用。小胶质细胞介导的脊髓神经炎症是神经病理性痛中枢敏化的发生基础，但在皮层边缘脑区的作用尚不清楚。我们最近的研究提示，大鼠前扣带皮层和海马小胶质细胞活化贡献于神经病理性痛诱发的厌恶和焦虑/抑郁样行为。本项目拟采用多学科方法，特别是光遗传学和化学遗传学方法，选择性激活或抑制小胶质细胞功能，明确小胶质细胞对皮层边缘脑区神经元兴奋性、突触传递和可塑性的调控，并探讨小胶质细胞激活的分子机制和小胶质细胞来源的促炎/抑炎细胞因子对皮层边缘脑区IDO酶代谢通路和神经元活动的调控，阐明小胶质细胞调控皮层边缘环路神经活动、介导慢性痛诱发焦虑和抑郁的中枢机制，为难治性慢性痛和抑郁共病提供潜在的治疗靶点。

Clinically，chronic pain is often accompanied by mood disorders such as anxiety and depression affecting the patient’s quality of life, so far, the mechanisms underlying this association remain unknown. The corticolimbic brain areas (including anterior cingulate cortex, medial prefrontal cortex, amygdala, and hippocampus) play a critical role in learning memory, motivation, decision-making, and affective-emotion of chronic pain. Spinal microglia-mediated neuroinflammatory processes are essential for the development of neuropathic pain; however, its role in supraspinal sites such as the corticolimbic brain areas is less understood. Our recent study suggests that the activation of microglia in the anterior cingulate cortex and hippocampus contributes to neuropathic pain-induced aversion and anxiodepression. In this project, using multidisciplinary approaches, especially optogenetics, chemical genetics (DREADDs, designer receptor exclusively activation by a designer drug) to selectively activate or inhibit microglia, we will explore whether and how corticolimbic microglia is involved chronic pain-induced anxiodepression in rodents. In particular, We seek to uncover whether the microglia-derived pro-inflammatory and anti-inflammatory factors directly modulate neuronal excitability, synaptic transmission and plasticity or indirectly reduce 5-HT and increase neurotoxic quinolinic acid through IDO metabolic pathway in the corticolimbic circuity. The proposed studies will reveal new insights into the role of microglia-to-neurons communication in neuropathic pain-induced anxiodepression, which could eventually lead to development of novel therapeutic strategies for treating refractory chronic pain-anxiodepressive comorbidity.