权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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.

越来越多的证据支持这样的假设：精神分裂症患者的睡眠纺锤体缺陷，