Closed-loop intervention in epilepsy.

 描述(申请人提供)：颞叶癫痫(TLE)是成人最常见的癫痫。TLE往往对现有的抗癫痫药物无效，全身治疗常常伴随着显著的副作用。然而，TLE的细胞和电路机制尚不清楚，这给新的治疗策略的开发带来了挑战。最近，我们发现，闭环光遗传干预(COI)可以显著减少慢性实验性TLE持续的电信号和行为发作，具有高度的空间、时间和细胞类型特异性，可以作为一种强大的、通用的假说检验工具来研究TLE的发病机制。在此，我们建议检验这一假设，即COI在TLE的慢性期和潜伏期都实现了长期的癫痫控制，以及认知共病和病理功能网络特性的改善。这一假说将在实验性的TLE小鼠模型中进行验证，并将使用电生理和行为技术以及在小鼠海马区CA1区的大规模在体功能成像方法进行评估。预计确定COI在TLE中的功能后果将对我们加深对活动依赖的病理过程在慢性癫痫和癫痫发生中的作用的理解产生重大影响，并有助于未来新的抗癫痫治疗策略的发展。

 DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common epilepsy in adults. TLE is often refractory to current anti- epileptic drugs, and systemic treatments are frequently accompanied by significant negative side effects. However, the cellular and circuit mechanisms underlying TLE are not yet understood, which poses a challenge for the development of novel treatment strategies. Recently, we discovered that closed-loop optogenetic intervention (COI) can significantly curtail on-going electrographic and behavioral seizures in chronic experimental TLE with high spatial, temporal, and cell-type specificity, and that it can be used as a powerful, versatile research tool for hypothesis testing o understand TLE mechanisms. Here we propose to test the hypothesis that COI achieves long-term seizure control, as well as the amelioration of cognitive comorbidities and pathological functional network properties, during both the chronic and latent phases of TLE. The hypothesis will be tested in experimental mouse models of TLE, and the assessment will be carried out with electrophysiological and behavioral techniques as well as large-scale in vivo functional imaging methods in the CA1 region of the mouse hippocampus. It is anticipated that defining the functional consequences of COI in TLE will have a significant impact by advancing our understanding of the role of activity-dependent pathological processes in chronic epilepsy and epileptogenesis, and aid the future development of novel anti-epileptic treatment strategies.