前扣带回MEK/ERK通路介导的级联反应异常在精神应激诱发的功能性胃肠病中枢致敏的机制研究

Central sensitization has been demonstrated to be closely correlated to the formation of the functional gastrointestinal disorders (FGIDs) induced by psychological stress. However, due to the complex material structures and functions of the brain, the pathological basis of central sensitization is still not clear. Psychological stress methods could be applied to establish visceral hypersensitive animal models, mimicking psychological stress related FGIDs in human. We applied in-vivo electrophysiology and genetic intervention on specific brain regions to study the mechanism of central sensitization, and found that the abnormal sensitivity of anterior cingulate cortex (ACC) played an important role in the regulation of gastrointestinal sensation reaction. It was found that the MEK/ERK pathway of ACC was significantly abnormal in visceral hypersensitive rats. The MEK/ERK cascade pathway is one important signal transduction and amplification channel in brain center. The abnormal change of this pathway could affect the processing or coding of the central nervous signal, therefore mediate some diseases. However, the mechanism of this process remains unclear. The mechanism of ACC sensitization will be explored, using techniques of neuropharmacology, molecular biology, and electrophysiology, etc., to locate the key point of the pathway, which will serve as theoretical basis of the brain intervention and specific substance target in future treatment of stress related FGIDs.

中枢异常致敏与精神应激相关功能性胃肠病（FGIDs）发病存在密切联系，然由于大脑中枢复杂的物质结构及机体调控功能，其参与介导FGIDs形成的具体发病机理仍未明确。采用不同精神应激方法可建立内脏高敏感动物模型，并模拟临床上精神应激相关的FGIDs。我们采用在体电生理、细胞膜片钳等手段对中枢致敏的内在机制进行初步探讨，发现ACC的异常致敏在调控胃肠感觉反应中发挥着重要的作用，研究中发现ACC内ERK/MEK通路在内脏高敏感大鼠显著异常。MEK/ERK级联通路作为大脑中枢重要的信号传导及信号放大通道，其异常可影响中枢神经信号的处理或编码从而介导疾病形成。但其内在的机制尚需进一步阐明。本研究拟采用神经药理学、分子生物学、电生理学等手段，对ACC致敏的内在机制进行深入探讨，探寻其通路中的关键环节及关键靶点，为精神应激相关FGIDs脑区干预及特定的物质靶标提供新的思路及理论依据.

功能性胃肠病(functional gastrointestinal disorders, FGIDs)又称脑-肠互动异常性疾病，临床发病率极高，难以治愈。精神应激被认为是FGIDs 发病的重要有关因素。目前认为其发病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。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。该研究首先采用慢性避水应激方法建立内脏高敏感动物模型，并对其排便情况及心理行为学变化进行记录分析，结果证实该动物模型可成功模拟临床上精神应激相关的FGIDs。后在动物模型基础上，采用在体电生理、脑片膜片钳、脑内微量注射以及分子生物学等手段，对精神应激相关功能性胃肠病的中枢致敏所涉及的关键脑区前扣带回内的物质基础改变与微环境调控两大关键科学问题进行进一步的深入研究。研究发现前扣带回中MEK/ERK级联放大通路在精神应激致敏内脏敏感信号反应中发挥着关键作用，STAT1/TREK1可能是ERK磷酸化介导慢性精神应激大鼠内脏敏感性增高的重要下游调控因子，TREK1通过影响θ节律（theta节律）参与介导内脏高敏感形成。本项目首次阐明前扣带回内MEK/ERK级联放大通路-激活STAT1/TREK1介导前扣带回theta节律增强在中枢致敏中关键作用，为未来精神应激相关功能性胃肠病中枢干预治疗理念及未来治疗策略的制定奠定坚实的理论基础。