Why do we get sleepy after being awake? Why does the sleep drive have such preemptive effects on behavior and performance? Formulating better answers to these simple questions is the purpose of this proposal. We use an animal model in our quest to understand the mechanisms mediating the homeostatic sleep drive (HSD), the drive that mediates the sleepiness following sleep loss or sleep deprivation (SD). Our earlier findings in animal models pointed to elevated extracellular levels of the neurochemical adenosine (AD) as a homeostatic sleep factor acting potently in the cholinergic basal forebrain (CBF) to increase sleepiness after as little as 3 to 6h of sleep deprivation (short term SD). We now think that with progressively longer periods of SD (6 or more h of SD), the HSD effects are progressively more mediated by non-CBF cortical regions. We note that "adenosine and sleep" is a scientific hot topic, with a February 2008 PubMed search revealing some 31 articles in the past year alone. To help advance our understanding, we propose the following studies relevant to the molecular, cellular, and behavioral mechanisms underlying the HSD.
Specific Aim 1). We will test whether changes in AD production and extracellular levels occur first in CBF and then, with longer SD, in cortical areas. We predict an increase in adenosine A1 receptor binding (number of active receptors) with 24h SD. We will test our preliminary data-derived hypothesis indicating that inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) is an immediate mediator of AD increases during SD, and we predict that iNOS and NO activity will show the same temporal-spatial distribution as AD.
Specific Aim 2). Using in vitro slice in a novel genetically modified mouse that expresses green fluorescent protein (GFP) in GABAergic neurons, we will investigate the cellular actions of NO to confirm preliminary data that NO initially excites cortically projecting CBF cholinergic and GABAergic neurons, and then produces an inhibition that is dependent on AD produced by NO. We further will study the intrinsic neurophysiological properties and pharmacology of identified cellular components of the CBF.
Specific Aim 3). We will investigate the effects and interaction of SD, AD and NO in the CBF on sleepiness and vigilance using a novel rodent version of the human multiple sleep latency test (rMSLT) and a rodent version of the human psychomotor vigilance task (rPVT). In summary, this project proposes to use what we view as state-of-the-art molecular, electrophysiological and behavioral methods, including several which are unique to our lab within the sleep field. These include the use of a novel dye (DAF) to identify the cellular sources of NO production;the use of genetically modified GFP mice which allow identification of GABAergic neurons prior to electrophysiological recordings and finally the use of rodent analogues of human tests measuring sleepiness (rMSLT) and vigilance (rPVT). We thus see this application as using state-of-the art technology to answer critical questions about the homeostatic sleep drive.
Sleep loss from disease (including insomnia and depression) and vocational demands (shift work, doctors, emergency workers) is known as a major contributor to diminished quality of life, to accidents and to decreased work and school efficiency. This proposal uses an animal model to enable understanding of the biological mechanisms mediating the sleepiness following sleep loss or sleep deprivation. By doing this we hope to lay the foundation for a rational treatment of insomnia and other sleep disorders.
|Zant, Janneke C; Kim, Tae; Prokai, Laszlo et al. (2016) Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study. J Neurosci 36:2057-67|
|McNally, James M; McCarley, Robert W (2016) Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities. Curr Opin Psychiatry 29:202-10|
|Shukla, Charu; Basheer, Radhika (2016) Metabolic signals in sleep regulation: recent insights. Nat Sci Sleep 8:9-20|
|Lin, Shih-Chieh; Brown, Ritchie E; Hussain Shuler, Marshall G et al. (2015) Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition. J Neurosci 35:13896-903|
|Kalinchuk, Anna V; Porkka-Heiskanen, Tarja; McCarley, Robert W et al. (2015) Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis. Eur J Neurosci 41:182-95|
|Kim, Youngsoo; Elmenhorst, David; Weisshaupt, Angela et al. (2015) Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain. J Sleep Res 24:549-58|
|Kim, Tae; Thankachan, Stephen; McKenna, James T et al. (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112:3535-40|
|Brown, Ritchie E; McKenna, James T (2015) Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal. Front Neurol 6:135|
|Kim, T; Ramesh, V; Dworak, M et al. (2015) Disrupted sleep-wake regulation in type 1 equilibrative nucleoside transporter knockout mice. Neuroscience 303:211-9|
|Zielinski, Mark R; Kim, Youngsoo; Karpova, Svetlana A et al. (2014) Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression. Neurosci Lett 580:27-31|
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