表观遗传学调控的中央杏仁核GABA神经环路参与慢性疼痛并发的抑郁症

Chronic pain acting as an inescapable stressor is one of the most important factors affecting emotion and memory. Persistent pain usually induces depressive-like behavior. The central amygdala (CeA), which serves as the output nucleus for major amygdala functions, is one of the key brain structures for emotion and memory acquisition and storage. Here we propose that epigenetic regulation of CeA GABA neuronal maladaptation mediates the development of depression in chronic pain states. The hypothesis is that in chronic pain states, CeA GABAergic synaptic efficacy is reduced, which disinhibites the neuronal network in the nucleus of CeA downstream target (e.g. paraventricular nucleus), leading to persistent hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis. The neural maladaptation in the CeA induced by chronic pain primes the development of depression. In addition, the chronic pain-induced synaptic maladaptive changes in the CeA are regulated by a MeCP2-mediated epigenetic mechanism. In the current project, by using optogenetic approaches with light-sensitive channels green algae channelrhodospin 2 (ChR2)-transgenetic mice, we first identify the function of CeA GABA circuitry in chronic pain-induced depressive-like behaviour. Second, we will investigate the changes in CeA GABAergic synaptic transmission in mice with chronic pain, which will be linked to a epigenetic mechanism via MeCP2 regulation. The aim of this project is to characterize the role GABA neuronal maladaptation in the development of depression in chronic pain states in an epigenetic manner, which will provide potential new therapeutic strategies for chronic pain-induced neurological disorders.

慢性疼痛应激是影响情感和记忆的重要环境因素之一，中央杏仁核（CeA）是调节情感和记忆功能的关键节点和路径。我们提出，表观遗传学机制调控的CeA GABA神经环路活动在慢性疼痛并发抑郁症中发挥至关重要作用。具体假设为：慢性疼痛状态下，CeA GABA突触效能降低去抑制了其投射核团（如室旁核）神经网络活性，导致HPA轴过度活化，从而参与了抑郁相关行为的调节，这种神经网络适应性是由DNA甲基化结合蛋白MeCP2介导的表观遗传学机制所调控。本课题拟采用光敏感通道特异性表达于GABA神经元的转基因鼠，描绘CeA GABA神经环路与室旁核等核团的结构连接及其在疼痛和抑郁相关行为中的功能；检测慢性疼痛并发抑郁行为过程中，CeA GABA能突触传递的变化及其对室旁核等核团突触传递的影响，并揭示其产生的表观遗传学机制。期望在表观遗传学水平阐述CeA GABA神经环路参与慢性疼痛并发抑郁症的作用和机制。

流行病学调研发现，慢性痛的病人中有高达52%的人群患有抑郁症，目前发病机制不清楚，也没有标准诊疗药物和方案。中央杏仁核（CeA）是调节情感和记忆功能的关键节点和路径。我们提出， CeA GABA神经环路活动在慢性疼痛并发抑郁症中发挥至关重要作用，并由DNA甲基化结合蛋白MeCP2介导的表观遗传学机制所调控. 我们利用逆向跨单级cre依赖的病毒示踪发现小鼠中缝背核(DRN)的5-羟色胺（5-HT）神经元投射到中央杏仁核(CeA)，支配并负向调控了SOM阳性的GABA神经元。慢性痛伴抑郁症发病过程中，5-HT支配的CeA GABA网络活性增强。在体大脑微透析连接HPLC实时分析发现，慢性痛伴抑郁的小鼠CeA 5-HT释放降低。利用光遗传学或化学遗传学调控该神经环路的活性，可以缓解慢性痛环境下的抑郁症状。有意思的是，这些操作对慢性应激产生的抑郁样行为无效。此外，MeCP2调控 bdnf基因表达活性，参与了CeA的GABA网络活性的改变，贡献与慢性痛诱导的行为学表型。. 综上所述，我们发现了5-HT:DRN→SOM:CeA通路直接参与了慢性痛伴抑郁样行为的形成，并接受MeCP2介导的表观遗传调控，为慢性痛伴抑郁症发病的机制研究提供了新的方向和理论基础。