The function of sleep and the biochemical nature of the restorative process that occurs during sleep are among the great mysteries of neuroscience. Experimental observations confirm the common experience that sleep deprivation (SD) leads to sleepiness and that restricted sleep time imposes a sleep """"""""debt"""""""" which ultimately must be """"""""repaid"""""""" by sleep extension. The hypothesis that underlies our studies is that the homeostatic sleep-related """"""""Process S"""""""" is biochemical in nature and the sleep-dependent restorative process involves macromolecular synthesis that can be detected at the RNA level. Consistent with this idea, during the previous funding period we have identified several genes whose expression is increased during sleep after SD. In the current application, we propose to determine expression of these and other genes at multiple times during recovery sleep after SD. Recent studies have determined that, although the time constant for the decay of Process S (taud) is highly conserved, the time constant for the increase of Process S (taui; referred to as sleep """"""""need"""""""") varies considerably among mouse strains. Therefore, we will compare the neural gene expression profile in three strains of mice that exhibit large differences in the buildup of sleep need to identify mRNAs whose expression may increase in parallel with sleep need. Building on the neural gene expression database that we have established in the current funding period, we will extend our microarray studies to pharmacologically induced sleep and compare the patterns of gene expression induced by clinically effective hypnotic agents to that observed during normal sleep. These experiments may determine whether a final common pathway for sleep induction can be identified. Last, building on a model of hypothalamic and preoptic area involvement in sleep regulation that has emerged over the last few years, we will test the hypothesis that clinically used hypnotics are effective in sleep induction through changing the functional activity of brain nuclei known to be sleep- or wake-active. These experiments should provide insights into the biochemical process occurring during wakefulness that predisposes to sleepiness as well as the restorative i 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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