前扣带回皮层酸敏感离子通道调节慢性痛及其可塑性改变的机制研究

Acid-sensing ion channels, one of the major ion channels sensing acidic environments in the body, are believed to be involved in a variety of pathological processes associated with acidosis, such as chronic pain, ischemic stroke, and neurodegenerative diseases. However, to date, less information is available on the mechanisms and roles of ASICs in higher cortical level of pain processing, such as anterior cingulated cortex (ACC). The present project aimed to investigate the potential role of ASICs in regulating chronic pain-related behavioral responses and central plastic changes in the mouse ACC, by a combination of several multidisciplinary approaches, including slice electrophysiology, molecular biology, biochemistry, anatomical circuit tracing, optogenetics and behavioral testing. Specifically, we will mainly focus on the following four research contents: (1) precise location and role of ASIC1a in the ACC in behavioral manifestations of chronic pain; (2) regulation of pain-related synaptic plasticity by ASIC1a in the ACC; (3) molecular mechanisms underlying the involvement of ASIC1a in chronic pain-induced behavioral sensitization and cortical plasticity; (4) cell type- and projection circuit-specific involvement of ASIC1a in chronic pain processing in the ACC. The research results from this project might provide novel insights into the mechanisms of synaptic plasticity in the ACC as well as the pathophysiological functions of ASIC1a in cortical regions. More importantly, the exciting findings derived from the current project may open new avenues for future development of better therapeutic strategies against chronic pain by targeting the aberrant synaptic/circuit plasticity in the brain.

酸敏感离子通道（ASIC）作为体内感受酸性环境的主要离子通道，广泛参与诸多与组织酸化密切相关的疾病发展过程，如疼痛、缺血性脑卒中、神经退行性疾病等。但目前为止，ASIC在高位脑区如前扣带回皮层（ACC）慢性痛信息处理中的贡献及其机制尚不清楚。本项目结合所在课题组的研究方向和技术优势，将综合运用脑片膜片钳电生理记录、离体多电极阵列记录、生物化学、分子生物学、光遗传学、行为学、神经环路示踪等多学科交叉手段，针对ASIC1a通道在ACC的表达定位、ASIC1a在慢性痛行为学和痛相关可塑性改变中的作用及其工作机制、ACC内ASIC1a贡献慢性痛可塑性改变的细胞类型和投射环路特异性等多个层次开展研究。预期研究结果可能为揭示ACC突触可塑性的发生机理和ASIC的生理病理功能提供新思路。此外，本项目的研究成果也将为设计靶向皮层突触环路功能异常的新型镇痛药物提供原始理论依据。

前扣带回皮层（ACC）作为哺乳动物体内一个非常重要的结构已被报道参与慢性疼痛情感成分的处理和下行痛觉信息的调控。但ACC参与这些过程的突触环路和细胞分子机制仍不是十分清楚。酸敏感离子通道1a（ASIC1a）已被证明在外周感觉神经元和脊髓中枢水平的痛觉相关信息的转导与传递中发挥重要的调节作用，但高位中枢大脑皮层表达的ASIC1a在慢性痛行为表型及皮层突触可塑性改变中的贡献及其可能的工作机制依旧缺乏研究。本项目综合运用电生理学、经典和条件性的基因敲除、行为学、药理学、离体多通道和单细胞电生理记录、生物化学与细胞分子生物学、光纤记录和光/化学遗传学操控等多种技术手段, 围绕ACC内ASIC1a调节慢性痛及其可塑性改变的突触和分子机制这一核心问题，深入系统地研究了ASIC1a亚基在ACC的表达及其对各类突触可塑性的影响，揭示了ASIC1a介导的皮层LTP在慢性痛发生发展中的贡献及其发挥作用的细胞类型特异性分子机理。另外，项目组还拓展研究了ACC区LTD突触可塑性贡献慢性痛发病的详细工作机制，并解析了中脑奖赏中心腹侧被盖区不同类型神经元编码痒觉不同情感组分的神经机制。上述研究结果有望为揭示ASIC1a在ACC慢性痛相关突触可塑性中的作用提供新思路，也为临床上设计靶向ASIC1a介导的异常突触可塑性的新型镇痛药物提供理论依据。本项目已在《Neuron》、《Cell Reports》、《Journal of Neuroscience》等国际学术期刊发表论文4篇，协助培养博士研究生5名。项目组成员共参加国内外学术会议6人次，圆满完成了预期目标。