能量信号分子OEA调控伏隔核区突触传递及可塑性对抑郁症的作用及机制

A variety of metabolic hormones have antidepressive effect. Chronic stress induces rewarding and motivation deficits and mal-synaptic adaptation in nucleus accumbens, which has been considered as the main cause of anhedonia in major depression. Oleoylethanolamine (OEA) is a gut anorexic messenger. It could rescue dopamine deficiency in dorsal striatum and enhance rewarding and motivation. However it is unknown whether OEA has antidepressive effect or not. Our recent work reveals that OEA was decreased in the intestine and serum of depression susceptible mice. We also found that exogenous OEA had anti-depressive effect, and alleviated dopamine deficiency in mice exposed to mild chronic unexpected stress. Given increased dopaminergic activity induced by OEA，we hypothesize that OEA has the ability to rescue stress-induced rewarding and motivation deficits，mal-synaptic adaptation in NAc and subsequently enhance the resistance to depression. This project will unravel the antidepressive effect and mechanism of OEA by electrophysiology, opotogenetics, molecular biology, immunocytochemistry, high performance liquid chromatography and behavioral test. We aim to find the clue for novel targets for the treatment of depression.

多种能量代谢激素有l良好抗抑郁作用。慢性应激导致奖赏和动机行为缺陷，且抑郁症中的快感缺失与伏隔核区突触可塑性异常密切相关。油酰单乙胺（Oleoylethanolamine，OEA）是由小肠分泌的一种抑制食欲的脂肪酸。OEA通过增加背侧纹状体多巴胺的分泌，改善食物动机和奖赏行为障碍。但OEA是否有抗抑郁作用尚未阐明。我们预实验发现：抑郁敏感鼠肠道和血液中OEA含量显著下降；外源性补充OEA则减轻抑郁敏感鼠伏隔核区多巴胺分泌缺陷，且改善慢性应激所致的抑郁样行为。鉴于伏隔核区突触传递及可塑性异常与抑郁症的密切关系，我们认为OEA可通过改善多巴胺通路功能障碍，减轻伏隔核区突触传递及可塑性损伤，对抗抑郁症的发生。本项目拟结合电生理、光遗传、分子生物学、免疫荧光、HPLC和行为学实验技术，探讨能量代谢信号分子OEA对慢性应激所致抑郁样行为的作用及机制。为抑郁症药物治疗提供新靶点和实验依据。

多种能量代谢激素具有良好的抗抑郁作用。已有研究证明慢性应激导致奖赏和动机行为缺陷，且抑郁样行为中的快感缺失与NAc脑区突触可塑性异常密切相关。油酰单乙胺（Oleoylethanolamine，OEA）是由小肠分泌的一种抑制食欲的脂肪酸。OEA通过增加背侧纹状体多巴胺的分泌，修复食物动机和奖赏行为障碍。但OEA是否有抗抑郁作用和具体机制尚未阐明。本项目结合电生理、分子生物学、免疫荧光、高效液相色谱法和行为学实验技术，结果发现OEA通过抑制超激化激活钾电流增加中脑腹侧被盖区 （ Ventral tegmental area，VTA）脑区多巴胺能神经元的放电，并逆转慢性应激所致的抑郁样行为。此外，化学遗传抑制VTA脑区到伏隔核区（nucleus accumbens , NAc)的多巴胺能投射则取消OEA的抗抑郁作用。因此我们得出如下结论：OEA通过增强奖赏和动机行为对抗抑郁症的发生。本项目为抑郁症药物治疗提供新靶点和实验依据。