Closed-Loop Modulation of Hippocampal-Cortical Communication in Temporal Lobe Epilepsy

项目总结/摘要 长期记忆障碍显著影响颞叶癫痫（TLE）患者，但没有针对性 治疗存在。有一个关键的需要，以了解破坏长期信息存储的机制， 癫痫大脑的年龄长期目标是制定改善和预防认知障碍的策略- 癫痫患者的治疗。总体目标是：i）阐明发作间期癫痫放电（IED） 在记忆巩固过程中影响大脑皮层的沟通，和ii）确定如何闭环 这种通讯的调节改变了TLE动物模型的长期记忆。核心假设 简易爆炸装置破坏了海马波纹和皮层睡眠纺锤波的相互作用， 模式和可塑性。此外，恢复生理性的大脑皮层-皮质耦合可以使长- 在TLE中观察到术语记忆缺陷。这个项目的基本原理是，阐明时空spe- 长期记忆中断的基础cific网络机制将能够预防病理性并发症， 在不损害生理交流的情况下进行交流，从而促进记忆巩固。的 将通过在TLE动物模型中追求三个具体目标来检验中心假设：i）评价 调制大脑皮层振荡耦合对神经尖峰模式; ii）确定调制的效果， 3）建立大规模分子间的联系， 在受损的记忆巩固过程中突触可塑性和海马-皮层振荡耦合的标记物， 是的。为了实现这些目标，体内电生理学和即刻早期基因表达的测定将 与闭环电刺激配对，在自由行为的大鼠中执行长期记忆任务。的 在申请人看来，所提出的研究是创新的，因为它集中于调节神经元通信， 在发作间歇期大脑区域之间的联系，以加强记忆的巩固。这些贡献 将是重要的，因为他们预计将提供机械基础的发展， 治疗和潜在预防癫痫患者记忆障碍的方法。

PROJECT SUMMARY/ABSTRACT Long-term memory impairment significantly impacts patients with temporal lobe epilepsy (TLE), but no targeted treatment exists. There is a critical need to understand the mechanisms that disrupt long-term information stor- age in the epileptic brain. The long-term goal is to develop strategies to ameliorate and prevent cognitive impair- ment in patients with epilepsy. The overall objectives are to i) elucidate how interictal epileptic discharges (IEDs) affect hippocampal-cortical communication during memory consolidation, and ii) determine how closed-loop modulation of this communication alters long-term memory in an animal model of TLE. The central hypothesis is that IEDs disrupt the interaction of hippocampal ripples and cortical sleep spindles, altering neural activity patterns and plasticity. Further, restoration of physiologic hippocampal-cortical coupling can normalize the long- term memory deficits observed in TLE. The rationale for this project is that elucidating the spatiotemporally spe- cific network mechanisms that underlie long-term memory disruption will enable prevention of pathologic com- munication without impairment of physiologic communication, thereby facilitating memory consolidation. The central hypothesis will be tested by pursuing three specific aims in a TLE animal model: i) evaluate the effect of modulating hippocampal-cortical oscillatory coupling on neural spiking patterns; ii) determine the effect of mod- ulating hippocampal-cortical coupling on long-term memory, iii) establish links between large-scale molecular markers of synaptic plasticity and hippocampal-cortical oscillatory coupling during impaired memory consolida- tion. To accomplish these aims, in vivo electrophysiology and assays of immediate early gene expression will be paired with closed-loop electrical stimulation in freely behaving rats performing long-term memory tasks. The research proposed is innovative, in the applicant’s opinion, because it focuses on modulating neuronal commu- nication between brain regions during the interictal period to enhance memory consolidation. These contributions will be significant because they are expected to provide the mechanistic groundwork for development of novel approaches to treat, and potentially prevent, memory impairment in patients with epilepsy.