慢性痛状态下前额叶皮层及其相关环路对痛觉信息编码的调控机制

Chronic pain is an unsolved medical problem. The prefrontal cortex (PFC), a high-order region of the brain, integrates multiple functions of the brain, including pain, emotion and cognition. The study on the mechanism of pain coding has great significance of both scientific value and applications. Our previous studies reveal the microcircuit changes of deactivation of the L2/3 pyramidal neurons in prelimbic subdivision (PL) with increased synaptic inputs in chronic pain rodents. Furthermore, optogenetic activation of the PL excitatory pyramidal neurons exerted analgesic and anxiolytic effects in chronic pain mice. Our preliminary data also indicate that the PFC neurons project to different brain regions. Based on the above results and literature, we propose the hypothesis that the dysfunction of PFC microcircuits is the key factor for the development and maintenance of chronic pain; PFC widely and dynamically modulates the multi-dimensional encoding of pain at the level of neural circuits through its diverse downstream targets. Moreover, the recovery of dysfunction of the microcircuits and neural circuits of PFC alleviates chronic pain. To prove the hypothesis, we will first determine the microcircuit patterns of PFC in the chronic pain mice, and explore the molecular mechanisms of microcircuit alteration. We will also demonstrate the modulation of PFC-downstream circuits on the encoding of pain under both physiological and chronic pain conditions. Our project will shed new insight into the important roles of the high-order brain regions in central sensitization of pain and provide new targets in clinical treatment of chronic pain.

慢性痛是未解的医学难题。前额叶皮层（prefrontal cortex，PFC）作为高级神经中枢，是痛觉、情绪与认知的功能交叉点，针对其进行的痛觉信息编码机制研究兼具科学性与应用性。我们的前期工作揭示，慢性痛状态下PFC 2/3层锥体神经元发生突触传入增加但兴奋性降低的微环路变化，改善其微环路病理状态可缓解痛感觉和痛相关负性情绪。预实验及已有文献显示，PFC与众多脑区存在直接的投射联系，形成的神经环路可能参与PFC复杂功能的实现。据此我们提出假说：PFC微环路功能异常是形成和维持慢性痛的关键原因；PFC通过与其他脑区形成的神经环路动态地调控痛觉信息的多维度编码；改善慢性痛状态下PFC微环路及神经环路的病理状态有助于缓解慢性痛。本项目将围绕该假说重点阐明PFC在慢性痛状态下微环路改变及其机制，明确PFC相关神经环路在生理状态和慢性痛状态下对痛觉信息编码的调控及其机制，为慢性痛治疗提供新思路。

疼痛是一种与实际存在或潜在组织损伤相关的感觉、情感、认知和社会因素等多维度的痛苦体验。慢性痛患者常伴有焦虑症、抑郁症、药物滥用和睡眠障碍等精神共病，与慢性痛交叉敏化，严重影响患者的生活质量。.前额叶皮层是疼痛的多维度整合处理的关键脑区。我们的研究表明，神经病理痛状态下，SNI神经损伤对侧前额叶皮层的亚区前边缘皮层（prelimbic cortex，PL）V层锥体神经元突触传入增加，兴奋性降低。激活对侧PL兴奋性神经元可以缓解小鼠的神经病理痛和焦虑行为，抑制PL兴奋性神经元可以增加机械痛和焦虑行为。全细胞膜片钳研究显示，SNI神经病理痛小鼠患肢对侧PL的V层锥体神经元的HCN通道电流幅度下降。同时，SNI小鼠对侧PL的HCN1通道蛋白含量增高，HCN2蛋白含量降低。我们基于Cre-LoxP系统构建了Hcn1fl/fl与Hcn2fl/fl的条件性基因敲除鼠。敲除对侧PL的Hcn1增强痛相关的焦虑样行为，敲除对侧PL的Hcn2减少痛相关的焦虑样行为，同时敲除对侧PL的Hcn1和Hcn2可以缓解小鼠神经病理痛状态下的机械痛觉敏化，降低基础焦虑水平。进一步研究表明，激活神经病理痛小鼠PL到背侧中脑导水管周围灰质（periaqueductal gray，PAG）通路，小鼠的机械痛阈值不变，但焦虑行为得到缓解；而激活神经病理痛小鼠PL到腹外侧PAG通路缓解神经病理痛小鼠的机械痛觉敏化，不改变焦虑行为。.综上，我们证明了PL的V层锥体神经元兴奋性同时调控神经病理痛的机械痛觉敏化和焦虑样行为，HCN1通道可抑制痛相关的焦虑行为，而HCN2通道可增加痛相关的焦虑行为。PL-背侧PAG通路调节痛相关的焦虑行为，而PL-腹外侧PAG通路则调节痛感觉。我们的研究结果为理解精神共病对慢性痛的敏化作用提供了新的启示，为治疗神经病理痛提供了新的方向。