The role of hippocampal processing and slow-wave activity in memory consolidation

 描述（由申请人提供）：睡眠在长期记忆巩固或近期记忆随时间的稳定中起着关键作用。 在人类中，与清醒时间相比，非快速眼动（NREM）睡眠与增强的记忆保持和跨大脑皮层网络的记忆表征的稳定性有关。 编码后睡眠期间的特定生理机制被认为支持这种记忆稳定：慢波活动或慢振荡，其在NREM睡眠期间协调和同步大规模神经活动，以及在广泛的海马-皮质网络相互作用期间代表先前经验的海马活动模式的再激活（“再激活”）。 慢波对于保持近期记忆的功能作用已经在人类中显示，并且在啮齿动物的NREM睡眠期间已经显示了记忆相关的海马再激活和相关的海马网络相互作用的有力证据。 然而，从先前的工作中还不清楚1）：哪些大脑区域对于支持成功的NREM记忆巩固的慢波的产生是至关重要的，先前的工作表明慢波密度和起源在内侧前额叶皮层（mPFC）上占主导地位，以及2）：海马再激活和大规模网络相互作用的机制是否支持人类NREM记忆巩固，因为很少有先前的工作测试了人类大脑中海马体重新激活和相关网络相互作用的证据。 通过将TMS与NREM大脑活动的高密度EEG和EEG-fMRI测量相结合，该提案试图通过以下方式弥补这些差距：1）测试mPFC完整性对慢波活动生成和相关NREM睡眠记忆巩固的因果贡献，以及2）：测试海马依赖性学习是否会导致在随后的NREM睡眠期间海马重新激活和大规模网络相互作用的有力证据，以及NREM海马活动测量是否在功能上预测记忆巩固成功（跨海马-皮层网络的记忆保持和神经稳定）。 总之，这项工作的目的是研究潜在的大脑区域和神经机制，这些区域和神经机制对人类睡眠期间的长期记忆保持至关重要。 这一提议将提高我们对基本记忆机制的理解，这些机制可能是精神和神经疾病状态下记忆缺陷的基础，这些状态通常表现为记忆和睡眠异常的共病损害。 此外，这项工作将阐明与几种神经系统疾病相关的睡眠丧失的功能意义，并将有助于成功开发治疗方法，通过针对睡眠生理学的可修改方面来改善记忆缺陷。

 DESCRIPTION (provided by applicant): Sleep plays a critical role in long-term memory consolidation, or the stabilization of recent memories over time. In humans, non-rapid-eye-movement (NREM) sleep, compared to time spent awake, is associated with enhanced memory retention and the stabilization of memory representations across hippocampal-cortical networks. Specific physiological mechanisms during post-encoding sleep are thought to support such memory stabilization: slow wave activity or slow oscillations, which coordinate and synchronize large-scale neural activity during NREM sleep, and the reactivation of hippocampal activity patterns representative of prior experience (`reactivation') during wide-spread hippocampal-cortical network interactions. A functional role of slow waves for the retention of recent memories has been shown in humans, and robust evidence for memory- related hippocampal reactivation and associated hippocampal network interactions has been shown during NREM sleep in rodents. However, it is unclear from prior work 1): which brain regions are critically necessary for the generation of slow waves that support successful NREM memory consolidation, with prior work indicating a predominance of slow wave density and origin over medial prefrontal cortex (mPFC), and 2): whether mechanisms of hippocampal reactivation and large-scale network interactions support human NREM memory consolidation, as little prior work has tested evidence for hippocampal reactivation and associated network interactions in the human brain. By combining TMS with high-density EEG and EEG-fMRI measurements of NREM brain activity, this proposal seeks to remedy these gaps by 1): testing the causal contribution of mPFC integrity to slow wave activity generation and associated NREM sleep memory consolidation, and by 2): testing whether hippocampal-dependent learning results in robust evidence for hippocampal reactivation and large-scale network interactions during subsequent NREM sleep, and whether NREM hippocampal activity measures are functionally predictive of memory consolidation success (memory retention and neural stabilization across hippocampal-cortical networks). In sum, this work aims to study the underlying brain regions and neural mechanisms that critically contribute to long-term memory retention during sleep in humans. This proposal will improve our understanding of basic memory mechanisms that may underlie memory deficits in psychiatric and neurological disease states, which often express co-morbid impairments in memory and sleep abnormalities. Moreover, this work will elucidate the functional significance of sleep loss associated with several neurological disorders and will aid in the successful development of therapeutics to ameliorate memory deficits by targeting modifiable aspects of sleep physiology.