BDNF与CRHR1在早年应激损害小鼠海马可塑性中的调控作用

早年应激可影响海马发育与可塑性，损害认知功能与行为，是某些精神疾病如抑郁症和焦虑症的重要风险因素。然而，早年应激负面作用的分子神经生物学机制尚需深入研究。近年研究结果提示，早年应激可能影响BDNF-TrkB系统与CRH-CRHR1系统的表达与功能。然而，二者在海马内是否存在相互作用、二者如何参与早年应激的不良影响尚未明确。本项目以我们前期工作为基础，研究早年应激对海马BDNF与TrkB受体表达的影响。同时，结合条件性海马BDNF敲除小鼠，研究早年应激与早期BDNF敲除对海马锥体神经元形态可塑性与海马相关行为的影响。在此基础上，探讨CRH-CRHR1信号通路对BDNF-TrkB系统的调控作用及二者在早年应激损害海马形态与功能可塑性中的作用机制。本研究预期初步阐明BDNF与CRHR1在早年应激对海马形态与功能负面影响中的作用。本研究结果将有助于深入理解早年应激相关认知障碍及抑郁症的病理学机制。

Early-life adverse experiences compromise the development and plasticity of the hippocampus, impair cognitive function and behavior, and increase the risk to develop psychiatric disorders such as depression disorder and anxiety-related. However, the molecular and neurobiological mechanisms underlying the negative effects of early-life stress are still not fully understood. Recent findings indicate that early-life stress may affect the expression levels and functioning of the BDNF-TrkB and CRH-CRHR1 systems. However, it is unclear whether the two systems interact in the hippocampus and how they are involved in early-life stress-evoked abnormalities. Based on our previous work, this study aims to examine the effects of early-life stress on the protein expression levels of BDNF and TrkB receptor in the hippocampus. Moreover, in combination with conditional hippocampal BDNF knockout mice, the effects of early-life stress and postnatal reversible BDNF knockout on the structural plasticity of hippocampal pyramidal neurons and hippocampus-dependent behaviors will be studied. In addition, the regulation of BDNF and TrkB by CRH-CRHR1 signaling as well as their involvement in stress-induced structural and functional impairments of the hippocampus will be investigated. Our findings may elucidate the essential roles of BDNF and CRHR1 in the adverse effects of early-life stress on hippocampal morphology and function, and shed light on the pathophysiology of early-life stress-related cognitive dysfunction and depression.