The role of the septum in social memory

隔膜在社会记忆中的作用

• 批准号: 10674932
• 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/10674932
• 关键词: Antipsychotic Agents; Bathing; Biological Assay; Cells; Cognitive; Data; Development; Disease; Dorsal; Electrophysiology (science); Emotional; Goals; Hippocampus; 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; Schizophrenia; Slice; Social Behavior; Social Controls; Social Interaction; Synapses; Synaptic plasticity; Testing; Therapeutic; Translational Research; Vasopressins; Viral; Virus Integration; antagonist; autism spectrum disorder; cell type; disabling symptom; experimental study; hippocampal subregions; improved; in vivo; innovation; interdisciplinary approach; memory acquisition; mouse model; neuroregulation; new technology; optogenetics; receptor; 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。虽然 海马体已被公认为社会记忆、海马体输入区域中的关键角色 可能调节社会记忆的机制尚未被探索。隔膜直接和间接发送强 神经元投射到海马体，并与情绪处理和社会互动密切相关。 然而，目前还不清楚哪些突触变化和细胞类型驱动隔膜在社会记忆中的作用。此外，本发明还 隔膜在社交记忆相关疾病如自闭症中的作用还没有得到充分研究。因此，我们认为， 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 用于创造额外的和潜在的改进的治疗选择。 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。整体 目的是确定隔区调节社会记忆的回路和突触基础， 社会记忆障碍小鼠模型中社会记忆缺陷的补救策略。根据我 根据初步结果，我假设某些隔细胞类型的突触可塑性发生在社会暴露之后 而这些突触变化很可能是增强社会记忆的关键因素。所以我会 追求两个具体的目标：1）解剖电路和突触机制的社会记忆调制的 隔膜;和2）开发ASD相关小鼠模型中社交记忆缺陷的拯救策略， 社交记忆障碍在第一个目标中，我将系统地确定参与社会性的隔细胞类型。 使用病毒追踪和免疫组织化学相结合的记忆。我将决定社会记忆- 用离体脑片电生理学方法观察隔神经元对海马神经元的诱导输入变化， FosTRAP 2小鼠。最后，我将确定隔在社会记忆获得，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ASD相关的突触改变， 小鼠模型，Neuroligin-3R 451 C和SynGAP 1het系，显示社交记忆缺陷。而且，我会 开发通过体内光遗传学刺激改善这些小鼠系的社会记忆的策略 和微量注入神经调节剂 本提案中详述的方法是创新的，因为它利用了新的技术进步， 将病毒追踪与体内和离体光遗传学相结合，以研究控制社会性疾病的机制。 记忆初步研究表明，隔到海马的投射在调节社交活动中起作用。 而隔膜对社会记忆的控制是双向的。因此，拟议的研究是 这是非常重要的，因为社会记忆的双向控制提供了巨大的治疗潜力。最后， 这一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