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.

项目概要 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。 海马体已被确定为社会记忆、海马体输入区域的关键角色 可能调节社会记忆的隔膜传递强烈的直接和间接的作用尚未被探索。 对海马体的投射，与情绪处理和社交互动密切相关。 然而，尚不清楚哪些突触变化和细胞类型驱动隔膜在社会记忆中的作用。 隔膜对社交记忆相关疾病（例如自闭症谱系障碍）的影响尚未得到充分研究。 研究社会记忆的机制以及相关的突触和细胞变化至关重要 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整体机制。 目标是确定隔膜社会记忆调节的电路和突触基础，并开发 社交记忆障碍小鼠模型中社交记忆缺陷的挽救策略基于我的研究。 初步结果，我认为某些隔膜细胞类型的突触可塑性发生在社会暴露之后 这些突触变化很可能是增强社会记忆的关键因素。 追求两个具体目标：1）剖析社会记忆调节的电路和突触机制 隔膜；和 2) 制定 ASD 相关小鼠模型社交记忆缺陷的救援策略 在第一个目标中，我将系统地识别参与社交的隔膜细胞类型。 然后我将结合病毒追踪和免疫组织化学来确定社会记忆。 通过离体切片电生理学诱导从间隔神经元到海马神经元的输入变化 最后，我将确定隔膜在社会记忆获取、巩固和回忆中的作用。 通过体内光遗传学，我计划识别两个 ASD 相关的突触改变。 小鼠模型，Neuroligin-3R451C 和 SynGAP1het 系，显示出社交记忆缺陷。 制定通过体内光遗传学刺激改善这些小鼠品系的社会记忆的策略 和神经调节剂的微量输注。 该提案中详述的方法是创新的，因为它利用了新技术进步 将病毒追踪与体内和离体光遗传学相结合，以检查控制社会的机制 初步研究表明，隔膜到海马的投射在调节社交方面发挥着作用。 因此，隔膜对社会记忆的控制是双向的。 非常重要，因为社会记忆的双向控制最终提供了巨大的治疗潜力。 研究结果可能会为改善社会记忆的转化研究提供一个框架 赤字。