缝隙连接功能变化对抑郁模型大鼠海马神经重塑的影响及中药干预研究

Depression is a common affective disorder disease with an increasing incidence year by year but the pathogenesis is still unknown. Recent studies suggest that the decline of hippocampal neuronal plasticity is highly related to depression. Gap junctions play an important role in the normal functions of neurons as well as in the maintenance of the internal and external environment stability of nerve cells. Gap junctions are also involved in nerve regeneration and functional remodeling, and its dysfunction will induce core symptoms of depression. Based on modern medical understanding of the pathogenesis of depression, the purpose of this project is to prepare stressing rat model of depression via chronic stimulation and intervene with traditional Chinese medicine. This project is also going to clarify the gap junction function of the changing pattern of hippocampal nerve remodeling, which will be mainly achieved in two directions. From the microscopic and submicroscopic level, observation of the neuronal cell morphology, structure and number of changes are to be performed, while from the molecular level, analysis of the hippocampus of the gap junction protein, connexin phosphorylation and gap junction binding protein expression changes also lead to the goal. The study contributes to understanding the pathogenesis of depression, providing theoretical and experimental basis to traditional Chinese medicine treatment of depression, and to laying the foundation for new drug development of Chinese medicine treatment for clinical use.

抑郁症是一种常见的情感性精神障碍疾病，其发病率逐年上升但发病机制不明。近年来的研究提示抑郁症与海马神经可塑性下降密切相关。缝隙连接对维持神经细胞内外环境稳定及神经元正常功能中起重要作用，参与神经再生与功能重塑，其功能障碍会诱发抑郁症的核心症状。本课题旨结合现代医学对抑郁症发病机理的认识，采用慢性应激方法制备抑郁模型大鼠并用中药进行干预，从显微和亚显微水平观察海马神经细胞形态结构和数量的改变，从分子水平分析海马区缝隙连接蛋白、缝隙连接蛋白磷酸化和缝隙连接相关结合蛋白的表达变化，以阐明缝隙连接功能变化模式对海马神经重塑的影响。该研究有助于认识抑郁症的发病机制，为临床采用中药复方治疗抑郁症提供理论和实验依据，为开发治疗抑郁症的中药新药奠定基础。

抑郁症是一种常见的情感性精神障碍疾病，其发病率在逐年上升。近年来的研究表明抑郁症与海马神经可塑性下降密切相关。缝隙连接对维持神经细胞内外环境稳定及神经元正常功能中起重要作用，参与神经再生与功能重塑。. 本研究采用慢性应激方法制备抑郁模型大鼠并用百事乐胶囊进行干预，通过敞箱实验、糖水偏好度检测、水迷宫实验研究了大鼠的行为学变化，通过HE染色、尼氏染色和电镜观察了海马神经细胞结构和功能变化，BrdU免疫组织化学法观察了海马增殖细胞，免疫组织化学法、RT-PCR法和Western blot法染色法检测了海马缝隙连接蛋白和缝隙连接相关蛋白的表达变化。结果表明，百事乐胶囊具有促进慢性应激抑郁大鼠的体质量增加，提高大鼠的自发活动能力、对新奇环境的探索能力以及对幸福事件的反应性；具有神经保护作用，能减轻慢性应激引起大鼠海马神经元的萎缩和凋亡，并有海马神经功能恢复的作用。百事乐胶囊的促进海马神经再生作用主要与激活海马DG区NPCs有关。百事乐胶囊促进慢性应激抑郁大鼠神经可塑性作用可能与提高GFAP、MAP2、SYP、BDNF、Cx32、Cx36、Cx43、β-catenin、N-Cadherin、ZO-1和 Caveolin-1的表达，下调Cx43的磷酸化和CTGF的表达有关。缝隙连接的功能变化可能是百事乐胶囊促进慢性应激抑郁大鼠海马神经可塑改变的重要机制，而Cx43及其磷酸化以及缝隙连接相关蛋白对缝隙连接的调节作用可能在其中发挥了重要作用。. 本项目分析了百事乐胶囊对缝隙连接蛋白、缝隙连接蛋白磷酸化和缝隙连接相关结合蛋白的表达变化，阐明了缝隙连接功能变化对海马神经重塑的作用。该研究为进一步认识抑郁症的发病机制，为临床采用中药复方治疗抑郁症提供了理论和实验依据，为开发防治抑郁症的中药新药奠定了基础。