早年应激影响小鼠前额叶发育与功能的分子机制

The cerebral cortex undergoes dramatic growth during early postnatal development, which is characterized by the elaboration of neural connections and shaping of circuits. During this critical period, the cerebral cortex is extremely sensitive to adverse environmental factors such as early-life stress. Early-life stress may exert profound and persistent negative influences on the cerebral cortex, especially the development of medial prefrontal cortex (mPFC) and mPFC-dependent cognitive function. However, the underlying molecular mechanisms remain to be elucidated. By using the limited nesting and bedding material paradigm and applying morphological, behavioral, molecular, and pharmacological approaches, we aim to evaluate the effects of early-life stress on neuronal migration, the development of dendrites and dendritic spines, and mPFC-dependent spatial working memory and temporal order memory. Moreover, the involvement of key stress mediators (glucocorticoids and glucocorticoid receptors as well as corticotropin-releasing hormone and its type 1 receptor) will be investigated. Additionally, to further address the molecular mechanisms of early-life stress-induced mPFC maldevelopment and dysfunction, the expression levels of neurodevelopment-related molecules such as Emx2, Pax6, Fgf8, doublecortin, and nectins will be examined following postnatal stress exposure. In summary, our study will provide insight into the influences of early-life stress on the development and function of the prefrontal cortex, and identify the stress mediators and neurodevelopment-related molecules responsible for the detrimental effects of early-life stress.

个体在出生后早期，大脑皮层迅速发育，神经环路逐渐精细。在这一发育关键期，大脑皮层对不良环境因素如早年应激极为敏感。早年应激对大脑皮层尤其是前额叶的发育与相关认知功能具有显著而持久的负面影响，然而其分子机制尚未阐明。本研究选用限制性筑窝材料与垫料模型，通过形态学、行为学、分子生物学与药理学等多种手段，观察早年应激对小鼠内侧前额叶神经元迁移以及树突和树突棘发育的作用，评估早年应激对成年小鼠前额叶依赖性空间工作记忆与时间序列记忆的影响，并研究两大主要应激系统（糖皮质激素及其受体系统、促肾上腺素皮质激素释放激素及其1型受体系统）的调控作用。此外，检测早年应激之后神经发育相关分子如Emx2、Pax6和Fgf8等在内侧前额叶表达的改变，进一步探讨早年应激损害前额叶发育、结构与功能的分子机制。本研究预期揭示早年应激影响前额叶发育与功能的特点，并且有望发现介导早年应激负面作用的应激因子和神经发育相关分子。

个体在出生后早期，大脑皮层迅速发育，神经环路逐渐精细。在这一发育关键期，大脑皮层对不良环境因素如早年应激极为敏感。早年应激对大脑皮层尤其是前额叶的发育与相关认知功能具有显著而持久的负面影响，然而其分子机制尚未阐明。本研究选用限制性筑窝材料与垫料模型，通过形态学、行为学、分子生物学与药理学等多种手段，观察早年应激对小鼠内侧前额叶神经元迁移以及树突和树突棘发育的作用，评估早年应激对成年小鼠前额叶依赖性空间工作记忆与时间序列记忆的影响，并研究两大主要应激系统（糖皮质激素及其受体系统、促肾上腺素皮质激素释放激素及其1 型受体系统）的调控作用。我们发现早年应激可以持久损害小鼠前额叶和海马锥体神经元的发育轨迹，表现出应激动物树突生长受阻、突触形成障碍、突触细胞黏附分子nectin-1和nectin-3表达下调，动物的学习记忆出现明显损害。在应激期间给予促肾上腺皮质激素释放激素1型受体（CRHR1）拮抗剂安他拉明，可以阻断早年应激对前额叶与海马神经元结构、突触蛋白表达以及学习记忆的损害作用。与此相比，糖皮质激素受体拮抗剂米非司酮不具有此作用。这些结果提示CRHR1是介导早年应激损害小鼠前额叶结构与功能的核心因子，并为早年应激相关精神疾病的药物靶点研发提供了实验证据。