压后皮质生长抑素中间神经元在创伤记忆提取中的作用及环路机制研究

Post-traumatic stress disorder (PTSD) is a high-risk mental illness for individuals after traumatic events, which seriously affects patients' lives. Traumatic re-experience is the core symptom of PTSD, but its neural circuit mechanism is still unclear. Our previous study found that there is an enhanced functional coupling between retrosplenial cortex (RSC) and dorsal medial prefrontal cortex (dmPFC) in PTSD model mice. Neural Circuit tracing revealed that SST-positive inhibitory neurons (SSTIN) in RSC project to dmPFC. These projections may be involved in modulating the functional coupling between RSC and dmPFC. In addition, we also found that increased SSTIN excitability in RSC promotes traumatic re-experience-like symptoms of PTSD model mice. So, we hypothesize that the excitability of SSTIN in RSC is enhanced in PTSD. The enhanced excitability enhances the functional coupling between RSC-dmPFC, through its inhibitory projection in RSC and dmPFC, promotes the retrieval of fear memory, and leads to the occurrence of traumatic re-experiences in PTSD. This project will use transgenic mice to study the role of the RSC-dmPFC circuitry in the traumatic re-experience of PTSD, and to elucidate its neural circuitry mechanism, so as to provide new ideas and potential targets for the treatment of this symptom.

创伤后应激障碍（PTSD）是个体经历创伤事件后高发的精神疾病，严重影响患者生活。创伤性再体验作为PTSD的核心症状，其神经环路机制还不清楚。我们前期研究发现压后皮质（RSC）与背内侧前额叶（dmPFC）的功能耦合在PTSD模型鼠中增强，进一步环路示踪显示RSC和dmPFC间存在由SST阳性的抑制性神经元（SSTIN）发出的投射连接，可能参与调制RSC-dmPFC间的功能耦合。此外，我们还发现提高RSC中SSTIN兴奋性会促进小鼠创伤性再体验样症状的发生。因此，我们提出假设：PTSD中RSC的SSTIN兴奋性增强，通过其对RSC和dmPFC的抑制性投射，增强RSC-dmPFC间的功能耦合，促进了恐惧记忆的提取，进而导致PTSD中创伤性再体验的发生。本项目将采用转基因小鼠研究RSC-dmPFC环路在PTSD创伤性再体验中的作用，并阐明其环路机制，从而为这一症状的治疗提供新的思路和潜在靶点。

创伤后应激障碍是涉及情绪与记忆调节紊乱的高发疾病，与边缘结构的神经环路损伤密切相关。本项目针对边缘结构中参与记忆和情绪调控的关键脑区腹侧海马内神经元的单突触连接结构以及与创伤后的应激行为障碍的突触环路机制进行了研究，形成了如下主要成果：我们发现（1）腹侧海马CA3区（vCA3）存在2种形态和电生理性质均不同的2类兴奋性神经元，可被COCH基因区分为COCH阳性和COCH阴性，其中COCH阳性神经元具有簇发放特性并参与创伤后应激行为反应；（2）vCA3的COCH神经元的簇发放特性由T型钙离子通道决定并受MTF1的转录调控；（3）vCA3的COCH神经元单突触支配外侧隔核的GABA能神经元（GILS）；（4）创伤后的应激行为由COCH-GILS环路中Ca2+-AMPAR介导的突触传递增强所形成的创伤记忆所致。揭示了创伤引发应激行为的分子和环路机制，为创伤导致的应激障碍提供潜在的治疗靶点和干预途径。