The Influence of Sleep on Plasticity and Stability in Hippocampal-Prefrontal Networks.

大脑如何能够在不破坏现有记忆的情况下同时支持新信息的学习仍然是一个悬而未决的问题。系统巩固理论认为，成功的记忆巩固需要将新的学习--在高度可塑性的海马体中获得--整合到更稳定的皮质网络中。彻底测试这一理论需要有能力跟踪多天来大脑皮层神经元与学习相关的长期变化，这直到最近才因技术限制而变得困难。虽然钙成像的进步现在可以长期跟踪体内的神经元活动，但其有限的时间分辨率阻碍了对海马-皮质相互作用的一个可能候选因素的研究：在慢波睡眠(SWS)期间发生的被称为尖波波动(SWR)的高频海马振荡。我建议直接检验这一假设，即睡眠期间海马体-大脑皮层的相互作用有助于诱导和维持与学习相关的可塑性。为了解决这一假设，我建议将海马区的电生理记录与啮齿类动物前额叶皮质的长期钙成像结合起来，这是长期记忆回忆所必需的区域。在目标1中，我将描述睡眠期间海马区SWR活动如何影响获得联想学习任务后与学习相关的长期前额叶神经元活动变化。在目标2中，我将利用睡眠剥夺来测试睡眠、长期记忆和前额神经元可塑性之间的关系。在目标3中，我将描述支持逐渐获得更困难的长期记忆任务的海马-前额叶对话的时间进程。睡眠障碍是当今社会的地方性疾病，在正常衰老过程中出现，并在阿尔茨海默病(AD)过程中缓慢增加。此外，睡眠不足会加剧tau和淀粉样β蛋白的流行，这是AD的两种标志性病理变化，在海马体和皮质中。了解睡眠如何影响海马-皮质协调和长期可塑性，可以为睡眠剥夺、正常衰老和阿尔茨海默病造成的记忆缺陷提供有价值的见解，从而指导干预措施改善记忆结果。

How the brain is able to simultaneously support learning of new information without corrupting existing memories remains an unanswered question. Systems consolidation theory argues that successful memory consolidation requires integrating new learning - acquired in the highly plastic hippocampus - into more stable cortical networks. Thoroughly testing this theory requires the ability to track long-term, learning-related changes in cortical neurons across multiple days, which has been difficult until recently due to technological limitations. While advances in calcium imaging now permit the long-term tracking of neuron activity in vivo, its limited temporal resolution prevents the study of one likely candidate for hippocampal-cortical interactions: high-frequency hippocampal oscillations dubbed sharp-wave ripples (SWRs) that occur during slow-wave sleep (SWS). I propose directly testing the hypothesis that hippocampal-cortical interactions during sleep facilitate the induction and maintenance of learning related plasticity. To address this hypothesis, I propose combining electrophysiological recordings in the hippocampus with long-term calcium imaging in the prefrontal cortex of rodents, a region necessary for long-term memory recall. In Aim 1, I will characterize how hippocampal SWR activity during sleep influences long-term, learning-related changes in prefrontal neuron activity following the acquisition of an associative learning task. In Aim 2, I will utilize sleep deprivation to test the relationship between sleep, long-term memory, and prefrontal neuron plasticity. In Aim 3, I will characterize the time course of the hippocampal-prefrontal dialog supporting the gradual acquisition of a more difficult long-term memory task. Sleep disturbances are endemic to today’s society, emerge during normal aging, and slowly increase through the course of Alzheimer’s Disease (AD). Moreover, sleep deprivation can exacerbate the prevalence of tau and amyloid beta, two hallmark AD pathologies, in the hippocampus and cortex. Understanding how sleep influences hippocampal-cortical coordination and long-term plasticity could provide valuable insights into memory deficits caused by sleep deprivation, normal aging, and AD, which could guide interventions to improve memory outcomes.