中枢5-羟色胺在创伤后应激障碍发病过程中的作用和环路机制

The clinical post-traumatic stress disorder (PTSD) drug treatment is mainly dependent on the selective serotonin (5-HT) reuptake inhibitors (SSRI), but the neuronal mechanism is unclear. Contextual fear memory is the classic behavioral paradigm in the study of PTSD, and the acquisition and retrieval is hippocampal-dependent. Previous study showed that contextual fear memory in the central 5-HT deficiency mice was markedly enhanced a long time, one possible mechanism is that 5-HT deficiency caused facilitation of fear memory retrieval, activating the system can inhibit this process. Therefore, this project will use the direct intervention method of transgenic mice and virus induced intervention method to explore whether central 5-HT is involved in the retrieval of contextual fear memory by pro and con; at the same time, to clarify the key nucleus of raphe nucleus which participate in the retrieval of contextual fear memory accurately. On this basis, using AAV2-Retro-Cre inverse tracing virus infected the raphe nucleus neurons which had projections to the hippocampus, combined with the raphe nucleus infected with the type of restriction or activation virus, to determine the functions and circuits mechanism of raphe-hippocampal neural circuits in regulating the retrieval of contextual fear memory by pharmacology and electrophysiology. We hope to provide experimental evidence for the use of SSRIs in the treatment of neuropsychological disease with abnormal fear memory, such as PTSD patients.

创伤后应激障碍（PTSD）的临床药物治疗主要依赖于选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs），但其机制尚不清楚。场景恐惧记忆是研究PTSD的经典行为学范式，其形成和提取是海马依赖的。前期研究发现脑内5-HT缺失小鼠的场景恐惧记忆能长时间维持在较高水平，一种可能的机制是中枢5-HT的缺失易化了恐惧记忆的提取，而激活该系统可以抑制该过程。因此，本课题将利用转基因小鼠直接干预和病毒诱导干预两种手段从正反两面探索中枢5-HT是否参与场景恐惧记忆的提取；同时精确地阐明参与恐惧记忆提取的中缝核簇关键核团。在此基础上，利用AAV2-Retro-Cre逆追踪病毒感染投射到海马的中缝核神经元，结合中缝核感染抑制型或激活型病毒，通过药理学、电生理等技术确定中缝核-海马神经环路在调控场景恐惧记忆提取中的作用和环路机制。期望为应用SSRIs治疗PTSD等恐惧记忆异常的精神疾病提供实验证据。

创伤后应激障碍（PTSD）的药物治疗主要依赖于选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs），但其机制尚不清楚。场景恐惧记忆是研究PTSD的经典行为学范式，其形成和提取是海马依赖的。前期研究发现脑内5-HT缺失小鼠的场景恐惧记忆能长时间维持在较高水平，一种可能的机制是5-HT缺失易化了恐惧记忆的提取，而激活该系统可以抑制该过程。因此，本课题利用转基因小鼠和病毒诱导干预两种手段从正反两面证实了中枢5-HT参与场景恐惧记忆的提取；同时精确地阐明参与恐惧记忆提取的中缝核簇关键核团——中缝中央核（MR）。药理学研究发现，5-HT参与场景恐惧记忆的提取离不开背侧海马（DH）的参与，因此，我们结合化学遗传手段，利用AAV/retro逆追踪病毒感染DH，从而激活或抑制MR投射到DH的神经元，证实中缝核-海马神经通路参与调控场景恐惧记忆的提取。此外，我们发现，从MR向DH投射的神经元中，5-HT神经元约占30%，谷氨酸能神经元约占50%，另外还有少量的GABA能神经元，因此，我们利用Pet1-cre五羟色胺转基因小鼠和化学遗产手段相结合，最终证实中缝中央核MR的5-HT神经元参与场景空间记忆的提取。目前的科研成果期望能为应用SSRIs治疗PTSD等恐惧记忆异常的精神疾病提供实验证据。