Sleep-dependent memory processing in schizophrenia

精神分裂症的睡眠依赖性记忆处理

基本信息

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
项目类别：
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

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

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项目摘要

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.

融合的证据线支持了以下假设，即精神分裂症的睡眠纺锤体不足（SZ），有助于高度残疾和治疗难治性认知缺陷和症状，重要的是可以治疗。在此R01的第一个三年周期中，我们检查了埃索普隆（Lunesta）对睡眠的影响 SZ中的主轴和睡眠依赖性记忆巩固。尽管它大大增加了纺锤体，并且纺锤体与内存相关，令人失望的是，埃索普隆无法改善内存。最近的发现我们的实验室和其他实验室为这种失败提供了解释，并激发了当前的建议。记忆合并不仅依赖于主轴数量，还依赖于其与其他睡眠的时间协调振荡。在睡眠期间，海马尖锐波浪波纹（SWR），对应于记忆重新激活，与纺锤体和皮质慢波（CSW）协调，以从临时存储中转移新记忆海马在皮质中更永久表示。在SZ中，我们最近表明纺锤体数量及其与CSW的时间协调预测记忆巩固。我们的初步调查结果表明，埃索普尔酮在人类中破坏了这种纺锤-CSW的时间，并抑制了大鼠的SWR。 Eszopiclone对睡眠振荡的这些影响可能无法改善其记忆力。目标这个赠款周期是开发和验证管道，以有效地识别最有希望的药物通过确定其对所有三个振荡的影响来改善睡眠依赖性记忆巩固（纺锤-CSWS-SWRS），其时间协调和内存合并，然后再移至较大和更昂贵的临床试验。因为海马SWR难以无创，所以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型神经元集合记录以检查唑吡坦和埃索普隆对海马协调的影响 SWR，睡眠主轴和CSW以及记忆。平行的人类研究将获得高密度的空间同时获得的脑电图/磁脑摄影（MEG）的数据在白天午睡中健康的个体和SZ患者测试唑吡丁对纺锤体，CSW及其协调的影响以及这些影响与睡眠依赖性声明记忆巩固的变化如何相关。这 Zolpidem的选择是基于发现它增加了纺锤-CSW耦合和海马SWR的发现还可以改善与睡眠有关的声明性记忆，但尚未在SZ中进行测试。此外确定未来临床试验的最有希望的药物，以改善SZ的认知缺陷并评估 Zolpidem是潜在的候选人，该研究计划将阐明睡眠振荡如何协同作用介导记忆合并。这些知识将为识别和治疗睡眠开辟新的途径 - 以异常睡眠为特征的一系列疾病中的相关认知缺陷。