The significance of this proposal lies in two areas. First, common experience confirms experimental observations that sleep deprivation leads to sleepiness and that restricted sleep time imposes a sleep """"""""debt"""""""" which ultimately must be """"""""repaid"""""""" by sleep extension. This property of homeostatic regulation of sleep has profound societal and economic impacts because the maintenance of optimal performance in the work environment is dependent on the neural mechanisms which facilitate sustained alertness and attention. Recent analyses have implicated restricted sleep as a major contributory factor to impaired performance in the Challenger, Exxon Valdez and Chernobyl catastrophes. The second area of significance for the proposal is that the function of sleep and the biochemical nature of the restorative process which occurs during sleep remain among the great mysteries of neuroscience. We will address these issues by applying state-of-the-art physiological and molecular biological techniques to determine what genes are activated in the brain during normal sleep, during period of extended wakefulness and during recovery sleep after sleep restriction. Our experiments will be guided by the two-process model of sleep regulation which posits that an increased homeostatic """"""""drive"""""""" to sleep occurs during prolonged wakefulness. We hypothesize that (1) a molecular basis exists for the homeostasis regulation of sleep and that some molecules must be expressed in brain proportional to time spent awake; (2) perturbations of the sleep homeostatic system result in compensatory changes in gene expression in brain that increase the likelihood of subsequent sleep; and (3) sleep after prolonged wakefulness involves a change in macromolecular synthesis that facilitates neuronal recovery or restoration. To test these hypotheses, we will employ computerized sleep state determination coupled to automated sleep deprivation procedures in rodents. Gene expression in brain will be assessed using two novel technologies (cDNA microarrays and high density oligonucleotide arrays) which allow assessment of the expression of thousands of genes in parallel, as well as by conventional molecular biological procedures. We estimate that we will be able to evaluate the expression of 10% of the genome using technologies that should be in place by summer, 1997. Genes which appear to undergo significant change across experimental conditions will be confirmed by Northern Analysis and in situ hybridization. These studies should identify candidate genes for subsequent targeting approaches to determine their relevance for the regulation of sleep and wakefulness. These experiments should provide insights into the biochemical proces occurring during wakefulness that predisposes to sleepiness as well as the restrorative process that occurs during sleep itself.
| Williams, Rhîannan H; Vazquez-DeRose, Jacqueline; Thomas, Alexia M et al. (2018) Cortical nNOS/NK1 Receptor Neurons are Regulated by Cholinergic Projections From the Basal Forebrain. Cereb Cortex 28:1959-1979 |
| Williams, Rhîannan H; Black, Sarah W; Thomas, Alexia M et al. (2018) Excitation of Cortical nNOS/NK1R Neurons by Hypocretin 1 is Independent of Sleep Homeostasis. Cereb Cortex : |
| Gerashchenko, Dmitry; Pasumarthi, Ravi K; Kilduff, Thomas S (2017) Plasticity-Related Gene Expression During Eszopiclone-Induced Sleep. Sleep 40: |
| Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S (2017) Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol 152:89-113 |
| Schwartz, Michael D; Kilduff, Thomas S (2015) The Neurobiology of Sleep and Wakefulness. Psychiatr Clin North Am 38:615-44 |
| Dittrich, Lars; Morairty, Stephen R; Warrier, Deepti R et al. (2015) Homeostatic sleep pressure is the primary factor for activation of cortical nNOS/NK1 neurons. Neuropsychopharmacology 40:632-9 |
| Morairty, Stephen R; Dittrich, Lars; Pasumarthi, Ravi K et al. (2013) A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity. Proc Natl Acad Sci U S A 110:20272-7 |
| Sunkin, Susan M; Ng, Lydia; Lau, Chris et al. (2013) Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res 41:D996-D1008 |
| Dittrich, Lars; Heiss, Jaime E; Warrier, Deepti R et al. (2012) Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species. Front Neural Circuits 6:31 |
| Wisor, Jonathan P; Gerashchenko, Dmitry; Kilduff, Thomas S (2011) Sleep-active neuronal nitric oxide synthase-positive cells of the cerebral cortex: a local regulator of sleep? Curr Top Med Chem 11:2483-9 |
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