GnRH信号通路在成体海马神经发生中的作用及其对小鼠抑郁样行为的影响

Depression is a serious mental disorder, and adult hippocampal neurogenesis play an important role in the effects of clinical antidepressants. In our preliminary experiments, we found that there is co-localization of Gonadotropin-Releasing Hormone receptor (GnRHR) and immature neuron marker DCX in the hippocampal dentate gyrus of adult mouse. And the promoting (such as environmental enrichment or voluntary exercise) or the suppressing (chronic restraint stress) neurogenesis intervention could enhance or decrease the expression of GnRHR and DCX in the hippocampus of mice, respectively. Moreover, Gonadotropin-Releasing Hormone (GnRH) treatment could rescue the down-regulated DCX and depression-like behaviour induced by chronic restraint stress in mice. Thus we infer that activation of GnRH signaling could promote adult hippocampal neurogenesis, which then prevent the impaired neurogenesis and improve the depression-like behaviour induced by chronic restraint stress in mice. This project intends to verify the concept through the in vitro and in vivo model by using behavioral, morphologic and biological methods. The result would facilitate our understanding of the mechanism underlying the adult hippocampal neurogenesis, and provide new target in the prevention of depression.

抑郁症是危害人类健康的重大疾病之一，成体海马神经发生及其调控对抑郁症的防治具有重要意义。我们预实验发现小鼠海马齿状回促性腺激素释放激素受体（GnRHR）与未成熟神经元标记物DCX共表达，促成体神经发生的行为干预（丰富环境刺激与自主运动）或者抑制神经发生的干预（慢性限制应激）分别上调或者下调小鼠海马GnRHR与DCX的表达；促性腺激素释放激素（GnRH）干预逆转慢性限制应激小鼠海马DCX的低表达，并改善其抑郁样行为。我们提出以下科学假说：GnRH可能是促成体神经发生因子，并且对慢性限制应激所致海马神经发生障碍具有保护作用，从而产生抗抑郁样效应。为了验证这一假说，本项目结合行为学、形态学与分子生物学的方法，从离体和在体两方面阐述GnRH信号通路对成体海马神经发生及小鼠抑郁样行为的影响。本研究有助于揭示调控成体神经发生的新机制，为抑郁症的防治提供新的靶点。

抑郁症是一种以情绪低落、快感缺失和认知功能障碍为主要临床症状的精神类疾病，具有发病率高、治愈率低、易复发等特点，给患者、家庭和社会造成沉重的负担，深入研究抑郁症发病机制、发现新的靶标意义重大。GnRH是下丘脑肽能神经元分泌的肽类物质，经典的理论认为它主要通过下丘脑-垂体-性腺轴调控生殖功能，申请人前期研究表明GnRH具有极其重要的垂体外功能，尤其是抗抑郁样作用，其机制与MAPK介导的成体海马神经发生有关，因此本研究主要从多个角度阐明GnRH是否具有抗抑郁作用及其发挥抗抑郁作用的分子机制这一科学问题。研究发现：（1）GnRH激动剂曲普瑞林可以改善慢性限制应激、早期社会隔离应激、LPS炎症、慢性疼痛诱导的小鼠抑郁样行为；（2）使用GnRH受体拮抗剂西曲瑞克或者采用携带GnRHR shRNA慢病毒阻断GnRH信号均可逆转曲普瑞林对LPS小鼠抑郁行为的改善作用；（3）外源性给予曲普瑞林对LPS小鼠海马GnRH及血浆睾酮含量无影响；（4）LPS所致抑郁模型小鼠海马内小胶质细胞和星形胶质细胞异常激活，炎症因子大量释放，谷氨酸能信号异常，海马神经发生降低；而外源性给予GnRH激动剂曲普瑞林可以逆转上述异常表现。因此，本项目的研究证实了GnRH具有抗抑郁作用；明确了GnRH可以通过抑制LPS模型小鼠海马内小胶质细胞和星形胶质细胞的活化，减少炎症因子的释放，促进海马神经发生，从而改善抑郁行为；揭示了GnRH具有重要的垂体外功能，为抑郁症的防治提供了新的靶点。