An Essential Role for Corticothalamic Slow Waves in Sleep Regulation

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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.