Sleep and the neurobiological mechanisms controlling sleep/wakefulness have been an enigma in spite of important recent advances in the field. Although it is well known now that sleep affects a variety of systems, including the cardio-respiratory, endocrine and autonomic systems, we still do not understand why we sleep and the mechanisms that control sleep. For example, we do not have a good understanding of the mechanisms that induce or maintain sleep or those mechanisms that are activated with sleep deprivation. One of the potentially important areas that have started to develop is the role of brain metabolism in sleep. Although metabolic studies during sleep have been done in the past few decades, new developments in brain imaging and spectroscopy have made it possible only recently to examine the importance of metabolism in sleep research. Furthermore, and of major interest, is the growing evidence that glia play a critical role in maintaining neuronal function through metabolic support through glutamate re-cycling and possibly by providing neurons with substrates for glucose oxidation. Glycogen is found only in glia and hence glycogen metabolism, the glutamine-glutamate cycling and glucose oxidation involve links between glia and neurons. Hence, in order to understand sleep and its mechanisms, it becomes important to study the functional integrity and coupling of neurons and glia and their relationship as a function of state. For conceptual reasons and in order not to complicate the experimental matrix, we will focus this application on stage III-IV sleep and will address our questions comparing this sleep stage to a well defined state of wakefulness. Furthermore, since previous studies have taught us about sleep and its mechanisms by studying sleep deprivation, we will, in a subset of our children, address the same questions after sleep deprivation. Our specific hypotheses are as follows: 1. Stage IV sleep has a lower metabolic requirement and a lower glutamate turnover rate (tricarboxylic acid cycle rate) in both neurons and glia, as compared to wakefulness. 2. As compared to wakefulness, sleep stage IV is characterized by a lower rate of brain neuronal glutamate release and glial glutamate uptake in children; this reduced glutamate/glutamine cycling during this sleep stage in brain of children is prevented by sleep deprivation. 3. Brain glycogen content increases during the course of sleep in children and sleep deprivation markedly lowers glycogen content. Our long term aims are a) to better understand sleep and b) to be able to better understand diseases that afflict children or adult and which impact on their sleep or diseases that are sleep-related that impact on other functions including neurocognitive, cardiovascular or behavioral functions. As seen from reviewing the state-of-the-art above, there are major gaps in our knowledge and this application focuses on a number of these gaps.
