早年应激与nectin-afadin系统调控海马环路发育与可塑性的分子机制

Early environmental factors interact with genetic background to shape the development and function of brain circuits. Adverse early environment, especially early-life stress, impairs the development and plasticity of neural circuits and serves as a key risk factor for psychiatric disorders. Therefore, it is crucial to unravel the molecular mechanisms underlying the detrimental effects of early-life stress on neural circuits. Recent studies by the applicant highlight the importance of the nectin-afadin system in mediating stress-induced hippocampus-dependent memory deficits. However, its role in hippocampal development and plasticity remains to be elucidated. The current study aims to investigate the influences of early environmental factors on the expression levels of nectin-afadin system-related molecules in the mouse hippocampus, the structural and functional organization of the entorhinal-CA1 pathway as well as learning and memory. Moreover, by disrupting the function of the nectin-afadin system pre- or post-synaptically, the involvement of nectins and l-afadin in the development and plasticity of the entorhinal-CA1 pathway will be examined. To further uncover the molecular substrates of stress-evoked hippocampal abnormalities, the potential roles of the downstream molecules of the nectin-afadin system in modulating the negative stress effects will be explored. This study will reveal the characteristics and molecular mechanisms of the influences of early environmental factors, especially early-life stress, on the development and plasticity of neural circuits, and provide insight into the pathophysiology of stress-related psychiatric disorders and the development of novel therapeutic strategies.

早年环境因素与个体遗传背景共同调控大脑神经环路发育与功能。有害环境因素，尤其是早年应激，损害神经环路发育与可塑性，是多种精神疾病的重要风险因素。因此，明确早年应激影响神经环路的分子机制至关重要。申请人最新研究发现，nectin-afadin系统参与应激对海马相关记忆的损害作用，然而该系统如何调控海马发育与可塑性有待深入研究。本研究旨在探讨早年环境因素对小鼠内嗅皮层-海马CA1环路的nectin-afadin系统分子表达与形态功能组构以及学习和记忆的影响。通过在突触前和突触后水平干扰nectin-afadin功能，研究该系统在海马环路发育与可塑性中的作用。此外，探索介导早年应激负面效应的nectin-afadin下游分子，深入阐述应激所致海马功能障碍的分子机制。本研究预期揭示早年环境因素尤其是早年应激调控神经环路发育与可塑性的特点与分子基础，为应激相关精神疾病机制研究与新药研发提供理论依据。

早年环境因素与个体遗传背景相互作用，共同调控大脑神经环路发育与功能。有害环境因素，尤其是早年应激，损害神经环路发育与可塑性，是多种精神疾病的重要风险因素。因此，探讨早年应激损害神经环路尤其是与认知功能密切相关的海马环路的分子机制至关重要。本项目结合分子生物学、形态学和行为学等方法，探讨早年应激对小鼠内嗅皮层—海马CA1环路nectin-afadin系统分子表达、环路组构与功能以及学习记忆的影响，进而探索介导早年应激负面效应的nectin-afadin系统下游分子。结果表明，早年应激持久下调内侧内嗅皮层（medial entorhinal cortex，MEC）和海马CA1区nectin-1、nectin-3蛋白的表达水平，导致MEC—CA1环路特异性突触发育障碍，进而损害小鼠成年后的学习记忆。在幼年期敲低小鼠MEC的nectin-1而非nectin-3的表达水平可以模拟早年应激对突触发育和学习记忆的不良效应。此外，我们的工作亦揭示了：1）nectin-3在海马齿状回神经元发育、结构可塑性和记忆中具有重要作用；2）nectin-1表达水平减少与慢性应激所致旁嗅皮层突触可塑性损害密切相关；3）calbindin是nectin-afadin系统的重要下游分子，海马兴奋性神经元calbindin表达下调介导了早年应激所致认知损害。综上，本项目揭示了早年环境因素尤其是早年应激调控海马相关环路发育与可塑性的分子机制，为应激相关精神疾病的基础研究与新药研发提供了理论依据。