Optimizing sleep spindle measurements as translational assays of memory consolidation

优化睡眠纺锤波测量作为记忆巩固的转化分析

• 批准号: 10112344
• 负责人: DARA S MANOACH
• 金额: $ 73.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112344
• 关键词: Acoustic Stimulation; Address; Affect; Alzheimer' s Disease; Animals; Auditory; Biological Assay; Biological Markers; Brain; Clinic; Clinical Trials; Cognition; Cognitive deficits; Coupled; Coupling; Data; Data Set; Detection; Disease; Dose; Early Intervention; Electric Stimulation; Electroencephalography; Electrophysiology (science); Epilepsy; Eszopiclone; Evaluation; Event; Follow-Up Studies; Future; Genetic study; Goals; Health; Hippocampus (Brain); Human; Intervention; Longevity; Machine Learning; Measurement; Measures; Mediating; Memory; Memory impairment; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Patients; Pharmaceutical Preparations; Phase; Physiological; Play; Polysomnography; Rattus; Research; Research Proposals; Rodent; Scalp structure; Schizophrenia; Sleep; Sleep disturbances; Time; Translations; Treatment Efficacy; Work; autism spectrum disorder; base; brain circuitry; clinical candidate; density; drug development; effective therapy; efficacy evaluation; improved; memory consolidation; neuropsychiatric disorder; non rapid eye movement; novel; optogenetics; preservation; response; screening; sleep spindle; therapeutic target; therapy development

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.

这项研究提案解决了药物开发的关键挑战：揭示生物标志物的匮乏 干预措施是否会在早期，动物和人类中影响涉及的脑电路 在漫长而昂贵的临床试验中。对人类和啮齿动物的研究已经建立了睡眠主轴，定义了 第2期非比型眼运动（NREM）睡眠的EEG振荡，作为记忆巩固的机制。 越来越多的工作暗示了神经发育和神经退行性的睡眠主轴异常 以记忆障碍为特征的疾病。在精神分裂症中，睡眠主轴缺陷预测睡眠受损 依赖记忆合并。通过药物，听觉或经颅大脑增加纺锤体的发现 睡眠期间的刺激可改善健康人的记忆力，为目标主轴提供动力以改进 疾病中的记忆。但是靶向主轴并不能不可避免地改善内存。互补的啮齿动物和 人类研究提供了一个解释：与睡眠有关的记忆巩固不依赖于纺锤，而是依赖于纺锤 在其与其他两个基本NREM睡眠振荡的精确时间协调下：皮质慢 振荡（SOS）和海马锋利波纹波。这些发现清楚地表明，虽然主轴是 有望改善记忆的有希望的目标，（i）有效的疗法需要增加纺锤体并保存或 增强其与SOS和纹波的耦合，以及（ii）评估功效，我们需要新的测定方法来识别纺锤体 那对SOS和涟漪的夫妇可以调解记忆与没有记忆的夫妇。我们建议：（i）确定 最强大的睡眠纺锤转化度量作为睡眠依赖性记忆巩固的测定 （ug3），（ii）无创操纵它们以比较他们在健康的人和啮齿动物中的反应 （UH3）。使用大鼠癫痫患者和局部田间电位（LFP）中的侵入性记录，我们将首先 证明与SOS和Ripples（三个：三耦合纺锤体）的主轴是相关的 通过内存巩固，从而验证了Trics作为内存的转化生物标志物。然后我们将使用 机器学习以开发仅根据头皮脑电图功能来识别三元素的分类器。我们将 通过将其应用于健康人的数据集来证明这三项 但不偶联的纺锤体与内存巩固相关。在这两个物种中，我们都将确定哪个 主轴测定三项，所谓的纺锤体（SOC）或总纺锤体预测记忆力最好。最后，我们会的 非侵入性操纵人类和大鼠的主轴测定法。遗传研究涉及特定 精神分裂症和自闭症中纺锤体缺陷的病理生理机制，并识别新的靶标和 治疗。我们将开发的啮齿动物和人体主轴测定法将有助于这些测定 通过允许对治疗早期的潜在干预措施进行有效评估，前进到诊所 开发管道和临床试验最有希望的候选人的鉴定。