RAGE信号通路在慢性应激诱导抑郁样行为中的作用机制研究

Recent several clinical and animal studies have indicated the association of RAGE/NF-κB signaling pathways with major depression. However, how RAGE signaling pathways are involved in the pathophysiological mechanisms of major depression are still poorly understood. Our preliminary study found chronic unpredictable stress increased the expression of RAGE in hippocampus CA1 area while reduced the expression of RAGE in DG area. The expression of RAGE is inducible in mature cells but persistent in embryo cells. The present hypothesis is chronic stress may induce the RAGE expression of mature neurons, activate the inflammation reaction. Meanwhile the RAGE expression of premature neurons was inhibited as well as neurongenesis leading to the development of depression. The present study will investigate the different roles of RAGE/NF-κB signaling pathway in hippocampus CA1 and DG area in depressive-like behavior by using chronic stress, antidepressant, RAGE gene silence and over-expression. The findings will be helpful to learn better the neurobiological significance of RAGE/NF-κB signaling pathway as well as its potentials to become a target for antidepressant treatment.

目前一些临床和基础的研究提示了RAGE/NF-κB信号通路与抑郁症的相关性，但该通路是否介导了抑郁症发病的病理生理机制还有待阐明。本项目预实验的结果发现在慢性不可预见性应激大鼠抑郁模型上海马CA1区RAGE表达水平升高，而DG区RAGE表达水平减少。RAGE在成熟期细胞呈可诱导性表达，而在胚胎期细胞呈持续性表达。据此本研究假设慢性应激可能通过诱导CA1区成熟神经元表达RAGE，激活炎症信号途径，同时抑制DG区未成熟神经细胞RAGE的表达，抑制神经再生，最终导致抑郁症的发生。本研究通过慢性应激、抗抑郁药、基因沉默和过表达等干预手段研究了RAGE/NF-κB信号通路在CA1区和DG区作用的差异，以阐明RAGE/NF-κB信号通路介导抑郁样行为的机制。研究结果有助于更好的了解RAGE/NF-κB信号通路的神经生物学意义，以及其作为抑郁症治疗药物靶点的潜力。