丘脑皮质环路HCN和TASK离子通道涉及全麻药物导致的慢波振荡分子机制

The cellular and molecular mechanisms of general anesthetics have not been elucidated. The research has experienced more than one century, put forward various theories and views, but are not completely accepted. In micro-level anesthetics can affect many ion channels, molecular targets; but the macro-studies indicate that eliminating of these proteins, ion channels only slightly change anesthesia actions. Recent studies have paid attention to the influence of anesthetics on the neural network, especially the views of increasing of EEG low frequency slow wave oscillation and inducing electrical signal interference across the brain by anesthetics attracted great attention, but we know little of how these changes caused by anesthetics. Based on the facts of important roles of thalamocortical loop on generating low frequency slow wave effect and some molecular candidate of anesthetics actions such as TASK, HCN and GABAA receptors are involved in the signal transferring in thalamocortical loop, we, therefore, propose that synergistic effect of anesthetics on TASK, HCN channels and GABAA receptors in the thalamocortical loop achieve the effect of general anesthesia, by increasing brain low-frequency slow wave generation, and interfering electrical signal connection between different areas of the brain. This proposal design and employ technologies of multi-electrode stimulation and recording, electroencephalogram in brain slices, dynamic patch clamp and computational neuroscience and method of double gene knockout mice to verify the above hypothesis, to explore the cellular and molecular mechanism of general anesthesia.

全麻药作用的分子机制一直没有被阐明。其研究经历了一个多世纪，提出了各种学说和观点，但都没有被完全接受。微观上观察到全麻药对很多离子通道、分子靶点都有作用；但宏观上剔除这些蛋白质、离子通道只是轻微改变全麻药的作用。最近的研究关注到全麻药对神经网络的影响，特别是全麻药通过增加脑电低频慢波振荡、干扰脑区的电信号联系的观点引起了极大关注，但全麻药怎样引起这些改变不得而知。本申请基于丘脑皮质环路在低频慢波振荡的重要作用以及一些被认为是全麻作用的候选靶蛋白比如TASK、HCN通道和GABAA受体均参与丘脑皮质环路的电信号传导的分析，提出全麻药通过影响TASK、HCN通道和GABAA受体在丘脑皮质环路协同作用增加低频慢波振荡的产生，干扰脑区之间的电信号联系从而达到全麻作用。本课题设计应用多电极刺激和记录、脑片脑电图、动态膜片钳和计算机神经科学技术和双基因剔除小鼠方法验证上述假设，探讨全麻作用的分子机制。