出生后发育期社交认知记忆的形成机制研究

Social recognition memory is evolutionary conserved behavior in mammals to distinguish strangers and partners. The ability relies on the formation and functional establishment of cognition-related nucleus, which are gradually mature as development. Brain development retardation results in abnormal circuit connectivity, in particular hippocampus, core area for memory and cognitive control, which causes severe cognitive and social disorders such as autism. However, the nucleus responsible for social memory formation during development and underling molecular mechanism remain partially understood. The proposed studies will focus on the mechanism of social cognitive memory formation at juvenile period and by using behavioral and biological methods combined with functional analysis to clarify structural and functional changes in the Lnx1-EphB complex mediated hippocampal CA3 area, and to reveal the mechanisms of this signaling in regulating social memory during critical period of development. Our studies would lead to an increased understanding of the mechanisms for social cognitive behavior, which helps bring a novel potential therapeutic target for treatment of neurodevelopmental disorders.

社交认知记忆是哺乳动物长期进化过程中形成的一种区分同伴与陌生伙伴必备的能力。这种能力依赖于认知相关核团的形成与功能的建立，并伴随着发育过程的进行而逐渐完善。脑发育迟缓导致这些特异核团神经环路连接发生异常，尤其是调控认知与记忆的中心枢纽海马结构的异常，产生严重的认知与社交行为障碍，如自闭症。然而关于早期大脑发育调控先天性社交记忆形成的具体核团以及相关的分子机制尚不明确。本项目围绕调控早期社交认知记忆的分子形成机制这一核心问题，结合行为学，细胞生物学和各种功能检测等实验手段，研究发育关键期Lnx1-EphB受体复合物介导的海马CA3区神经元的结构和功能变化过程，明确该信号转导对社交记忆形成的调控机制。本研究将有助于深入理解早期社交认知形成分子机制，并带来新的神经发育性疾病治疗靶点。

社交行为是指在特定环境下不同个体之间相互往来和交流的社会活动，是生存和繁衍至关重要的环节。而这个过程中，记住并辨别同伴是社交行为的基础。人类疾病状态或者小鼠发育异常往往伴随着社交认知的异常，而这与大量的突触兴奋性受体以及对应的PDZ结合蛋白的基因突变有着密不可分的关系。然而，在出生后发育阶段，哪些关键蛋白特异性表达并介导了初始社交行为仍有待研究。对此，本项目鉴定了一个在发育阶段海马CA3区特异表达的PDZ支架蛋白能够调控初始社交行为。通过基因敲除手段发现Lnx1缺陷会导致海马内部亚区域的神经元活性异常，以及幼年时期对熟悉同伴的识别缺陷并发展至成年的认知异常。进一步机制解析发现Lnx1缺失会导致突触后NMDA受体功能受损，阻止NMDAR-EphB2受体复合物形成从而影响突触传递功能并最终导致社交认知缺陷。因此，本项目围绕发育早期社交认知的形成机制这一核心问题，阐述了Lnx1-NMDAR-EphB2复合物调控社交缺陷的发生发展分子机制，为我们更加深入了解并治疗情感障碍如自闭者疾病提供了新的思路。