Sleep-dependent memory processing in schizophrenia

精神分裂症的睡眠依赖性记忆处理

• 批准号: 10218026
• 负责人: DARA S MANOACH
• 金额: $ 52.22万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218026
• 关键词: Affect; Animals; Antipsychotic Agents; Cell Nucleus; Chronic; Clinical Trials; Cognition; Cognitive deficits; Complement; Coupling; Data; Development; Disease; Electroencephalography; Eszopiclone; Failure; First Degree Relative; Future; Goals; Grant; Health; Heritability; Hippocampus (Brain); Human; Impaired cognition; Individual; Knowledge; Learning; Long-Term Potentiation; Magnetoencephalography; Measures; Mediating; Memory; Memory impairment; Napping; Neurobehavioral Manifestations; Neurons; Patients; Pharmaceutical Preparations; Pharmacology Study; Physiology; Play; Population; Rattus; Refractory; Research; Rodent; Role; Schizophrenia; Severities; Sleep; Symptoms; Testing; Thalamic structure; Work; base; cost; density; effective therapy; endophenotype; executive function; functional outcomes; gamma-Aminobutyric Acid; human study; improved; memory consolidation; memory process; non rapid eye movement; optogenetics; preservation; programs; risk variant; schizophrenia risk; sleep abnormalities; sleep spindle; translational pipeline; zolpidem

Converging lines of evidence support the hypothesis that the sleep spindle deficit in schizophrenia (SZ), contributes to highly disabling and treatment-refractory cognitive deficits and to symptoms and, importantly, is treatable. In the first three-year cycle of this R01, we examined the effects of eszopiclone (Lunesta) on sleep spindles and sleep-dependent memory consolidation in SZ. Although it significantly increased spindles, and spindles correlated with memory, disappointingly, eszopiclone failed to improve memory. Recent findings from our labs and others provide an explanation for this failure and motivate the present proposal. Memory consolidation relies not only on the number of spindles, but also on their temporal coordination with other sleep oscillations. During sleep, hippocampal sharp wave ripples (SWRs), which correspond to memory reactivation, coordinate with spindles and cortical slow waves (CSWs) to transfer new memories from temporary storage in the hippocampus to more permanent representation in the cortex. In SZ we recently showed that both the number of spindles and their temporal coordination with CSWs predict memory consolidation. Our preliminary findings indicate that eszopiclone disrupts this spindle-CSW timing in humans and suppresses SWRs in rats. These effects of eszopiclone on sleep oscillations may account for its failure to improve memory. The goal of this grant cycle is to develop and validate a pipeline to efficiently identify the most promising drugs for improving sleep-dependent memory consolidation by determining their effects on all three oscillations (spindles-CSWs-SWRs), their temporal coordination and memory consolidation before moving to larger and more costly clinical trials. Because hippocampal SWRs are difficult to measure noninvasively, this pipeline requires complementary rodent and human studies. The rodent studies will use large-scale neuronal ensemble recordings to examine the effects of zolpidem and eszopiclone on the coordination of hippocampal SWRs, sleep spindles and CSWs and on memory. The parallel human study will obtain high-density spatial data from simultaneously-acquired EEG/magnetoencephalography (MEG) during a daytime nap from both healthy individuals and SZ patients to test the effects of zolpidem on spindles, CSWs, and their coordination and how these effects correlate with changes in sleep-dependent declarative memory consolidation. The choice of zolpidem is based on findings that it increases both spindle-CSW coupling and hippocampal SWRs and also improves sleep-dependent declarative memory, but has not been tested in SZ. In addition to identifying the most promising drugs for future clinical trials to ameliorate cognitive deficits in SZ and evaluating zolpidem as a potential candidate, this research program will elucidate how sleep oscillations act in concert to mediate memory consolidation. This knowledge will open new avenues for identifying and treating sleep- related cognitive deficits in a range of disorders characterized by abnormal sleep.

越来越多的证据支持这一假设，即精神分裂症（SZ）的睡眠梭形缺陷， 导致高度致残和治疗难治性认知缺陷和症状，重要的是， 可以治疗的在R 01的前三年周期中，我们检查了右佐匹克隆（Lunesta）对睡眠的影响 纺锤波和睡眠依赖性记忆巩固。虽然它显著增加了纺锤体， 纺锤体与记忆相关，但令人遗憾的是，右佐匹克隆未能改善记忆。最近的调查结果来自 我们的实验室和其他实验室为这种失败提供了解释，并激发了本提案。存储器 巩固不仅依赖于纺锤波的数量，还依赖于它们与其他睡眠的时间协调。 振荡在睡眠期间，海马尖波波纹（SWR），这对应于记忆的重新激活， 与纺锤波和皮层慢波（CSW）协调，将新的记忆从临时存储转移到大脑中。 海马体在大脑皮层中的永久性代表。在深圳，我们最近发现， 纺锤波的数量及其与CSW的时间协调预测记忆巩固。我们的初步 研究结果表明，右佐匹克隆破坏了人类的这种纺锤体-CSW定时，并抑制了大鼠的SWR。 右佐匹克隆对睡眠振荡的这些影响可能是其未能改善记忆的原因。的目标 这个赠款周期是为了开发和验证一个管道，以有效地确定最有前途的药物， 通过确定它们对所有三种振荡的影响来改善睡眠依赖性记忆巩固 （纺锤体-CSW-SWR），他们的时间协调和记忆巩固之前，移动到更大的， 更昂贵的临床试验。由于海马体SWR难以无创测量， 需要啮齿动物和人类的互补研究啮齿动物研究将使用大规模的神经元 整体记录以检查唑吡坦和右佐匹克隆对海马协调的影响 睡眠纺锤波和CSW以及内存。平行人类研究将获得高密度的空间 在白天小睡期间， 测试唑吡坦对纺锤波、CSW及其协调性的影响 以及这些效应如何与睡眠依赖的陈述性记忆巩固的变化相关。的 选择唑吡坦是基于它增加纺锤体-CSW耦合和海马SWR的发现 也改善了睡眠依赖的陈述性记忆，但尚未在SZ中进行测试。除了 确定未来临床试验中最有前途的药物，以改善SZ的认知缺陷，并评估 唑吡坦作为一个潜在的候选人，这项研究计划将阐明睡眠振荡如何协同作用， 介导记忆巩固。这些知识将为识别和治疗睡眠开辟新的途径- 在一系列以异常睡眠为特征的疾病中与认知缺陷相关。