Optimizing sleep spindle measurements as translational assays of memory consolidation

这项研究计划解决了药物开发的一个关键挑战：缺乏生物标志物， 干预措施是否会在动物和人类的早期阶段影响相关的脑回路， 进行漫长而昂贵的临床试验对人类和啮齿动物的研究已经建立了睡眠纺锤波， 第二阶段非快速眼动（NREM）睡眠的EEG振荡，作为记忆巩固的机制。 越来越多的研究表明，睡眠纺锤体异常与神经发育和神经退行性疾病有关。 以记忆受损为特征的疾病。在精神分裂症中，睡眠梭形缺陷预示着睡眠受损- 依赖性记忆巩固通过药物或听觉或经颅脑增加纺锤波的发现 睡眠期间的刺激改善了健康人的记忆，为目标纺锤波提供了动力， 记忆混乱但是瞄准纺锤波并不一定能提高记忆力。补充啮齿动物和 人类研究提供了一种解释：睡眠依赖的记忆巩固不仅依赖于纺锤波， 与其他两种主要的NREM睡眠振荡的精确时间协调：皮层慢波 振荡（SO）和海马尖波波纹。这些发现清楚地表明，虽然纺锤体是 改善记忆的有前途的目标，（i）有效的治疗需要增加纺锤体并保持或 增强它们与SO和波纹的耦合，以及（ii）为了评估功效，我们需要新的检测方法来识别纺锤体 与SO和涟漪相结合来介导记忆，而不是与SO和涟漪相结合。我们建议：（一）确定 睡眠纺锤波的最有力的翻译措施，作为睡眠依赖性记忆巩固的测定 (UG3)和（ii）非侵入性地操纵它们，以比较它们在健康人类和啮齿动物中的反应 （UH3）。使用癫痫患者的侵入性记录和大鼠的局部场电位（LFP），我们将首先 证明与SO和波纹耦合的纺锤体（TriCS：三重耦合纺锤体） 与记忆巩固，从而验证TriCS作为记忆的翻译生物标志物。然后我们将使用 机器学习开发分类器，仅基于其头皮EEG特征识别TriCS。我们将 通过将其应用于健康人的数据集来验证EEG纺锤体分类器，以证明TriCS， 而不是非耦合的心轴，与存储器整合相关。在这两个物种中，我们将确定 纺锤体测定TriCS、SO偶联纺锤体（SOCS）或总纺锤体最好地预测记忆。最后我们将 非侵入性地操纵人类和大鼠中的纺锤体测定。基因研究表明 精神分裂症和自闭症纺锤体缺陷的病理生理机制，并确定新的靶点， 治疗。我们将开发的啮齿动物和人类纺锤体测定将促进这些蛋白的翻译。 通过在治疗早期有效评估潜在干预措施， 开发管道和确定最有前途的候选人进行临床试验。

This research proposal addresses a key challenge to drug development: the paucity of biomarkers that reveal whether interventions affect implicated brain circuitry at early stages, in animals and humans, before embarking on lengthy and expensive clinical trials. Studies of humans and rodents have established sleep spindles, defining EEG oscillations of stage 2 non-rapid eye movement (NREM) sleep, as a mechanism of memory consolidation. A growing body of work implicates sleep spindle abnormalities in neurodevelopmental and neurodegenerative disorders characterized by memory impairment. In schizophrenia, sleep spindle deficits predict impaired sleep- dependent memory consolidation. Findings that increasing spindles via drugs or auditory or transcranial brain stimulation during sleep improves memory in healthy people, provides the impetus to target spindles to improve memory in disorders. But targeting spindles does not inevitably improve memory. Complementary rodent and human studies provide an explanation: sleep-dependent memory consolidation relies not on spindles alone, but on their precise temporal coordination with the other two cardinal NREM sleep oscillations: cortical slow oscillations (SOs) and hippocampal sharp-wave ripples. These findings make it clear that while spindles are promising targets for improving memory, (i) effective therapies need to increase spindles AND preserve or enhance their coupling with SOs and ripples, and (ii) to evaluate efficacy, we need new assays to identify spindles that couple with SOs and ripples to mediate memory versus those that do not. We propose to: (i) identify the most powerful translational measures of sleep spindles as assays of sleep-dependent memory consolidation (UG3), and (ii) to noninvasively manipulate them to compare their responses in healthy humans and rodents (UH3). Using invasive recordings in epilepsy patients and local field potentials (LFPs) in rats, we will first demonstrate that spindles that couple with both SOs and ripples (TriCS: triple-coupled spindles) are associated with memory consolidation, thereby validating TriCS as a translational biomarker of memory. We will then use machine learning to develop a classifier that identifies TriCS based solely on their scalp EEG features. We will validate the EEG spindle classifier by applying it to a dataset from healthy humans to demonstrate that TriCS, but not non-coupled spindles, correlate with memory consolidation. In both species, we will determine which spindle assay TriCS, SO-coupled spindles (SOCS) or total spindles predicts memory best. Finally, we will noninvasively manipulate the spindle assays in humans and rats. Genetic studies are implicating specific pathophysiologic mechanisms of spindle deficits in schizophrenia and autism and identifying novel targets and treatments. The rodent and human spindle assays that we will develop will facilitate the translation of these advances to the clinic by allowing the efficient evaluation of potential interventions early in the treatment development pipeline and the identification of the most promising candidates for clinical trials.