The role of the septum in social memory

隔膜在社会记忆中的作用

• 批准号: 10661150
• 负责人: Xiaoting Wu
• 金额: $ 24.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661150
• 关键词: Antipsychotic Agents; Bathing; Biological Assay; Cells; Cognitive; Data; Development; Disease; Dorsal; Electrophysiology (science); Emotional; Foundations; Goals; Hippocampus (Brain); Histocytochemistry; Immune; Immunohistochemistry; Impairment; Infusion procedures; Investigation; Knowledge; Link; Measures; Memory; Memory impairment; Molecular; Mus; Mutation; Neuromodulator; Neurons; Optics; Outcome; Output; Oxytocin; Pharmaceutical Preparations; Phase; Play; Population; Property; Proteins; Regulation; Research; Role; SYNGAP1; Slice; Social Behavior; Social Controls; Social Interaction; Synapses; Synaptic plasticity; Testing; Therapeutic; Translational Research; Vasopressin Receptor; Viral; antagonist; autism spectrum disorder; base; cell type; disabling symptom; experimental study; hippocampal subregions; improved; in vivo; innovation; interdisciplinary approach; memory acquisition; mouse model; neural circuit; neuroregulation; optogenetics; social; social deficits; targeted treatment; translational framework

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.

项目摘要 社交记忆障碍是自闭症谱系障碍（ASD）最令人衰弱的症状之一。尽管 海马已被确定为社交记忆的关键参与者，海马输入区域 可能没有探索这个调节社会记忆。隔膜发出强烈的直接和间接 对海马的预测，并与情感处理和社交互动有关。 但是，尚不清楚哪种合成变化和细胞类型可以促进隔膜在社交记忆中的作用。更远， 隔膜在社会记忆有关的疾病（如ASD）中的影响已被理解。所以， 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 为了创建额外的可能改进的治疗选择。 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。总体 目的是确定隔膜的社会记忆调节的电路和突触基础并发展 社交记忆障碍的鼠标模型中的社交记忆防御策略。基于我 初步结果，我假设某些分子细胞类型的合成可塑性发生在社会暴露后 这些综合变化可能是增强社交记忆的关键因素。因此，我会的 追求两个具体的目的：1）剖析社交记忆调制的电路和突触机制 隔膜; 2）制定社交记忆的救援策略，以与ASD相关的鼠标模型定义 社交记忆障碍。在第一个目标中，我将系统地确定社交中涉及的中间细胞类型 使用病毒追踪和免疫组织化学的组合记忆。然后，我将确定社交记忆 - 从间隔神经元到具有离体切片电生理学的海马神经元的诱导输入变化 Fostrap2小鼠。最后，我将确定隔隔在社会记忆中的作用，合并和召回中的作用 通过体内光遗传学。在第二个目标中，我计划确定两个与ASD相关的突触变化 鼠标模型，Neuroligin-3R451C和Syngap1Het线，显示社交记忆缺陷。而且，我会的 通过体内光遗传学模拟制定这些鼠标线上改善社交记忆的策略 和神经调节剂的微灌注。 该提案中详细介绍的方法具有创新性，因为它通过 将病毒追踪与体内和离体光遗传学相结合，以检查有关社会的机制 记忆。初步研究表明，海马投影的隔膜在调节社会中起作用 记忆和隔膜对社交记忆的控制是双向的。因此，拟议的研究是 非常重要的是，由于社会记忆的双向控制具有巨大的治疗潜力。最终， 结果可能会为改善社会记忆的转化研究提供一个框架 缺陷。