Hippocampal adult-born neurons in social memory circuits

社会记忆回路中的海马成年神经元

基本信息

批准号：
10716706
负责人：
Elise C Cope
金额：
$ 55.96万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-16 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716706
关键词：
Ablation Adult Affect Afferent Neurons Alzheimer&apos s Disease Behavioral Brain region Cells Clinical Cognitive Data Date of birth Development Electrophysiology (science)Event Frequencies Generations Genetic Goals Hippocampus Histologic Impairment Individual Intervention Knockout Mice Life Maintenance Major Depressive Disorder Memory Memory impairment Modeling Mus Neurons Pathway interactions Patients Performance Pharmacogenetics Process Publishing Quality of life Research Role Schizophrenia Site Source Symptoms Testing Transgenic Mice Transgenic Organisms Wild Type Mouse Work adult neurogenesis autism spectrum disorder brain circuitry cell type dentate gyrus experimental study functional improvement improved in vivo innovation member memory consolidation memory process memory recall mouse model nerve supply neural circuit neural stimulation neuronal circuitry neuropsychiatric disorder neuropsychiatric symptom neuropsychiatry novel novel strategies pharmacologic recruit social social deficits social influence social relationships therapeutic target

项目摘要

PROJECT SUMMARY Severe social impairment is a shared symptom of many neuropsychiatric illnesses. In particular, deficits in the ability to recognize and remember previously encountered individuals—often called social memory—can significantly compromise an individual’s ability to form and maintain social relationships, dramatically reducing quality of life. Among the brain regions associated with social impairment, the hippocampus is notable due to its essential role in social memory and its exceptional structural plasticity, including the continuous generation of new neurons in the dentate gyrus throughout adulthood. Harnessing naturally occurring structural plasticity in the hippocampus may be a valuable approach for stimulating neural circuits and restoring social memory function. Thus, the goal of this R01 proposal is to uncover the contribution of hippocampal structural plasticity to social memory circuits. Our published work demonstrated that adult-born neurons in the dentate gyrus are necessary for consolidating and/recalling social memories for conspecifics. Yet, the extent to which adult-born neurons are recruited to social memory traces and contribute selectively to social memory processes is undetermined. Adult-born neurons form multiple cellular connections within the hippocampus, including with CA2 neurons. While largely understudied, the CA2 region of the hippocampus has emerged as a critical hub for social memory function. We do not know whether adult-born neurons influence social memory circuits and function via their connections with CA2. In our preliminary studies using a mouse model of social dysfunction, the Shank3B KO mouse, we found impaired social memory along with hippocampal aberrations, including fewer adult-born neurons and diminished afferents from adult-born neurons to CA2 compared to wild-type littermates. We then used chemogenetics to activate CA2 neurons and the CA2-to-ventral CA1 pathway and were able to rescue social memory dysfunction in Shank3B KO mice, suggesting this circuitry as a pivotal intervention point for improving function. Here, we propose to use transgenic, chemogenetic, and pharmacologic manipulations combined with behavioral, histological, and in vivo electrophysiological analyses to test the hypothesis that afferent innervation of CA2 by adult-born neurons is critical in regulating social memory function, and that targeting this circuitry can alleviate social memory dysfunction. Specifically, we will elucidate the preferential recruitment of adult-born neurons to social memory engrams and their selective contribution to social memory function (Aim 1), identify the influence of adult-born neuron afferents to CA2 on CA2 oscillatory activity and social memory function (Aim 2), and explore enhancing hippocampal adult-born neuron circuitry to improve social memory deficits in Shank3B KO mouse (Aim 3). These studies will provide a mechanistic understanding of how adult-born neurons impact social memory circuits and function with the long-term goal of transforming how we approach alleviating social symptoms in patients with neuropsychiatric illnesses.

项目概要严重的社交障碍是许多神经精神疾病的共同症状，特别是社交障碍。识别和记住以前遇到过的人的能力（通常称为社交记忆）可以严重损害个人形成和维持社会关系的能力，大大降低在与社交障碍相关的大脑区域中，海马体因其独特的功能而引人注目。在社会记忆及其特殊的结构可塑性中发挥着重要作用，包括不断产生齿状回中出现的新神经元在整个成年期利用自然的结构可塑性。海马体可能是刺激神经回路和恢复社交记忆的重要途径因此，R01 提案的目标是揭示海马结构可塑性对功能的贡献。我们发表的研究表明，齿状回中的成年神经元是对于巩固和/回忆同种人的社会记忆是必要的，但成人出生的程度。神经元被招募到社会记忆痕迹中，并有选择地对社会记忆过程做出贡献成年神经元在海马体内形成多种细胞连接，包括与 CA2 的连接。虽然海马体的 CA2 区域尚未得到充分研究，但它已成为社交的重要枢纽。我们不知道成年神经元是否通过影响社会记忆回路和功能。在我们使用社会功能障碍小鼠模型 Shank3B 进行的初步研究中。 KO 小鼠，我们发现社交记忆受损以及海马体畸变，包括成年出生的小鼠数量减少与野生型同窝小鼠相比，成年神经元对 CA2 的传入神经元减少。使用化学遗传学激活 CA2 神经元和 CA2 到腹侧 CA1 通路，并能够挽救 Shank3B KO 小鼠的社会记忆功能障碍，表明该电路是关键干预点在这里，我们建议使用转基因、化学遗传学和药理学操作。结合行为学、组织学和体内电生理学分析来检验以下假设：成年神经元对 CA2 的传入神经支配对于调节社会记忆功能至关重要，并且针对该电路可以缓解社会记忆功能障碍。具体来说，我们将阐明这一点。成人出生的神经元优先招募到社会记忆印迹及其对社会记忆的选择性贡献记忆功能（目标 1），确定成年神经元传入 CA2 对 CA2 振荡活动的影响和社会记忆功能（目标 2），并探索增强海马成年神经元回路以改善 Shank3B KO 小鼠的社会记忆缺陷（目标 3）。研究成年神经元如何影响社会记忆回路和功能，以实现转变的长期目标我们如何减轻神经精神疾病患者的社会症状。