Closed-loop intervention in epilepsy.

 描述（由申请人提供）：颞叶癫痫（TLE）是成人中最常见的癫痫。TLE通常对当前的抗癫痫药物难治，并且全身治疗经常伴随有显著的负面副作用。然而，TLE的细胞和电路机制尚未被理解，这对开发新的治疗策略提出了挑战。最近，我们发现闭环光遗传学干预（COI）可以显著减少慢性实验性TLE中正在进行的电图和行为癫痫发作，具有高度的空间，时间和细胞类型特异性，并且它可以用作一个强大的，多功能的研究工具，用于假设检验以了解TLE机制。在这里，我们建议测试的假设，COI实现长期的癫痫控制，以及改善认知共病和病理功能网络特性，在慢性和潜伏期的TLE。该假设将在TLE实验小鼠模型中进行测试，并将在小鼠海马CA1区采用电生理和行为技术以及大规模体内功能成像方法进行评估。可以预期，定义COI在TLE中的功能后果将通过推进我们对活动依赖性病理过程在慢性癫痫和癫痫发生中的作用的理解而产生重大影响，并有助于未来开发新的抗癫痫治疗策略。

 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.