癫痫异常网络导致认知行为障碍的分子基础

Epilepsy, a common neurological disorder characterized by paroxysmal seizure attack, is based on formation of abnormal brain circuit. Patients with epilepsy always showed prominent cognitive impairment (especially for temporal lobe epilepsy). The abnormal brain circuit could be a major course of the cognitive decline in epilepsy, however, now the mechanism underlying the cognitive impairment remains unclear and we are still short of effective preventive and treating method. Latest studies and our preliminary data indicate that hippocampal circuit malfunction may be the crucial basis of cognitive impairment in temporal lobe epilepsy; meanwhile, IL1β may promote cognitive impairment and hippocampal circuit malfunction by regulating GABAergic neurons. In this study, we plan to test the above hypothesis both clinically and experimentally. To investigate the relationship between hippocampal circuit malfunction, we will use various techniques including fMRI, FDG-PET, optogenetic method, low frequency stimulation, in vivo field potential recording, neural unit discharge recording and some other electrophysiological methods; we also plan to use RNA interference, gene knock-out mice and pharmacological method to elucidate the role of IL1β in epilepsy-induced cognitive impairment and related mechanisms. Our study will shed light on the understanding of cognitive decline in epilepsy as well as help to find effective preventive and curative strategy.

癫痫是以脑内异常神经环路形成为基础的发作性疾病，患者还会出现认知功能障碍（尤其是颞叶癫痫），而癫痫异常神经环路可能是造成认知功能障碍的主要原因，但其发生机制尚不清楚，也缺乏有效的防治手段。新近的研究和课题组的前期研究提示，海马相关环路的功能改变可能是颞叶癫痫诱发认知功能障碍的关键基础，而IL1β可能通过作用于GABA能神经元调控海马环路的功能并损害认知功能。在本项目中，我们拟应用多种技术，包括fMRI和FDG-PET技术、光遗传学方法、低频率电刺激手段、在体场电位记录和神经元单位放电记录等电生理手段观察癫痫发病过程中海马相关环路的功能变化，分析它与癫痫诱发认知功能障碍的关系；并利用 RNA干扰、基因敲除小鼠和药理学手段阐明IL1β对认知障碍的调控作用及其机制。本项目将有助于阐明癫痫后认知障碍的发病机制、并发原因，为其共同干预治疗提供明确的理论基础。

癫痫是以脑内异常神经环路形成为基础的发作性疾病，还会出现认知功能障碍(尤其是颞叶癫痫)，而癫痫异常神经环路可能是造成认知功能障碍的主要原因，但其发生机制未明，也缺乏有效的防治手段。在本项目中，我们基础临床相结合，应用多种技术，包括MRI影像学技术、光遗传学、化学遗传学方法、低频率电刺激手段、基因干预、在体场电位记录和神经元单位放电记录等电生理手段观察癫痫发病过程中海马相关环路的功能变化，分析它与癫痫诱发认知功能障碍的关系。我们研究首次明确了海马相关环路的功能改变是颞叶癫痫诱发认知功能障碍的关键基础，进一步揭示了以IL-1β分子为主的炎症信号通路在调控在颞叶癫痫及认知障碍的相关机制。这些发现有助于阐明癫痫后认知障碍的发病机制、并发原因，为其共同干预治疗提供明确的理论基础及新的潜在精准干预的治疗方式。