癫痫耐药形成的机制还不完全清楚。颞叶癫痫中耐药性癫痫发生的比例较高，申请人基于前期预实验结果提出，颞叶癫痫中海马下托和相关神经环路的功能异常可能是引起耐药行为的重要原因。本项目中，我们将在多药耐药动物模型和临床研究两个层次上进一步验证该假说，并阐明海马下托--内嗅皮层通路是否起着关键作用并明确其作用机制。本项目通过基础结合临床，采用高分辨率功能磁共振、脑电分析、微电极记录、光遗传学调控等多种方法实现研究目标。本项目从神经环路的新角度探索颞叶癫痫中耐药形成的机制，如获成功将能为难治性癫痫的治疗提供新策略。

The pathogenesis of pharmacoresistance in epileptic patients has not been fully elucidated. The incidence of pharmacoresistance is higher in temporal lobe epilepsy. Based on preliminary finding in our pilot study, the applicant proposes that the abnormal function of the subicular circuit may play a role in the pharmacoresistance in temporal lobe epilepsy. In the current project, we will further test the hypothesis in clinical level as well as in animal model of multiple-AED resistance. Moreover, we would investigate the key role of subiculum--entorhinal cortex pathway in pharmacoresistance and explore its cellular mechanism. In summary, we will utilize fMRI, EEG recording, microelectrode recording and optogenic manipulations to reach our research goals. This project aims to shed light on the pathogenesis of pharmacoresistance on basis.of abnormal neural circuit; it may provide new treatment strategy for pharmacoresistant epilepsy in the future.