An Essential Role for Corticothalamic Slow Waves in Sleep Regulation

描述(由申请人提供)：睡眠质量差和睡眠不足是身体和精神疾病的重要风险因素，因此是重大的公共卫生问题。在统计上，肥胖、糖尿病和心血管疾病一般都与睡眠不足有关，具体而言，与以脑电(EEG)缓慢振荡为特征的睡眠部分的中断(“慢波睡眠”；SWS)有关。此外，睡眠不足会导致神经行为障碍，其中许多可归因于SWS的中断。SWS干扰的负面后果要求对睡眠脑电中慢波的机制和后果进行更多的研究。到目前为止，许多工作都集中在皮质下神经调节影响和丘脑细胞生理学在调节慢波中的作用。然而，大脑皮层神经元固有的电生理振荡在多大程度上调节脑电慢波的时间、频率和幅度尚不确定。因此，对慢波恢复作用的神经生物学基础的进一步研究是一个关键的未得到满足的需求。在这里，我们提出了一种独特的方法，将利用皮质锥体神经元的光遗传刺激来操纵皮质节律，并测量这种操纵对慢波活动的影响。需要解决的中心假设是，锥体神经元活动中的缓慢振荡(&lt；4赫兹)对于睡眠需求的释放和睡眠期间的大分子变化都是必要的。在拟议的实验中，我们将检验这样一个假设，即大脑皮层锥体神经元有规律的节律性激活会增加大脑皮层随后的慢波活动。我们将检验这一假设，即过度睡眠的放电需要在SD之后进行，通过脑电慢波活动随时间的下降来衡量，而对SD的大分子反应需要大脑皮层中不间断的慢波活动。拟议中的实验有可能确定一种新的机制，通过这种机制，大脑皮层内的细胞群可以调节脑电慢波的产生和睡眠需求。这些实验使用了首席研究员过去向许多受训者传授的技术，将满足西斯安那州立大学斯波坎分校学生对生物医学科学研究机会的未得到满足的需求。最后，这些实验将提供数据，验证我们的技术是研究慢波睡眠功能的一种新方法，这样做将使我们处于有利地位，寻求在R01水平上扩大NIH的资金。 与公共健康相关：睡眠不足对健康和福祉有许多负面影响。我们试图在细胞和生化水平上增加对睡眠不足的原因和后果的理解。我们建议确定大脑皮层中一类被称为锥体细胞的细胞是否在大脑对睡眠不足的反应中发挥重要功能。我们这样做的预期是，这些研究将导致针对睡眠不足对健康影响的潜在对策。

DESCRIPTION (provided by applicant): Poor-quality sleep and sleep insufficiency are significant risk factors for physical and mental illness and are, thus, of major public-health concern. Obesity, diabetes and cardiovascular disease are all statistically linked to sleep insufficiency generally and to the disruption of the portion of sleep characterized by slow electroencephalographic (EEG) oscillations ("slow wave sleep"; SWS), specifically. In addition, sleep insufficiency induces neurobehavioral deficits, many of which can be attributed to disruption of SWS. The negative consequences of SWS disruption mandate for additional research on the mechanisms and consequences of slow waves in the sleep EEG. Much work to date has focused on the roles of subcortical neuromodulatory influences and thalamic cell physiology in regulating slow waves. However, the degree to which the electrophysiological oscillations intrinsic to neurons of the cerebral cortex regulate EEG slow wave timing, frequency and amplitude re- mains uncertain. Thus, there is a critical unmet need for further studies on the neurobiological underpinnings of the restorative effects of slow waves. Here, we propose a unique approach that will utilize optogenetic stimulation of cortical pyramidal neurons to manipulate cortical rhythms and measure the effect of this manipulation on slow wave activity. The central hypothesis to be addressed is that slow oscillations (<4 Hz) in the activity of pyramidal neurons are necessary for both the discharge of sleep need and macromolecular changes during sleep. In the proposed experiments, we will test the hypothesis that regular rhythmic activation of pyramidal neurons in the cerebral cortex increases subsequent slow wave activity in the cerebral cortex. We will test the hypothesis that the discharge of excessive sleep need subsequent to SD, as measured by a decline in EEG slow wave activity across time, and the macromolecular response to SD require uninterrupted slow wave activity in the cerebral cortex. The proposed experiments have the potential to identify a novel mechanism by which a cell population within the cerebral cortex regulates EEG slow wave production and sleep need. These experiments, using techniques that the principal investigator has taught to a number of trainees in the past, will meet an unmet need for research opportunities for WSU Spokane's student population in the biomedical sciences. Finally, these experiments will provide data that validate our techniques as a novel way of studying slow wave sleep function, and in so doing, will place us in a strong position to seek expanded NIH funding at the R01 level. PUBLIC HEALTH RELEVANCE: Insufficient sleep has a number of negative effects on health and well-being. We seek to increase our understanding of the causes and consequences of insufficient sleep at the cellular and biochemical levels. We propose to determine whether a class of cells known as pyramidal cells in the cerebral cortex of the brain, serve an essential function in the brain's response to sleep insufficiency. We do so with the anticipation that these studies will lead to potential countermeasures for the health effects of insufficient sleep.