Functional Consequences of Adenosine-Mediated Changes in Homeostatic Sleep Needs

腺苷介导的稳态睡眠需求变化的功能后果

• 批准号: 9031520
• 负责人: Robert W Greene
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031520
• 关键词: ADORA1 gene; Acute; Adenosine; Adenosine Kinase; Affect; Animals; Attention; Behavior; Biological Markers; Carbohydrates; Circadian Rhythms; Complex; Data; Diet; Electroencephalogram; Environment; Enzymes; Fatty acid glycerol esters; Fourier Transform; Frequencies; Genetic; Genotype; Glutamates; Goals; High Prevalence; Hippocampus (Brain); Homeostasis; Hour; Human; Impairment; Individual; Ketones; Knockout Mice; Learning; Link; LoxP-flanked allele; Measures; Mediating; Memory; Memory impairment; Metabolism; Methods; Modeling; Mus; Names; Neurons; Performance; Phase; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prosencephalon; Purinergic P1 Receptors; Retrieval; Reversal Learning; Role; Rosa; Sleep; Sleep Deprivation; Sleep Disorders; Slow-Wave Sleep; Stimulus; System; Testing; Time; Training; Unconscious State; Veterans; awake; base; cognitive function; cognitive performance; design; experience; genetic manipulation; inattention; indexing; ketogenic diet; ketogentic; knock-down; memory process; mutant; object recognition; prevent; public health relevance; receptor; research study; response; sleep regulation

 DESCRIPTION (provided by applicant): Sleep homeostasis, in which the drive to sleep is a function of prior waking with sleep drive progressively increasing as waking time increases and sleep drive dissipating during sleep, controls the timing and duration of sleep in concert with circadian (time of day) input. Sleep homeostasis, or homeostatic sleep need, is often indexed by Slow Wave Activity (SWA), a 0.5-4.5 Hz oscillation in the electroencephalogram (EEG), since SWA power, as quantified by a Fast Fourier Transform of the EEG, increases with prolonged waking and decreases within sleep. Furthermore, SWA power is a better correlated to previous time awake than SWS duration and is more sensitive to sleep loss than overall sleep time or duration. Recently, we have characterized three sleep need parameters in control and genetically modified mice, including SWA power across states, SWS consolidation, and SWA decay, a new parameter that describes the dynamic expression of SWA within SWS bouts. Data from genetically modified mice indicate a critical role for adenosine, which has previously been linked to sleep homeostasis, with A1 receptor knockout mice showing fragmented sleep and an absence of SWA decay within SWS under baseline undisturbed conditions and a loss of rebound SWA following sleep deprivation, and adenosine kinase knockdown animals, in which the enzyme that converts adenosine to AMP is reduced resulting in greater adenosine levels, showing increased SWA power during both SWS and waking, more consolidated sleep, and slowed SWA decay within SWS under baseline undisturbed conditions. Additionally, further increases in SWA power and sleep consolidation in response to sleep deprivation in adenosine kinase knockdown animals. Interestingly, these changes in SWA are independent of overall SWS time. It is unknown whether these changes in homeostatic sleep need have consequences with respect to cognitive function. SWA is modified by prior waking experience and has been hypothesized to provide a mechanism by which sleep can influence learning and memory. The current proposal will use an inducible adenosine kinase knockdown model, along with a diet-based method of decreasing adenosine kinase, to investigate the effects of increased sleep need in the presence (ketogenic diet-induced adenosine kinase knockdown) and absence (inducible adenosine kinase knockdown) of overall sleep time changes on cognitive function. Y maze reversal and spatial object recognition will be used to measure prefrontal cortex and hippocampal-dependent learning and memory, respectively. The ability of increases in adenosine via SD or decreased adenosine kinase to alter cognitive function will be measured at four discrete points: acquisition, consolidation, acquisition of reversal (Y maze only), and retrieval. Furthermore, two adenosine receptor mutants (lacking A1 or lacking A2a receptors) will also be used to further investigate the effect of Ado action on sleep need. We expect that global increases in SWA acting through A1 receptors will result in learning and memory impairments irrespective of whether overall sleep time is changed.

 描述（由申请人提供）： 睡眠稳态，其中睡眠内驱力是先前醒来的函数，睡眠内驱力随着醒来时间的增加而逐渐增加，睡眠内驱力在睡眠期间消散，与昼夜节律（一天中的时间）输入相一致地控制睡眠的时间和持续时间。睡眠稳态或稳态睡眠需求通常以慢波活动 (SWA) 为索引，慢波活动是脑电图 (EEG) 中的 0.5-4.5 Hz 振荡，因为 SWA 功率（通过 EEG 的快速傅立叶变换量化）随着清醒时间的延长而增加，并在睡眠期间减少。此外，与 SWS 持续时间相比，SWA 功率与先前清醒时间的相关性更好，并且与总睡眠时间或持续时间相比，对睡眠缺失更敏感。最近，我们在对照小鼠和转基因小鼠中表征了三个睡眠需求参数，包括跨状态的 SWA 功率、SWS 巩固和 SWA 衰减，这是一个描述 SWS 发作中 SWA 动态表达的新参数。来自转基因小鼠的数据表明，腺苷发挥着关键作用，此前，腺苷与睡眠稳态有关，A1 受体敲除小鼠在基线未受干扰的条件下，显示出睡眠碎片化，SWS 内不存在 SWA 衰减，并且在睡眠剥夺后 SWA 回弹消失；而腺苷激酶敲低动物，其中将腺苷转化为 AMP 的酶减少，导致更大的 SWA 衰减。 腺苷水平，显示在 SWS 和清醒时 SWA 功率增加，睡眠更加巩固，并且在基线未受干扰的条件下 SWS 内 SWA 衰减减慢。此外，在腺苷激酶敲除动物中，针对睡眠剥夺，SWA 功率和睡眠巩固进一步增加。有趣的是，SWA 的这些变化与总体 SWS 时间无关。目前尚不清楚稳态睡眠的这些变化是否会对认知功能产生影响。 SWA 会根据之前的清醒经历进行修改，并被假设提供了一种睡眠影响学习和记忆的机制。目前的提案将使用诱导型腺苷激酶敲低模型以及基于饮食的减少腺苷激酶的方法，以研究在存在（生酮饮食诱导腺苷激酶敲低）和不存在（诱导型腺苷激酶敲低）整体睡眠时间变化的情况下增加的睡眠需求对认知功能的影响。 Y 迷宫反转和空间物体识别将分别用于测量前额皮质和海马依赖性学习和记忆。通过 SD 增加腺苷或减少腺苷激酶改变认知功能的能力将在四个离散点进行测量：获取、巩固、逆转获取（仅限 Y 迷宫）和检索。此外，两种腺苷受体突变体（缺乏A1或缺乏A2a受体）也将用于进一步研究Ado作用对睡眠需求的影响。我们预计，无论整体睡眠时间是否改变，通过 A1 受体起作用的 SWA 的整体增加都将导致学习和记忆障碍。