Sleep-dependent memory processing in schizophrenia

精神分裂症的睡眠依赖性记忆处理

• 批准号: 9538251
• 负责人: DARA S MANOACH
• 金额: $ 59.2万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9538251
• 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; programs; risk variant; sleep abnormalities; 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.

多种证据支持这样的假设：精神分裂症 (SZ) 存在睡眠纺锤波缺陷， 导致高度残疾和难治性认知缺陷和症状，重要的是， 可治疗的。在 R01 的第一个三年周期中，我们检查了艾司佐匹克隆 (Lunesta) 对睡眠的影响 SZ 中的纺锤体和睡眠依赖性记忆巩固。虽然它显着增加了主轴，并且 纺锤体与记忆力相关，令人失望的是，艾司佐匹克隆未能改善记忆力。最近的发现 我们的实验室和其他实验室对这一失败提供了解释，并激发了当前的提案。记忆 巩固不仅依赖于纺锤体的数量，还依赖于它们与其他睡眠的时间协调 振荡。睡眠期间，海马尖波波纹（SWR）对应于记忆重新激活， 与纺锤体和皮质慢波（CSW）协调，从临时存储中转移新记忆 海马体在皮质中具有更持久的代表性。在深圳，我们最近表明， 纺锤体的数量及其与 CSW 的时间协调可以预测记忆巩固。我们的初步 研究结果表明，艾司佐匹克隆会扰乱人类的纺锤体-CSW 时序，并抑制大鼠的 SWR。 艾司佐匹克隆对睡眠波动的这些影响可能是其无法改善记忆的原因。目标是 这个资助周期是为了开发和验证一个管道，以有效地识别最有前途的药物 通过确定睡眠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），在转向更大和更大规模之前，它们的时间协调和记忆巩固 更昂贵的临床试验。由于海马 SWR 很难以无创方式测量，因此该管道 需要互补的啮齿动物和人类研究。啮齿动物研究将使用大规模神经元 整体录音以检查唑吡坦和艾司佐匹克隆对海马协调性的影响 SWR、睡眠纺锤波和 CSW 以及内存。并行人体研究将获得高密度空间 白天小睡期间同时采集的脑电图/脑磁图 (MEG) 数据 健康个体和 SZ 患者测试唑吡坦对纺锤体、CSW 及其协调的影响 以及这些影响如何与睡眠依赖性陈述性记忆巩固的变化相关。这 选择唑吡坦是基于它增加了纺锤体-CSW 耦合和海马 SWR 的发现 还可以改善睡眠依赖性陈述性记忆，但尚未在深圳进行测试。此外 确定未来临床试验中最有希望改善 SZ 认知缺陷的药物并进行评估 唑吡坦作为潜在候选者，该研究计划将阐明睡眠振荡如何协同作用 中介记忆巩固。这些知识将为识别和治疗睡眠障碍开辟新途径。 一系列以睡眠异常为特征的疾病中的相关认知缺陷。