Ghrelin的抗抑郁效应及中枢作用机制研究

Depression is a series of severe diseases also called as affective disorders or mood disorders with high prevalence. The "common cold of mental illness" also places a heavy burden on society. The low efficiency and many side effects of clinically available antidepressants stimulate the invention of new potent antidepressants. Nevertheless, the undefined mechanism of depression is the big obstacle of improving efficiency of antidepressant. Depression was identified as a multi-system disease, which is not a brain disease merely. The symptoms of depression involved in mood, cognizance, appetite, sleep and so on. Ghrelin is a peptide hormone produced and secreted in the stomach. Ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR1a) is expressed in numerous brain regions, such as hypothalamus, hippocampus, ventral tegmental area, rapphe nucleus, and so on. Most of these brain regions are involved in the etiopathology of depression. The hypothalamic effects of ghrelin are well known, and include food intake, body-weight regulation, glucose homeostasis, and sleep regulation. Ghrelin has also been more recently recognized as exerting other physiological functions, such as promoting learning and memory, enhancing reward and motivation, preventing neurodegeneration, and regulating mood, anxiety and depression. But there are merely several researches concerned about the effect of ghrelin on depression. In this project, we focus on the role of ghrelin-GHSR1a in depression and further pursue some researches on the underling neuronal circuitry and the molecular mechanisms involved in the effect of ghrelin on depression.

抑郁症的高发病率和严重的社会负担及抗抑郁药有效率低、副作用大等问题使得加强防治，寻找新的抗抑郁药具有重要的社会意义。而抑郁症的发病机制不明切实阻碍了新型抗抑郁药物的研发。抑郁症是一种"全身性"疾病，临床症状涉及情绪、认知、躯体等多个方面。因此，多器官、多脑区的系统研究被认为是阐明抑郁症发病机制的必经之路。ghrelin作为一种由胃合成、分泌的多肽类激素，其受体GHSR1a主要位于中枢神经系统的下丘脑、海马、腹侧被盖区、中缝核等多个脑区。而这些脑区多与抑郁症的发病机制有关。另已有研究提示ghrelin除促进摄食、调节睡眠外，还具有加强学习记忆、参与奖赏与动机形成、神经保护、致焦虑及抗抑郁的作用。本项目旨在抑郁症动物模型上，阐明不同脑区ghrelin受体GHSR1a在抑郁症发生发展过程中的变化和作用及ghrelin的抗抑郁效应及中枢机制，从而为开发新的抗抑郁药提供新的思路或借鉴。

抑郁症的高发病率和严重的社会负担及抗抑郁药有效率低、副作用大等问题使得加强防治，寻找新的抗抑郁药具有重要的社会意义。而抑郁症的发病机制不明切实阻碍了新型抗抑郁药物的研发。抑郁症是一种“全身性”疾病，临床症状涉及情绪、认知、躯体等多个方面。因此，多器官、多脑区的系统研究被认为是阐明抑郁症发病机制的必经之路。ghrelin 作为一种由胃合成、分泌的多肽类激素，其受体GHSR1a 主要位于中枢神经系统的下丘脑、海马、腹侧被盖区、中缝核等多个脑区。而这些脑区多与抑郁症的发病机制有关。另已有研究提示ghrelin 除促进摄食、调节睡眠外，还具有加强学习记忆、参与奖赏与动机形成、神经保护、致焦虑及抗抑郁的作用。本项目在CUS和CSDS两种抑郁症及焦虑症的动物模型上，观察到外源性给予ghrelin或者是GHSR激动剂具有显著的抗抑郁及抗焦虑的作用， 同时阐明在遭受外源性应激刺激时，机体的ghrelin-GHSR脑肠轴并未被抑制，反而被激活。该研究结果表明机体在遭受外源性应激刺激时，调动ghrelin-GHSR脑肠轴发挥抗抑郁抗焦虑作用去抵抗抑郁和焦虑行为的形成。此外，研究结果还表明ghrelin可能是通过促进海马神经发生、抗线粒体损伤、抗氧化应激等机制发挥抗抑郁抗焦虑作用。而电针和抗抑郁药是否通过进一步上调机体内的ghrelin-GHSR脑肠轴而上调海马神经发生，促进增殖型干细胞增殖、抑制静息型干细胞凋亡的作用，尚需进一步的研究阐明。但是，本项目的研究结果对于阐明ghrelin-GHSR在情绪调控中的作用具有重要的理论意义，为开发新的抗抑郁药提供新的思路或借鉴。