The role of the septum in social memory

项目总结 社会记忆障碍是自闭症谱系障碍(ASD)最令人衰弱的症状之一。虽然 海马体已被公认为是社会记忆的关键角色，即海马体的输入区域 可能调节社会记忆的机制还没有被探索过。隔发出强烈的直接和间接 投射到海马体，并与情绪处理和社会互动密切相关。 然而，目前还不清楚是哪些突触变化和细胞类型驱动了隔膜在社会记忆中的作用。此外， 隔在ASD等社会记忆相关障碍中的作用尚未得到充分研究。因此， 研究社会记忆的机制以及相关的突触和细胞变化将是至关重要的 用于创建额外的和可能改进的治疗方案。 我的长期目标是使用综合方法来研究社会功能障碍的机制。整体而言 目的是确定隔区调节社会记忆的回路和突触基础，并发展 社会记忆受损小鼠模型中社会记忆缺陷的救治策略。基于我的 初步结果，我假设某些隔细胞类型的突触可塑性发生在社交暴露之后。 这些突触变化很可能是增强社会记忆的关键因素。因此，我会 追求两个具体目标：1)剖析社会记忆调制的回路和突触机制 以及2)为ASD相关小鼠模型的社会记忆缺陷制定救援策略 社会记忆受损。在第一个目标中，我将系统地识别参与社会生活的隔细胞类型 使用病毒追踪和免疫组织化学相结合的方法进行记忆。然后我会测定社会记忆- 用体外脑片电生理学方法诱发大鼠隔区神经元对海马神经元的传入变化 FosTRAP2小鼠。最后，我将确定隔膜在社会记忆获得、巩固和回忆中的作用 通过体内光遗传学。在第二个目标中，我计划识别两个与ASD相关的突触变化 小鼠模型、神经连接素-3R451C和SynGAP1het系，表现出社会记忆缺陷。而且，我会 开发通过体内光遗传刺激改善这些小鼠系的社会记忆的策略 和微量神经调节剂的输注。 本提案中详细说明的方法是创新的，因为它通过以下方式利用新的技术进步 将病毒追踪与体内和体外光遗传学相结合，以研究支配社会的机制 记忆。初步研究表明，隔向海马区的投射在调节社会交往中起作用。 而隔膜对社会记忆的控制是双向的。因此，拟议的研究是 非常重要，因为社会记忆的双向控制提供了巨大的治疗潜力。最终， 这一结果可能会为改善社会记忆的翻译研究提供一个框架 赤字。

Project summary Social memory impairment is one of the most debilitating symptoms of autism spectrum disorder (ASD). Although the hippocampus has been well established to be the key player in social memory, hippocampal input regions that may regulate social memory have not been explored. The septum sends strong direct and indirect projections to the hippocampus and has been heavily implicated in emotional processing and social interactions. However, it is unclear which synaptic changes and cell-types drive the septum’s role in social memory. Further, the impact of the septum in social memory-related disorders such as ASD is understudied. Therefore, investigating the mechanism of social memory and the associated synaptic and cellular changes will be critical for creating additional and potentially improved treatment options. My long-term goal is to use integrative approaches to study the mechanisms of social dysfunction. The overall objective is to identify circuit and synaptic underpinnings of social memory regulation by the septum and develop rescue strategies for social memory deficits in mouse models with social memory impairments. Based on my preliminary results, I hypothesize that synaptic plasticity in certain septal cell-types occurs after social exposure and that these synaptic changes are likely to be the critical factor in enhancing social memory. Therefore, I will pursue two specific aims: 1) Dissect the circuit and synaptic mechanisms of social memory modulation by the septum; and 2) Develop rescue strategies for social memory deficits in ASD-associated mouse models with social memory impairment. In the first aim I will systematically identify the septal cell-types involved in social memory using a combination of viral tracing and immunohistochemistry. I will then determine social memory- induced input changes from septal neurons onto hippocampal neurons with ex vivo slice electrophysiology in FosTRAP2 mice. Finally, I will determine the septum’s role in social memory acquisition, consolidation and recall via in vivo optogenetics. In the second aim, I plan to identify the synaptic alterations in two ASD-associated mouse models, Neuroligin-3R451C and SynGAP1het lines, which display social memory deficiency. Moreover, I will develop strategies for the improvement of social memory in these mouse lines via in vivo optogenetic stimulation and micro-infusion of neuromodulators. The approach detailed in this proposal is innovative, because it harnesses new technological advances by integrating viral-tracing with in vivo and ex vivo optogenetics to examine the mechanisms governing social memory. Preliminary studies suggest that the septum to hippocampal projection plays a role in regulating social memory and that the control of social memory by the septum is bi-directional. The proposed research is therefore highly significant, as the bi-directional control of social memory offers immense therapeutic potential. Ultimately, the outcome will likely provide a framework for translational research towards the improvement of social memory deficits.