GSK-3β/β-catenin信号通路与抑郁症海马神经再生关系的研究

Depression is the most common psychiatric illness that involves the disturbance of mood, yet the mechanisms underlying the pathophysiology are still poorly understood. Recently, increasing evidence demonstrated that adult hippocampal neurogenesis might have important implication in the neurobiological basis underlying the etiology and treatment of depression. Based on the effect of GSK3β/β-catenin on the regulation hippocampal neurogenesis, the present study will aim to investigate whether GSK3β/β-catenin is involved in the alteration of neurogenesis according to depression and antidepressant treatment. Firstly, we will investigate the expression of GSK3β/β-catenin in different areas of brain in a rat model of depression, chronic unpredictable mild stress (CUMS), and explore the relationship between the expression and the behavior changes. Furthermore, the hippocampal neurogenesis and behavioural tests will be evaluated under two opposing regime where GSK3β is suppressed by specific inhibitor or β-catenin is down-regulated by sh-β-catenin. Finally, we will investigate the effect of fluoxetine treatment on the expression of GSK3β/β-catenin in neuronal progenitor cells derived from hippocampus of fetal Sprague-Dawley rats and identify whether GSK3β/β-catenin is involved in the increased neurogenesis and behavior changes induced by fluoxetine treatment. We expect that these studies will contribute to our understanding of the mechanisms of depression and provide new target for treatment of depression.

抑郁症是一种常见的、严重危害人类健康的情感障碍性疾病，发病机制至今不明。近年来，"海马神经再生障碍"假说已成为抑郁症病因学研究领域的热点。基于GSK3β/β-catenin信号通路在海马神经再生中的重要调控作用，本研究从动物和细胞两个层面探讨GSK3β/β-catenin信号通路在抑郁症海马神经再生障及抗抑郁药促进神经再生中的作用。首先利用CUMS大鼠抑郁模型，探讨各脑区GSK3β/β-catenin信号通路的表达与抑郁行为变化的关系；然后利用特异性抑制剂和RNA干扰技术调节GSK3β/β-catenin信号通路活性，探讨其功能状态与海马神经再生和抑郁行为变化的关系；最后探讨抗抑郁药对神经前体细胞GSK3β/β-catenin功能状态的影响，同时深入分析该信号通路在抗抑郁药促进神经再生和改善抑郁行为中的作用。本研究将有助于阐明抑郁症发生的神经生物学机制，并为新型抗抑郁药物的开发提供依据。

基于GSK-3β/β-catenin信号通路在海马神经再生中的重要调控作用，本研究从细胞和动物两个层面探讨GSK-3β/β-catenin信号通路在抑郁症发病及抗抑郁药促进海马神经再生中的作用。在细胞研究中发现抗抑郁药物氟西汀可显著促进海马神经前体细胞的增殖，增加磷酸化Ser9-GSK-3β和细胞核β-catenin的蛋白表达；过表达不被降解的ΔN89 β-catenin可显著促进海马神经前体细胞的增殖，而抑制β-catenin的表达，神经前体细胞的增殖明显降低，并显著逆转氟西汀的促进神经前体细胞增殖作用；5-羟色胺1A受体特异性的拮抗剂WAY-100635可显著逆转氟西汀诱导的Ser9-GSK-3β磷酸化和细胞核内β-catenin的表达。在动物研究中发现慢性不可预知的温和应激（chronic unpredictable mild stress, CUS）模型大鼠的学习记忆功能明显减退，海马区磷酸化Ser9-GSK-3β、细胞总β-catenin、细胞核内β-catenin的表达明显降低；GSK-3β特异性的抑制剂SB216763可显逆转CUS大鼠学习记忆功能的减退，海马区过表达GSK-3β则导致正常大鼠出现抑郁样行为和学习记忆功能的减退；CUS可显著增加大鼠海马Wnt信号通路拮抗体Dkk-1的表达；长期皮质酮干预可显著促进海马区DKK-1的表达、抑制磷酸化Ser9-GSK-3β的表达，并导致大鼠学习记忆功能的减退。