Cadherins与nectins在青少年期慢性社会应激损害小鼠前额叶形态可塑性与功能中的作用

Adolescence is a critical developmental period, during which neural circuits undergo substantial structural and functional remodeling. The developmental plasticity of the adolescent brain, especially the prefrontal cortex, may make it particularly vulnerable to perturbations from adverse life events such as chronic stress, which may cause behavioral abnormalities and contribute to the onset of psychiatric disorders. However, it remains largely unknown whether and how chronic stress during adolescence would affect prefrontal cortex-mediated cognitive behaviors and its structures and functions. It has been recently proposed that synaptic cell adhesion molecules such as cadherins and nectins may be involved in the pathophysiology of stress-related mental disorders. Based on our previous findings and current research progress, using the chronic social instability stress paradigm, in this study we aim to examine the effects of chronic social stress during adolescence on prefrontal cortex-dependent cognitive behaviors and the synaptic structural plasticity and function in this region. The involvement of synaptic cell adhesion molecules in stress-induced structural remodeling and dysfunction will be investigated via in vivo viral-mediated knockdown or overexpression of related genes. This study will provide further understanding towards neurobiological mechanisms underlying adolescent stress-induced changes in cognitive behaviors, which we hope can shed light on the pathophysiology and treatment of stress-related psychoses, such as depression.

青少年期是大脑发育的重要阶段，期间神经环路构筑和功能不断成熟完善。由于大脑（尤其是前额叶）在该阶段的高度可塑性特点，不良生活事件如慢性应激可阻碍其发育与可塑性，损害认知与行为，进而诱发多种精神疾病。然而，目前关于青少年期慢性应激对个体认知行为及前额叶结构和功能影响的神经生物学机制研究相对欠缺。近年来，研究提示突触细胞黏附分子如cadherins、nectins表达水平的改变可能参与了应激相关精神疾病的发病。根据我们的前期研究基础和目前研究进展，本研究拟采用青少年期慢性社交不稳定应激小鼠模型，探讨青少年期慢性社会应激对小鼠认知行为及前额叶突触形态可塑性和功能的影响；并从突触细胞黏附分子入手，利用病毒载体介导的基因在体敲低或过表达技术，深入探讨突触形态和功能改变的可能机制。本研究将有助于了解青少年期应激相关认知行为损害的神经生物学机制，对于揭示抑郁症等精神疾病的病理机制及潜在治疗靶点提供帮助。

青少年期是大脑发育的重要阶段，期间神经环路构筑和功能不断成熟完善。由于大脑（尤其是前额叶）在该阶段的高度可塑性特点，不良生活事件如慢性应激可阻碍其发育与可塑性，损害认知与行为，进而诱发多种精神疾病。然而，青少年期慢性应激负面作用的分子神经生物学机制尚不明确。近年来，研究提示突触细胞黏附分子如cadherins、nectins表达水平的改变可能参与了应激相关精神疾病的发病。本研究选用效度较高的青少年期慢性社交不稳定应激模型，模拟现代社会青少年期复杂易变动的社会关系，重点考察青少年期应激对前额叶结构和功能的影响，并从突触细胞黏附分子nectin3入手，利用病毒载体介导的基因在体敲低或过表达技术，深入探讨青少年期应激所致前额叶结构和功能改变的可能分子神经生物学机制。结果发现，青春期应激破坏了成年小鼠空间工作记忆与社会记忆能力；下调了内侧前额叶nectin3的表达；干扰了小鼠前额叶锥体神经元树突及树突棘的正常发育。利用病毒转染技术特异性敲低或过表达内侧前额叶nectin3的表达，模拟或逆转了青少年期应激的上述负性效应。上述实验结果初步阐明了神经粘附因子nectin3在青少年期应激引起小鼠前额叶结构和功能改变中的参与作用，为抑郁症等应激相关精神疾病的治疗提供了新的思路。