Hippocampal adult-born neurons in social memory circuits

项目总结 严重的社会功能障碍是许多神经精神疾病的共同症状。特别是，美国的财政赤字 识别和记住以前遇到的个人的能力-通常被称为社会记忆-可以 极大地损害了个人形成和维持社会关系的能力，大大减少了 生活质量。在与社交障碍相关的大脑区域中，海马体是值得注意的，因为它 在社会记忆中的重要作用及其特殊的结构可塑性，包括连续产生 成年期齿状回中的新神经元。利用自然产生的结构可塑性 海马体可能是刺激神经回路和恢复社会记忆的一种有价值的方法 功能。因此，R01方案的目标是揭示海马区结构可塑性对 社会记忆回路。我们发表的研究表明，成年出生的齿状回神经元 对于巩固和/或回忆共同细节的社会记忆来说是必要的。然而，成年出生的人在一定程度上 神经元被招募到社会记忆痕迹，并选择性地对社会记忆过程做出贡献 未定。成年出生的神经元在海马区形成多个细胞连接，包括与CA2的连接 神经元。虽然在很大程度上没有得到充分的研究，但海马体的CA2区域已经成为社交网络的关键枢纽 记忆功能。我们不知道成人出生的神经元是否通过 它们与CA2的联系。在我们使用社会功能障碍的小鼠模型进行的初步研究中，Shank3B Ko小鼠，我们发现社会记忆受损并伴有海马区异常，包括较少的成年出生 与野生型相比，成年出生的神经元对CA2的传入减少。然后我们 利用化学遗传学激活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，提示该回路是一种关键的干预点 提高功能。在这里，我们建议使用转基因、化学遗传和药物操作。 结合行为学、组织学和活体电生理分析来检验这一假设 成年神经元对CA2的传入神经支配在调节社会记忆功能中起着关键作用。 以这个回路为靶点可以缓解社会记忆功能障碍。具体地说，我们将澄清 社会记忆印记中优先招募成年出生的神经元及其对社会记忆的选择性贡献 记忆功能(目标1)，确定成年出生的神经元传入CA2对CA2振荡活动的影响 和社会记忆功能(目标2)，并探索增强成年海马神经元回路的改善 Shank3B KO小鼠的社会记忆缺陷(目标3)。这些研究将提供一种机械性的理解 关于成年出生的神经元如何影响社会记忆电路和功能的长期目标是转变 我们如何缓解神经精神疾病患者的社会症状。

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.