疼痛-抑郁共病神经环路的优先级效应

Pain and depression are highly comorbid. Patients with chronic pain are often accompanied by depressive symptoms, meanwhile patients with depression also show increased sensitivity to pain. The comorbidity of pain and depression leads to increased difficulty in clinical diagnosis and treatment. The neurobiological mechanism of pain-depression comorbidity is still unclear. The main reason is that pain and depression have shared neural circuits. It is necessary to firstly determine the mode on coding and dividing information of pain or depression in the key brain regions. Our previous study found that the sensory-discriminative component of pain and the emotional-affective component of pain are independent and coordinated. Different brain region has a priority effect during information processing. For instance, anterior cingulate cortex gives priority to the emotion component and transfers the information of sensory component to other regions. This project proposes a hypothesis that the neural circuit of pain-depression comorbidity also has this priority effect. In pain or depression, the changes in synaptic transmission and plasticity lead to the destabilization of structure, which in turn affects the long-distance synaptic projections in between brain regions. This could be the structural and functional basis for the priority effect of pain and depression information processing in different brain regions. By using 2-photon excitation microscope combine with whole-cell patch clamp technologies, this project will clarify the specific neural circuits of pain and depression, reveal the patterns of information transmission between brain regions under different pathological conditions. In the long term, this project will propose a feasible solution for the diagnosis and treatment of pain-depression comorbidity.

疼痛与抑郁具有高度共病性，慢性痛患者通常伴随抑郁症状，抑郁症患者也表现出痛敏感性增加，两者共病导致临床诊疗难度增大。目前疼痛-抑郁共病的神经机制尚不明确，主要因为疼痛与抑郁有共享的神经环路，需先确定在加工信息时脑区的编码和分工。申请人前期研究发现，疼痛的感觉和情绪环路既独立又协作，具有优先级效应，例如当感觉和情绪信息同时传入时，前扣带皮层会优先处理情绪成分，并把感觉成分发送至下行脑区进行处理。据此，本项目提出假说：疼痛-抑郁共病的神经环路也存在优先级效应，此效应是大脑编码感觉和情绪的基础模式。本项目将在验证假说的基础上，研究优先级效应的结构和功能基础：拟利用双光子结合全细胞膜片钳技术，检测感觉和眶额皮层中兴奋性神经元突触传递效率、突触可塑性和突触结构，并进一步检测关键脑区之间的长距离投射连接，揭示疼痛-抑郁病理状态下脑区之间的信息传递模式，为治疗疼痛-抑郁共病提供位点调控策略。

慢性顽固性疼痛引起的抑郁症是抑郁症发病的主要诱因之一，超过50%的慢性痛患者有抑郁的症状。很多临床观察表明慢性痛患者遭受的抑郁和厌世情绪给病人造成的身心伤害远比疼痛本身更为严重，同时抑郁症及其导致对疼痛治疗的消极反应又在很大程度上增强了疼痛的感受。研究慢性痛的治疗手段和药物靶点一直是国内外医学界的研究热点，而疼痛的负面情绪的研究由于与多种高级认知状态相关，对其分子机制和神经环路的探索也是研究难点所在。申报人团队通过结合前期研究结果发现：疼痛感觉、情绪与认知组分也具有信息处理的主导效应，即在特定脑区中，其中一种疼痛组分会得到优先加工。本研究通过建立大鼠慢性疼痛模型以及慢性痛诱导抑郁症模型，运用啮齿类动物虚拟现实系统、核磁共振成像、双光子钙成像、在体电生理记录、蛋白和分子技术等研究方法，对比了疾病鼠与正常鼠的神经活动和神经网络差异，深入探讨在疼痛发展的不同时期，海马与皮层脑区之间的编码与整合关系，确认了疼痛的不同组分之间信息整合的神经基础及神经调控机制。项目成果共发表SCI论文5篇，会议论文1篇，中文核心期刊论文1篇。申请两项发明专利（已获批1项）。