The Pharmacological Enhancement of Sleep for Memory Improvement

睡眠增强记忆力的药理作用

• 批准号: 8788794
• 负责人: SARA CAROLE MEDNICK
• 金额: $ 30.23万
• 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/8788794
• 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; Health; 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; memory consolidation; motor learning; non rapid eye movement; novel; older patient; 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，训练后睡眠期中的睡眠纺锤波（非快速眼动（NREM）睡眠中的瞬时神经事件，9-15 Hz）的数量与陈述性记忆改善的幅度相关（例如，有意识的、情景记忆），而REM睡眠的分钟数与非陈述性记忆的改善相关（例如，无意识、知觉或感觉运动技能）。虽然这些研究报告说，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睡眠依赖性记忆关于1）睡眠特征（即，睡眠纺锤波对其它睡眠特征），2）记忆域（即陈述性对非陈述性），和3）药理学试剂（即，唑吡坦（ZOL）对比羟丁酸钠（SO）对比安慰剂）。在相关睡眠研究和针对精确记忆领域的药物干预之间建立联系，将推进我们开发记忆障碍药物治疗的长期目标。我们假设增加ZOL的纺锤体会改善陈述性记忆，但不会改善非陈述性记忆，而减少SO的纺锤体会减少陈述性记忆。强有力的初步数据证明了项目目标在申请人手中的可行性。首先，来自PI的K 01的初步数据证明了睡眠纺锤波的成功药理学调节（即，与安慰剂相比，ZOL增加，SO减少）;第二，试验数据显示，睡眠纺锤波的调节确实影响记忆表现。我们对健康年轻受试者的睡眠依赖性记忆巩固的药理干预结果将被用来为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中进行翻译干预（例如，老年痴呆症和阿尔茨海默病患者）。一个令人信服的观察结果支持了我们的方法：沿着陈述性记忆的标志性损伤，老年人和痴呆症和阿尔茨海默氏症患者的睡眠也会恶化，包括睡眠纺锤波的数量减少。此外，老年人似乎没有像年轻人那样从睡眠依赖性巩固中获益。然而，认知老化治疗策略并没有解决改善或调整睡眠以逆转这些记忆障碍的可能性。拟议中的研究调查了一个假设，即与非陈述性记忆和安慰剂相比，增强老年人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，因为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550万美国人受阿尔茨海默氏症影响，每年花费2000亿美元; 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。