神经肽CRF经小脑核团环路对情绪活动及焦虑样和抑郁样情感障碍调控的机制研究

Cerebellar atrophy or lesion is not only characterized by motor incoordination and postural instability, but also manifested with anxiety, depression and social dysfunction. The past decade has witnessed significant progress in the role of cerebellum in non-somatic functional regulation. Recent studies have demonstrated that there are neural pathways directly and/or indirectly connecting the cerebellum with several important centers for emotional control, such as the ventral tegmental area and amygdala. However, the exact mechanisms and circuits underlying the cerebellar regulation of mood are still unclear. The central CRFergic system plays an important role in stress-related mood disturbance, and its dysfunction is considered to be one of the pathophysiological mechanisms of anxiety and depression. Interestingly, abnormal mRNA levels of CRF have been detected in the olivo-cerebellar system after acute or chronic stress, indicating that the central CRF may actively involve in the regulation of mood through the cerebellar related neural circuit. In this research, we will be using in situ hybridization, tracing, immunohistochemistry, electrophysiological recording and behavioral test, to define a previously unknown neural circuit for cerebellar nucleus in the control of emotion, to reveal new targets for CRF in mood disturbance, and to provide new insights into the etiology, pathophysiology, and therapeuctical strategy of anxiety and depression.

小脑萎缩或病变不仅表现出运动不协调和姿势不稳，同样也伴随着焦虑、抑郁和社交功能障碍。过去几十年来，关于小脑在非躯体性调控功能上的研究取得了重要进展。最近一系列的研究表明小脑与一些重要的情绪控制中枢如腹侧背盖区和杏仁核之间存在着直接或间接的环路联系。然而，目前关于小脑参与情绪情感调控的精确机制和神经环路基础仍然知之甚少。中枢CRF能神经系统广泛参与应激相关的情绪调控，其功能失调被认为是焦虑和抑郁样情绪障碍的病理生理机制之一。有趣的是，在急性或慢性应激刺激后，橄榄小脑系统中CRF mRNA的表达水平发生异常变化，提示中枢CRF能神经系统可能通过调节小脑介导的神经环路，参与对情绪功能的调控。因此，本项目拟采用荧光原位杂交、神经通路示踪、电生理学及行为学测试等手段，研究结果将首次确立CRF经小脑核团介导的情绪活动调控的神经环路，为焦虑症和抑郁症的病理生理机制和防治策略打开全新的视角。

CRF是一种主要由下丘脑室旁核合成并分泌的神经肽，CRF及其受体广泛参与应激反应和应激障碍相关行为调控。小脑核团接受直接的CRF能神经纤维投射，且表达大量的CRF受体。目前关于小脑核团CRF神经系统及相关环路是否参与应激诱导的情感障碍（焦虑症）的调控有待研究。本项目采用分子生物学、免疫组织化学、电生理学、神经药理学、分子遗传学和行为学相结合的方法，从分子、细胞、行为水平上，深入研究CRF对于小脑间位核神经元放电活动的调控，并探究小脑间位核调控情绪障碍（焦虑症和抑郁症）的神经环路基础。研究结果发现，下橄榄核核CRF能神经元与小脑间位核之间直接的神经环路连接，参与了焦虑症等情感障碍疾病的发生发展进程。基因遗传学操控或药理学阻断小脑间位核的CRF受体则能显著改善焦虑样行为。本项目已发表高水平SCI论文3篇，后续部分结果正在整理当中。综上，本项目研究结果将进一步验证中枢CRF神经系统的功能失调是情绪功能障碍的发病机制这一假说，也极大地丰富了情感障碍发病机制的神经环路基础，有助于更深层次认识情绪功能障碍发病的多系统性和多靶点性，为临床开发抗焦虑症药物提供可靠的理论基础