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)： 睡眠动态平衡，其中睡眠驱动力是先前醒来的函数，睡眠驱动力随着唤醒时间的增加而逐渐增加，睡眠驱动力在睡眠期间消散，与昼夜(一天的时间)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，通常由脑电(EEG)中0.5-4.5赫兹的慢波活动(SWA)来衡量，因为SWA的功率，正如脑电的快速傅立叶变换所量化的那样，随着醒着时间的延长而增加，并在睡眠中减少。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，并且比整体睡眠时间或持续时间对睡眠损失更敏感。最近，我们在对照组和转基因小鼠中表征了三个睡眠需要参数，包括跨状态的SWA功率、SWS巩固和SWA Decay，一个新的参数描述了SWS发作中SWA的动态表达。来自转基因小鼠的数据表明腺苷可以发挥关键作用，腺苷先前被认为与睡眠稳态有关，A1受体敲除小鼠显示出零散的睡眠，在基线未受干扰的条件下，SWS内没有SWA衰退，并且在睡眠剥夺后失去了反弹的SWA；以及腺苷激酶基因敲除动物，其中将腺苷转化为AMP的酶减少，导致更高的腺苷水平，显示出在SWS和清醒时SWA能力增加，更巩固的睡眠，以及在基线未受干扰的条件下，减缓SWS内的SWA衰退。此外，在腺苷激酶基因敲除的动物中，由于睡眠不足，SWA的能力和睡眠巩固能力进一步增加。有趣的是，SWA中的这些变化与总体SWS时间无关。目前尚不清楚这些动态平衡睡眠的变化是否会对认知功能产生影响。SWA被先前的清醒经验所改变，并被假设为提供了一种睡眠可以影响学习和记忆的机制。目前的建议将使用诱导性腺苷激酶基因敲除模型，以及基于饮食的减少腺苷激酶的方法，来研究在存在(生酮饮食诱导的腺苷激酶基因敲除)和不存在(诱导性腺苷激酶基因敲除)总体睡眠时间变化的情况下，睡眠需求增加对认知功能的影响。Y迷宫反转和空间物体识别将分别用于测量前额叶皮质和海马区依赖的学习和记忆。通过SD增加的腺苷或减少的腺苷激酶改变认知功能的能力将在四个分立点上进行测量：获得、巩固、获得反转(仅Y迷宫)和恢复。此外，两个腺苷受体突变体(缺失A1或缺失A2a受体)也将被用来进一步研究腺苷对睡眠需求的影响。我们预计，无论整体睡眠时间是否改变，通过A1受体作用的SWA的全球增加都将导致学习和记忆障碍。