The Pharmacological Enhancement of Sleep for Memory Improvement

睡眠增强记忆力的药理作用

• 批准号: 8615813
• 负责人: SARA CAROLE MEDNICK
• 金额: $ 31.16万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8615813
• 关键词: Address; Affect; Alzheimer' s Disease; American; Animal Model; Aphorisms; Basic Science; Clinical; Cognitive aging; Conscious; Data; Data Analyses; Dose; Drug Prescriptions; Elderly; Emotional; Episodic memory; Event; Future; Goals; Grant; Hand; Impairment; Individual; Intervention; Investigation; Knowledge; Lead; Link; Measures; Memory; Memory impairment; Mission; Motor Skills; Outcome Study; Patients; Perceptual learning; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Placebos; Population; Populations at Risk; Prevention approach; REM Sleep; Relative (related person); Reporting; Research; Role; Sampling; Sanofi brand of zolpidem tartrate; Sleep; Sleep Disorders; Sodium Oxybate; Specificity; Testing; Training; Unconscious State; United States National Institutes of Health; base; cost; density; design; education cost; experience; human subject; improved; motor learning; non rapid eye movement; novel; older patient; public health relevance; relating to nervous system; skills; translational approach; treatment strategy; young adult; zolpidem

DESCRIPTION (provided by applicant): A growing body of research shows that sleep facilitates the consolidation of memories. For example, the number of sleep spindles (transient neural events in non-rapid eye movement (NREM) sleep, 9-15 Hz) in a post-training sleep period correlates with the magnitude of declarative memory improvement (e.g., conscious, episodic memories), whereas minutes in REM sleep correlate with improvement in non-declarative memories (e.g., unconscious, perceptual or sensorimotor skills). Although these studies report that individual sleep features correlate with improvement in specific memory domains, we do not know if manipulating these sleep features will lead to changes in these precise memory domains. The central aim of this application is to use pharmacological intervention to address the specificity of sleep-dependent memory with respect to 1) sleep feature (i.e., sleep spindles vs. other sleep features), 2) memory domain (i.e. declarative vs. non-declarative), and 3) pharmacological agents (i.e., zolpidem (ZOL) vs. sodium oxybate (SO) vs. placebo). Establishing a link between correlational sleep studies and pharmacological interventions that target precise memory domains will advance our long-term goal of developing pharmacological treatments for memory impairments. We hypothesize that increasing spindles with ZOL will improve declarative, but not non-declarative memory, and decreasing spindles with SO will reduce declarative memory. Strong preliminary data demonstrate the feasibility of the project aim's in the applicant's hands. First, preliminary data from the PI's K01 demonstrates successful pharmacological modulation of sleep spindles (i.e., increased with ZOL and decreased with SO, vs. placebo); and second, pilot data shows that pharmacologically modulating sleep spindles does affect memory performance. Results of our pharmacological intervention on sleep-dependent memory consolidation in healthy young subjects will be leveraged to develop novel treatment approaches for older adults with pharmacologically tailored sleep. Outcomes from these studies will lead to future translational interventions in populations with more severe memory impairment (e.g., dementia and Alzheimer's patients). A compelling observation supports our approach: along with hallmark impairments in declarative memory, older adults and patients with dementia and Alzheimer's also have deteriorated sleep, including a reduced number of sleep spindles. Furthermore, older adults do not appear to benefit from sleep-dependent consolidation as much as younger adults. Yet, cognitive aging treatment strategies do not address the possibility of improving or tailoring sleep to reverse these memory impairments. The proposed studies investigate the hypothesis that pharmacologically boosting sleep spindles in older adults will improve declarative memory, compared with non-declarative memory and placebo. Outcomes of studies will have broad impact given 1) that over 70 million people in the U.S. suffer from disordered sleep at an annual cost of $150 billion; 2) the need to improve treatments for cognitive aging as well as the 5.5 million Americans affected by Alzheimer's at a cost of $200 billion annually; and 3) that improved mechanistic understanding of memory can influence education that costs $1 trillion annually.

描述(申请人提供)：越来越多的研究表明，睡眠有助于巩固记忆。例如，训练后睡眠期间睡眠纺锤体的数量(非快速眼动(NREM)睡眠中的瞬时神经事件，9-15赫兹)与陈述性记忆改善的幅度(例如，意识、情景记忆)相关，而REM睡眠中的分钟数与非陈述性记忆(例如，无意识、知觉或感觉运动技能)的改善相关。尽管这些研究报告称，个别睡眠特征与特定记忆领域的改善相关，但我们不知道操纵这些睡眠特征是否会导致这些精确记忆领域的变化。本申请的中心目的是使用药理学干预来解决以下方面的睡眠依赖记忆的特异性：1)睡眠特征(即睡眠纺锤波与其他睡眠特征)，2)记忆结构域(即陈述性与非陈述性)，以及3)药理制剂(即唑吡坦(ZOL)与羟丁酸钠(SO)与安慰剂)。在相关睡眠研究和针对精确记忆领域的药理学干预之间建立联系，将推进我们开发记忆障碍药物治疗的长期目标。我们假设使用ZOL增加磁盘轴将改善声明性内存，但不会改善非声明性内存，而使用ZOL减少磁盘轴将减少声明性内存。强劲的初步数据证明了项目目标在申请者手中的可行性。首先，PI‘s K01的初步数据表明，药物成功地调节了睡眠纺锤波(即，与安慰剂相比，ZOL增加了睡眠纺锤体，而SO减少了睡眠纺锤波)；第二，试点数据表明，药物调节睡眠纺锤体确实会影响记忆性能。我们对健康年轻受试者睡眠依赖记忆巩固的药物干预结果将被用来为具有药物定制睡眠的老年人开发新的治疗方法。这些研究的结果将导致未来在记忆障碍更严重的人群(例如痴呆症和阿尔茨海默氏症患者)中进行翻译干预。一项令人信服的观察支持了我们的方法：除了陈述性记忆的显著损害外，老年人以及痴呆症和阿尔茨海默氏症患者的睡眠也恶化，包括睡眠纺锤体数量减少。此外，老年人似乎不像年轻人那样从依赖睡眠的巩固中受益。然而，认知衰老治疗策略并没有解决改善或定制睡眠以逆转这些记忆损伤的可能性。与非陈述性记忆和安慰剂相比，这项拟议的研究调查了一种假说，即药物增强老年人的睡眠纺锤波将改善陈述性记忆。研究结果将产生广泛的影响，原因如下：1)美国有超过7000万人患有睡眠障碍，每年花费1500亿美元；2)需要改善认知老化的治疗方法，以及550万受阿尔茨海默氏症影响的美国人，每年花费2000亿美元；以及3)对记忆的机械理解的提高可以影响每年花费1万亿美元的教育。