小胶质细胞调控记忆连接和衰老相关记忆连接障碍的分子细胞和微环路机制研究

目前对于不同时间编码的多个记忆之间的联合及机制了解甚少，这方面研究对理解相似或时间相近的记忆如何在脑内高效存储和检索至关重要。我们最近的研究发现，消除小鼠脑内小胶质细胞显著延长海马CA1区编码不同场景记忆的神经元集群重叠的时间窗，从而促进多个场景记忆之间的连接。这一发现提示脑内主要的免疫细胞-小胶质细胞对场景记忆之间的连接起关键的调控作用，具体作用机制尚不清楚。本研究将利用在体微小显微镜钙成像、化学遗传、TetTag工具小鼠、全细胞膜片钳等先进的在体和离体研究工具，探索小胶质细胞调控记忆连接的分子、细胞及局部微环路机制。小胶质细胞的促炎性活化被认为与衰老及相关疾病的认知障碍密切相关。因此，我们还将利用老年小鼠研究小胶质细胞促炎性活化在衰老记忆连接障碍中的作用和机制。研究旨在探索记忆连接的神经免疫新机制，并为衰老及相关疾病（如AD）认知障碍的治疗提供理论指导，具有潜在的转化及应用前景。

The majority of learning and memory studies have been focused on the mechanisms that encodes, consolidates and retrive individual memories, little is known about how multiple memories across time are linked. Studying the mechanisms of memory linking is critical for understanding how memories that are temporal close or sharing similarity are linked together so that they can be stored and retrieved properly and efficiently under physiological conditions. Our previous studies using in vivo calcium imaging and head-mounted miniscope have shown that elimination of majority microglia in the mouse hippocampus dramatically extended the temporal window for overlap among CA1 neuronal ensembles encoding separate contextual information, and resulted in a dramatic extension of the temporal window to link contextual memories, therefore enhanced memory linking. These findings indicated that microglia play a critical role in controlling the temporal window for linking different contextual memories, however the underlying mechanism is unknown. Here, we propose to use state-of-the-art tools, including in vivo miniscope, chemogenetics, TetTag mice and whole-cell patch clamp recordings to explore the molecular, cellular and microcircuit mechanisms underlying the roles that microglia plays in linking multiple memories across time. The pro-inflammatory activation of microglia is thought to be closely related to cognitive impairment associated with aging and neurodegenerative diseases such as AD. Therefore, we will also study the role and mechanism of abnormally activated microglia in temporal memory-linking impairment associated with aging by using aged mice. Our study aims to address a novel mechanism of how neuro-immune interactions regulate memory linking in normal learning, and more importantly, a neuroinflammatory mechanism, which may contribute to memory linking deficits in aging-related disorders. Therefore, it will be of important significance for the treatment of memory disorders associated with aging and neurodegenerative diseases such as AD.