Sleep-dependent memory processing in schizophrenia

越来越多的证据支持这样一种假设，即精神分裂症(SZ)的睡眠纺锤体缺陷， 导致高度残疾和治疗--难治性认知障碍和症状，更重要的是， 是可以治疗的。在R01的第一个三年周期中，我们检查了埃索匹克隆(LUNESTA)对睡眠的影响 SZ中的纺锤波和睡眠依赖的记忆整合。尽管它显著增加了磁盘轴，而且 纺锤波与记忆相关，令人失望的是，eszopiclone未能改善记忆。最新发现来自 我们的实验室和其他实验室为这一失败提供了解释，并推动了本提案。记忆 合并不仅取决于纺锤波的数量，还取决于它们与其他睡眠的时间协调性 震荡。在睡眠期间，对应于记忆重新激活的海马体尖锐波纹(SWR)， 与纺锤波和皮质慢波(CSW)协调，将新的记忆从临时存储中转移到 使海马体在大脑皮层有更多的永久代表。在深圳，我们最近展示了两个 纺锤体的数量及其与CSW的时间协调可以预测记忆的巩固。我们的预赛 研究结果表明，埃索匹克隆扰乱了人类的纺锤体-CSW计时，并抑制了大鼠的SWR。 埃索匹克隆对睡眠振荡的这些影响可能是它未能改善记忆的原因。的目标是 这一资助周期是为了开发和验证一个流水线，以有效地确定最有希望的药物 通过确定它们对所有三种振荡的影响来改善睡眠依赖的记忆巩固 (主轴-CSWS-SWR)，它们的时间协调和记忆巩固，然后转移到更大和 更昂贵的临床试验。因为海马区的SWR很难无创测量，所以这条管道 需要对啮齿动物和人类进行补充研究。啮齿动物的研究将使用大规模的神经元 研究唑吡坦和埃索匹克隆对海马区协调性影响的总体记录 SWR、睡眠主轴和CSW以及内存。平行的人类研究将获得高密度的空间 白天小睡时同时采集的脑电/脑磁图(MEG)数据 健康个体和SZ患者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联。这个 选择唑吡坦是基于研究结果，它增加了纺锤体-CSW耦合和海马区SWR 而且还改善了睡眠依赖的陈述性记忆，但尚未在深圳进行测试。除了……之外 确定最有希望用于未来临床试验的改善SZ认知障碍的药物并进行评估 作为一个潜在的候选者，这个研究项目将阐明睡眠振荡如何与 调解记忆巩固。这一知识将为识别和治疗睡眠开辟新的途径-- 以睡眠异常为特征的一系列障碍中的相关认知缺陷。

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.