5-HT1A受体下调介导的前扣带回活性改变在精神应激诱发内脏高敏感的作用机制研究

Visceral hypersensitivity induced by psychological stress is closely correlated to the abnormal activation of anterior cingulate cortex (ACC). In-depth investigation of the pathological basis of this visceral hypersensitivity will significantly contribute to elucidating the pathogenesis of functional gastrointestinal disease (FGIDs). From our preliminary observation and experimental investigations, it shows that the visceral hypersensitivity induced by psychological stress may be mediated by the change of local neural activity of ACC. This local neural activity change of ACC may be caused by down-regulation of 5-HT1A receptor, in which process the NMDA receptor phosphorylation may play a critical role. Based on above investigations, we will explore the change of visceral sensation, ACC activity and signal transduction pathway, which were caused by psychological stress stimulus. We will also identify the role of central sensitization in the formation of visceral sensation and corresponding molecular basis. The rat model of chronic mental stress and the technique of brain slice in vitro culture will be applied. The research will be conducted in neural pharmacology, molecular biology, and physiology aspects of view. It will serve as theoretical basis for the mechanism research of stress related FGIDs, and scientific basis for potentially new therapeutic strategies and targets.

前扣带回（ACC）的异常活化与精神应激诱发的内脏高敏感反应有着密切联系，深入探讨其具体物质基础对阐明精神应激相关功能性胃肠病（FGIDs）的发病机制尤为关键。既往研究成果及前期预实验提示：精神应激诱发的内脏高敏感反应可能由ACC中5-HT1A受体下调改变其局部区域神经活性介导，其中NMDA受体磷酸化可能是5-HT1A受体发挥作用的一个关键环节。在此基础上，拟通过慢性精神应激大鼠模型在体研究及脑片体外培养技术，运用脑区质粒转染和RNA干扰技术，结合神经药理学、分子生物学、电生理学等手段，研究精神应激刺激后内脏感觉、ACC的活性及其信号转导通路的改变，以新视角探讨中枢致敏在内脏感觉形成中的作用及功能改变的分子基础，为精神应激相关FGIDs发病的机制研究提供重要的理论依据，并为进一步寻找新的治疗策略和靶点提供科学依据。

功能性胃肠病临床发病率极高，精神应激是其发病的重要诱因之一，其症状的产生与内脏感觉的高致敏状态有关，迄今仍是医学研究的热点及难题。2016年刚刚公布的ROMEⅣ共识中将功能性胃肠病更名为脑-肠互动异常，强调脑-肠互动异常是与神经胃肠病学和脑-肠互动等多方面有关的一组疾病，其症状产生与精神因素、中枢神经系统(CNS)处理功能异常密切相关。然而中枢神经系统如何介导胃肠道症状产生，与精神应激诱发的内脏高敏感反应有着怎么样的内在联系，尚不明确。既往有研究显示：前扣带回（ACC）的异常活化与精神应激诱发的内脏高敏感反应有着密切联系， 深入探讨其具体物质基础对阐明精神应激相关功能性胃肠病（FGIDs）的发病机制尤为关键。该研究针对ACC活性变化、物质基础改变与微环境调控三大关键科学问题展开深入研究，采用特定脑区定位及药物微量注射、在体多通道电生理记录仪及电刺激、脑区质粒转染和 RNA 干扰技术、脑片膜片钳等手段，明确前扣带回是中枢致敏机制的关键脑区，其胞膜上5-HT1A受体下调激活细胞内MER/pERK通路，诱发theta节律增强，引起中枢致敏。该项目首次阐明了“ACC内5-HT1A受体下调-激活MER/pERK通路-theta节律增强”可能是精神应激相关的功能性胃肠病中枢致敏机制的关键所在，为提出“特定脑区经颅低频磁刺激改善精神应激相关功能性胃肠病患者的临床症状”这一新的治疗理念奠定理论基础.