Functional Consequences of Adenosine-Mediated Changes in Homeostatic Sleep Needs

 描述（由申请人提供）： 睡眠稳态，其中睡眠驱动是先前清醒的函数，随着清醒时间的增加睡眠驱动逐渐增加，并且睡眠驱动在睡眠期间消散，控制睡眠的时间和持续时间与昼夜节律（一天中的时间）输入一致。睡眠稳态或稳态睡眠需求通常由慢波活动（SWA）（脑电图（EEG）中的0.5- 4.5Hz振荡）来索引，因为如由EEG的快速傅立叶变换量化的SWA功率随着长时间的清醒而增加并且在睡眠中减少。此外，SWA功率比SWS持续时间更好地与先前清醒时间相关，并且比总体睡眠时间或持续时间对睡眠损失更敏感。最近，我们的特点是三个睡眠需要参数在控制和转基因小鼠，包括SWA功率跨国家，SWS巩固，和SWA衰减，一个新的参数，描述SWA内SWS发作的动态表达。来自转基因小鼠的数据表明腺苷的关键作用，其先前与睡眠稳态有关，A1受体敲除小鼠显示出片段睡眠，在基线未受干扰的条件下SWS内没有SWA衰减，并且在睡眠剥夺后失去反弹SWA，以及腺苷激酶敲除动物，其中将腺苷转化为AMP的酶减少，导致更高的腺苷水平，显示在SWS和清醒期间SWA功率增加，更巩固的睡眠，以及在基线未受干扰的条件下SWS内SWA衰减减慢。此外，在腺苷激酶敲低动物中，响应于睡眠剥夺，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。尚不清楚这些稳态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。目前的提议将使用诱导型腺苷激酶敲低模型，沿着基于饮食的降低腺苷激酶的方法，以研究在存在（生酮饮食诱导的腺苷激酶敲低）和不存在（诱导型腺苷激酶敲低）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迷宫逆转和空间物体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增加腺苷或降低腺苷激酶改变认知功能的能力将在四个离散点测量：获得、巩固、获得逆转（仅Y迷宫）和检索。此外，两种腺苷受体突变体（缺乏A1或缺乏A2 a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，通过A1受体作用的SWA的全球增加将导致学习和记忆障碍，而不管总体睡眠时间是否改变。

 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.