海马CA1区脑源性神经营养因子降低介导慢性炎症痛的细胞与神经回路机制

海马功能及与其它脑区连接度的降低，是慢性痛发生的重要危险因素，但其机制尚不清楚。项目组的前期工作提示，炎症痛小鼠海马区脑源性神经营养因子（BDNF）含量显著降低，与慢性痛的发生相关。本项目拟在此基础上，联合应用基因编辑、清醒小鼠在体电生理记录、在体钙成像、膜片钳、光遗传学等多项先进技术，在慢性炎症痛小鼠模型中，研究海马CA1区调控疼痛的机制。项目首先验证慢性炎症痛小鼠海马CA1区BDNF含量降低，并通过遗传学技术上调或下调各型神经元BDNF的表达，明确其对痛行为的影响；其次，应用电生理和钙成像技术研究慢性炎症痛及下调BDNF含量对CA1区各型神经元功能的影响；最后，通过电生理和光遗传学技术探讨CA1锥体神经元调控痛行为的神经通路机制，及炎症痛中过表达BDNF的挽救效果。本项目从分子、神经元、神经通路层面，揭示海马脑区调控慢性痛的生物学机制，并对发展慢性痛新疗法有临床指导意义。

Decreased hippocampal functions and connectivity with other brain regions are risk factors of chronic pain. But the underlying mechanisms are not fully understood. Our pilot work has revealed that decreased hippocampal levels of brain-derived neurotrophic factor (BDNF) correlate with the development of chronic inflammatory pain. With a combinative application of gene editing, in vivo electrophysiological recording, calcium imaging, patch clamping and optogenetics, the present project aims to elucidate this question at molecular, cellular and circuit levels in a mouse model of inflammatory pain. We first confirm decreased hippocampal expression of BDNF in inflammatory pain, and further observe the effects of up- or down-regulation of BDNF expression in various neuronal types of hippocampal CA1 on pain behaviors. Next, excitability and input strength changes of CA1 pyramidal and interneurons under down-regulated hippocampal BDNF expression and chronic pain condition are examined with in vivo / in vitro electrophysiology and calcium imaging. Finally, electrophysiological features and causal contribution of hippocampal pathways in pain behaviors are examined with in vivo electrophysiology and optogenetics, respectively. Potential rescue effects of BDNF overexpression are also examined. The project aims to elucidate molecular, neuronal and circuit mechanisms underlying hippocampal modulation of pain, and is instructive for developing novel treatment of chronic pain.