δ阿片肽能调控的中央导水管周围灰质-中央杏仁核环路与慢性痛伴抑郁症的发病

Depression and pain disorders are common comorbidities. The periaqueductal gray (PAG) and central amygdala (CeA) are the key brain structures for pain and emotion. Our preliminary results showed that CeA neurons were regulated by projecting fibers originated from PAG. GABAergic synaptic transmission in CeA was decreased and δ opioid receptors (DORs) expressed on the presynaptic plasma of PAG neurons were increased in mice with chronic pain and depression comorbidities. Here we propose that δ opioidergic modulation of PAG-CeA circuitry plays a crucial role in pain and depression comorbidities. The hypothesis is that chronic pain promotes DORs trafficking from GABA neuronal plasma to presynaptic terminals, which reduces presynaptic GABA release after activation by endogenous opioids. This disinhibits the PAG projecting glutamatergic neurons to CeA that enhances the excitability of CeA neuronal networks, leading to persistent hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis and contributing to depressive-like behaviors. We assume that this maladaptation is mediated by an epigenetic mechanism. In the current project, by using viral tracing, optogenetic, electrophysiological and epigenetic techniques, we first map the connectivity of δ opioidergic PAG-CeA circuitry and then identify its function in chronic pain-induced depressive-like behaviors. Second, we will examine the changes in PAG-CeA synaptic transmissions in mice with chronic pain and depression comorbidities, which will be affected by the activation of DORs. Last, we want to investigate the epigenetic mechanism in the PAG-CeA circuitry, which modulating chronic pain and depression comorbidities.

抑郁症和慢性痛共病普遍存在。中央杏仁核（CeA）和中央导水管周围灰质（PAG）是调节情绪和疼痛的节点和路径。我们预实验发现，CeA神经元接受PAG投射纤维支配。在慢性疼痛伴抑郁行为中，CeA GABA突触传递降低，PAG神经元δ阿片受体上膜增加。我们提出，δ阿片肽能调控的PAG-CeA神经环路在慢性痛伴抑郁症发病中作用至关重要。具体假设为：慢性痛诱发PAG GABA神经元内δ阿片受体迁移到突触前膜，激活后抑制GABA释放，使其支配的投射到CeA的谷氨酸能神经元去抑制，兴奋CeA神经网络，最终导致HPA轴过度活化，从而调节抑郁相关行为，这种神经网络适应性受表观遗传学机制调控。本课题拟采用病毒示踪、光遗传、电生理和表观遗传学等技术，描绘PAG-CeAδ阿片肽神经环路的结构连接及其在慢性痛伴抑郁行为中的作用，检测PAG-CeA突触传递变化及其受δ阿片受体激活的影响，并探索该环路的表观遗传学基础。

持续疼痛改变的大脑神经环路结构和功能如何产生情绪障碍（抑郁和焦虑等），尚不明确。申请人首先利用功能磁共振发现慢性痛伴抑郁患者的杏仁中央核和包含中缝背核的脑区功能连接减弱。基于此，在慢性疼痛致抑郁样行为的小鼠上，结合病毒示踪和光遗传手段，解析了中央杏仁核-中缝背核-外侧缰核的神经环路结构，并鉴定了该神经环路在慢性疼痛致抑郁样行为发生中的变化规律。该研究成果，申请人以共同第一作者发表于Nature Neuroscience期刊（2019，IF: 21.13）。此外，病理性疼痛（尤其是不明原因的疼痛），易产生焦虑情绪，焦虑同样会导致痛持续时间增长以及强度增大，其发生机制尚不清楚。申请人在小鼠炎性痛模型上发现，躯体感觉皮层S1 投射到背外侧纹状体（cDLS）的神经通路活性增加，利用光遗传或化学遗传调控该通路活性可显著影响疼痛诱发的焦虑样行为，但对疼痛的表型无影响。这提示，疼痛触发了大脑里负责焦虑的神经通路，该通路可能独立于疼痛神经环路。该成果申请人以第一作者于2019 年发表在PAIN 期刊（2019，IF：6.03）。本项目发现的慢性痛、抑郁症（焦虑症）及疼痛-抑郁（焦虑）共病的发病分子和神经环路机制，一方面有利于发现新的镇痛和抗抑郁（焦虑）药物性靶点，另一方面有助于为非药物手段（如经颅磁刺激和深部脑刺激等）治疗难治性症状提供新思路，具有重要的基础生物医学与临床转化意义。