基于皮质边缘多巴胺能突触传递探讨催产素抗抑郁的作用机制

Corticolimbic system is the core system for the emotion and reward regulation. Diminished dopaminergic transmission in the key brain region of corticolimbic system, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), is proposed to involve in the pathophysiology of major depressive disorder. Oxytocin, a key neuromodulator that is important for the brain reward activity, also play a critical role in the regulation of dopaminergic system in the brain. In recent years, the role and mechanism studies of oxytocin in the mood regulation process have become hot research areas. However, the oxytocin’s antidepressant effects and the mechanism connections with dopaminergic transmission in the corticolimbic is still unclear. Our preliminary data showed that microinjection of oxytocin in the mPFC exerts antidepressant effect, further mechanism studies revealed that the antidepressant effect of oxytocin may be associated with the increased presynaptic dopamine release and subsequently enhanced dopaminergic transmission in the mPFC. On the primary basis, the present project plan to apply multi-type depressive animal models to overall evaluate the antidepressant effects of oxytocin that is delivered by microinjection into corticolimbic brain regions (mPFC/NAc); combining with key technologies such as microdialysis, optogenetics and electrophysiology to explore the antidepressant mechanisms based on the dopaminergic transmission in the corticolimbic system. The expected results of this project will provide more theoretical basis for deeper understanding of oxytocin on brain reward functional regulation and may expand the application of oxytocin in the clinical treatment of depression.

皮质边缘系统是调控情绪和奖赏的核心系统，其代表性脑区内侧前额叶（mPFC）和伏隔核（NAc）多巴胺能突触传递功能低下与抑郁症的发生理密切相关。催产素作为可调节大脑奖赏活动的关键神经调质，对脑内多巴胺系统的功能有重要调控作用。催产素的调控情绪作用及机理是近年的研究热点，但关于催产素的抗抑郁与其调节皮质边缘（mPFC/NAc）多巴胺能突触传递功能之间的关系目前仍不清楚。课题前期证实催产素mPFC微注射可产生抗抑郁样作用，该作用可能与其促进mPFC突触前多巴胺释放继而加强多巴胺能突触传递功能相关。在此基础上本项目拟应用多种抑郁症动物模型综合评估催产素皮质边缘（mPFC/NAc）微注射的抗抑郁作用；结合微透析、光遗传和电生理等关键技术，基于多巴胺能突触传递功能探明催产素抗抑郁作用机理。预期结果将为加深理解催产素对大脑奖赏功能的调控机理和拓展催产素在抑郁症临床治疗中的应用提供科学依据。

催产素是一种神经肽，参与调控大脑奖赏活动，其功能涉及情绪调节、社会奖赏、认知、学习记忆等重要生理过程，但催产素调控脑功能的详尽机理仍有待深入阐明。本项目主要探索了催产素调控抑郁焦虑情绪的分子、细胞和神经环路机制。结果显示催产素在内侧前额叶（mPFC）微注射可在正常和慢性社交失败应激小鼠模型中产生抗抑郁作用；机制研究发现催产素以催产素受体激活依赖性方式增加mPFC多巴胺水平， 通过激活多巴胺受体相关通路（D1/PKA/DARPP32）促进mPFC锥体神经元兴奋性突触传递功能。发现慢性疼痛焦虑症模型小鼠在其下丘脑室旁核（PVN）脑区催产素水平及催产素能神经元活性显著降低；通过化学遗传激活和抑制PVN催产素能神经元产生抗焦虑和致焦虑样作用，表明PVN催产素能神经元在调控焦虑样行为中的关键作用；催产素在中央杏仁核（CeA）微注射产生明显抗焦虑样作用，且通过化学遗传技术激活和抑制PVN-CeA催产素能神经环路产生抗焦虑和致焦虑样作用，揭示了PVN-CeA催产素神经投射在调控小鼠焦虑样行为中的关键角色。此外，本项目拓展性地探索了mPFC神经微环路和相关胞内信号通路在快速抗抑郁治疗中的关键作用，结果证明了mPFC脑区抑制性突触传递功能的完整性和nNOS信号通路激活在氯胺酮和一氧化二氮快速抗抑郁中的作用。本项目结果证明了催产素可通过促进mPFC脑区多巴胺能突触传递功能发挥抗抑郁效应，丰富了催产素调控多巴胺系统的研究内涵，为充分理解催产素系统和多巴胺系统二者协同调控大脑奖赏活动的理论提供了基础。此外，我们的结果确立了PVN催产素能神经元活动及PVN-CeA催产素能神经环路在调控焦虑中的关键地位，为深入理解焦虑症的病因机理提供了科学依据。