TREK-1介导的前扣带回θ节律异常在内脏高敏感形成中的作用及其机制研究

Central sensitization is closely related to the pathogenesis of irritable bowel syndrome (IBS). The visceral hypersensitivity can be enhanced or inhibited by electrically stimulating or drug destroying anterior cingulate cortex (ACC). This effect may be caused by the change of local field potential (LFP) in ACC. However, the mechanism of how the LFP in ACC regulates the visceral hypersensitivity is not clear. In previous studies of this team, it has been found that the θ rhythm of LFP in ACC was significantly abnormal in IBS rat with visceral sensation sensitization. The result indicates that the abnormal change of θ rhythm in ACC may play an important role in the pathogenesis of visceral hypersensitivity. Besides, the change of θ rhythm may be related to the abnormal expression of potassium ion channel subtype TREK -1 in ACC. As a consequent study, this study aims to investigate the role of changed θ rhythm in regulating visceral hypersensitivity by intervening the θ rhythm of ACC. Besides, this study aims to prove that TREK-1 is the basis of causing the change of θ rhythm and then explore its underlying neural mechanism. The IBS rat model, brain slice in vitro culture, in vivo multi-channel electrophysiological test, the technique of plasmid transfection, RNAi interference, etc. will be applied. It will serve as theoretical basis for exploring the underlying mechanism of central sensitization and elucidating the pathogenesis of IBS in the further.

中枢致敏与肠易激综合征（IBS）发病密切相关，研究发现，电刺激或药物毁损大脑前扣带回可增强或抑制内脏高敏感反应，该作用可能与前扣带回局部场电位改变有关，但前扣带回局部场电位变化如何影响内脏高敏感产生尚不明确。本课题组发现，内脏感觉致敏的IBS大鼠前扣带回局部场电位中θ节律成分的活性存在显著异常，提示前扣带回θ节律改变可能在内脏高敏感产生中起着重要作用，而其改变可能与前扣带回内钾离子通道亚型TREK-1表达异常有关。本研究拟通过制备内脏感觉致敏的IBS动物模型，采用特定脑区定位、在体多通道电生理等技术对前扣带回内θ节律活性进行干预，明确前扣带回θ节律改变在内脏高敏感中的作用；从体外脑片及动物体内水平，采用质粒转染、RNAi干扰、脑片膜片钳等手段，明确TREK-1是导致前扣带回θ节律改变的重要物质基础并探索其内在的神经电生理机制。为进一步探索中枢致敏的产生基础及阐明IBS发病机制提供理论依据。

前扣带回（ACC）的异常活化与精神应激相关肠易激综合征（IBS）发病有着密切联系，中枢致敏是其核心发病机制。前期研究证实ACC是应激相关中枢致敏机制的关键脑区，探讨其具体物质基础及神经电活性改变对阐明精神应激相关IBS的发病机制尤为关键。我们团队前期研究证实ACC中5-HT1A受体下调改变其局部区域神经活性介导内脏高敏感形成中发挥关键作用。我们对应激相关的内脏高敏感大鼠前扣带回局部场电位变化情况进行观察，发现IBS 大鼠模型前扣带回局部场电位中θ节律成分的活性较假性对照组及正常对照组显著增强。后通过离体脑片制备、脑片培养及50μM Carbachol 和0.8μM Kainate干预等方式成功诱导了θ节律。后采用在体基因干预、拮抗剂、激动剂微量药物注射、在体电生理、脑片膜片钳等手段证实前扣带回θ节律是5-HT1A受体调控内脏高敏感形成的关键环节，该研究提示前扣带回θ节律改变在应激相关IBS形成中的关键作用。后通过对IBS大鼠模型前扣带回内离子通道变化情况进行研究，发现动物模型组前扣带回区内的钾离子通道亚型TREK1 受体表达水平显著高于假性对照及正常对照组。后进一步采用TREK1受体激动剂及拮抗剂进行干预试验研究，结果发现TREK1受体拮抗剂可抑制前扣带回θ节律形成，该结果证实前扣带回内钾离子通道亚型TREK-1 可通过影响θ节律导致内脏高敏感的形成从而介导IBS 形成。进一步探索中枢致敏在肠易激综合征发病中的作用及内在机制研究提供理论基础，并为肠易激综合征发病机制的阐明及未来临床治疗策略的制定提供了新视角，并将会具有良好的社会效益。