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: 9206883
• 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/9206883
• 关键词: ADORA1 gene; Acute; Adenosine; Adenosine Kinase; 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; Impaired cognition; 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; calmodulin-dependent protein kinase II; cognitive function; cognitive performance; design; experience; experimental study; genetic manipulation; inattention; indexing; ketogenic diet; ketogentic; knock-down; memory process; mutant; negative affect; object recognition; prevent; public health relevance; receptor; response; sleep regulation; ADORA1 gene; Acute; Adenosine; Adenosine Kinase; 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; Impaired cognition; 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; calmodulin-dependent protein kinase II; cognitive function; cognitive performance; design; experience; experimental study; genetic manipulation; inattention; indexing; ketogenic diet; ketogentic; knock-down; memory process; mutant; negative affect; object recognition; prevent; public health relevance; receptor; 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）： 睡眠体内平衡，在这种情况下，睡眠的动力是先前随着睡眠时间的增加而逐渐增加的函数，随着醒来时间的增加和睡眠动力在睡眠期间消散，控制了与昼夜节律（一天中的时间）输入一起睡眠的时间和睡眠时间。睡眠稳态或稳态睡眠需求通常是通过慢波活动（SWA）索引的，磁脑动透射图（EEG）的0.5-4.5 Hz振荡，因为SWA功率（通过EEG快速傅立叶变换而量化），随着EEEG的快速变换而量化，随着延长的醒来和降低的睡眠而增加。此外，与SWS持续时间相比，SWA功率与以前的清醒相关性更好，并且对睡眠损失比整体睡眠时间或持续时间更敏感。最近，我们表征了三个睡眠需求参数和一般修饰的小鼠，包括跨州的SWA功率，SWS巩固和SWA衰减，这是一个新参数，描述了SWS回合中SWA的动态表达。 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腺苷的水平显示在SWS和醒来时SWA功率增加，睡眠更加固结，SWA在基线不受干扰的条件下减缓了SWA衰变。此外，由于腺苷激酶敲低动物的睡眠剥夺，SWA功率和睡眠巩固的进一步增加。有趣的是，SWA中的这些变化与整体SWS时间无关。尚不清楚体内睡眠中的这些变化是否需要在认知功能方面产生后果。 SWA通过先前的醒来经验进行了修改，并已假设提供了一种机制，可以通过这种机制来影响学习和记忆。当前的提案将使用诱导的腺苷激酶敲低模型，以及一种基于饮食的减少腺苷激酶的方法，研究存在（酮饮食饮食诱导的腺苷激酶敲低）和缺失（诱导症腺苷激酶敲低的腺苷激酶敲低）的睡眠需求增加的影响（整体睡眠时间）对确定性的整体睡眠时间的变化）。 Y迷宫逆转和空间对象识别将分别用于测量前额叶皮层和海马依赖性学习和记忆。通过SD或改进的腺苷激酶改变认知功能的增加的能力将以四个离散点进行测量：获取，合并，逆转（仅迷宫）和检索。此外，还将使用两个腺苷受体突变体（缺乏A1或缺乏A2A受体）来进一步研究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，SWA通过A1受体表现的全球性增长都会导致学习和记忆力障碍。