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

项目摘要/摘要 长期记忆障碍对颞叶癫痫(TLE)患者有显著影响，但没有针对性 治疗是存在的。迫切需要了解扰乱长期信息存储的机制- 癫痫患者大脑的年龄。长期目标是制定策略，以改善和防止认知损害- 癫痫患者的精神状态。总体目标是：1)阐明癫痫发作间期放电(IED)是如何 影响记忆巩固期间的海马区-大脑皮层通讯，以及ii)决定如何闭合环路 这种交流的调节改变了TLE动物模型的长期记忆。中心假说 是IED破坏了海马波和皮质睡眠纺锤体的相互作用，改变了神经活动 图案和可塑性。此外，生理性海马-皮质连接的恢复可以使长时间的脑电活动正常化。 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空间-- 长期记忆中断背后的特定网络机制将使病理性COM得以预防。 在不损害生理沟通的情况下进行沟通，从而促进记忆巩固。这个 中心假说将通过在TLE动物模型中追求三个特定目标来检验：i)评估 调制海马-大脑皮层振荡耦合对神经元放电模式的影响；ii)确定MOD- 调节海马区-皮层耦合对长时记忆的影响，III)建立大尺度分子间的联系 记忆巩固受损时突触可塑性和海马皮层振荡偶联的标记物 提顿。为了实现这些目标，体内电生理学和即刻早期基因表达的检测将 在自由行为的大鼠进行长期记忆任务时，与闭环电刺激配对。这个 申请人认为，提出的研究是创新的，因为它专注于调节神经元通讯。 发作间歇期大脑区域之间的联系，以加强记忆巩固。这些贡献 将具有重大意义，因为它们有望为小说的发展提供机械基础 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.