The biological underpinnings of homeostatic sleep regulation are an important aspect of sleep research given the relevance of sleep deprivation (SD) to human health, well-being, and cognitive performance. More and more people either are forced to, due to vocational demands, or by choice, stay awake for long periods or at biologically non-optimal times of the day. Moreover, sleep loss-associated cognitive impairments are often observed in conditions such as depressive disorders, post-traumatic stress disorder, Alzheimer's and Parkinson's diseases. Central mechanisms that mediate the effects of SD causing attention and cognitive impairment as well as induction of homeostatic sleep response are critical to be understood to design treatment paradigms for alleviate such deleterious effects of sleep loss, and is close to the NIMH mission. One of the brain regions, the basal forebrain (BF), in addition to its important role in promoting wakefulness, is also recognized for its role i homeostatic sleep regulation as well as in attention and cognition. The BF consists of a variety of neurons that utilize acetylcholine or GABA or glutamate. The complexity of the neuronal composition in BF has long prevented a clear understanding of the causal role of each neuronal subtype on extracellular neurochemical alterations and modulation of cortical activity that underlies increased sleepiness and reduced alertness following prolonged neuronal activation during SD. Recent studies demonstrated that both cholinergic and parvalbumin (PARV) expressing GABAergic (PARV-pos GABA) neurons are active during wakefulness and are capable of modulating cortical activation. However, their distinct roles in sleep homeostasis are not clear. While neurotoxic lesions of cholinergic and GABAergic neurons have underlined the importance of these neurons in wakefulness and homeostatic sleep response, a direct cause and effect evaluation is best studied by selective manipulation of each neurotransmitter-specific neuronal cell types. The overall goals of this application is to discern the differences in the functional role of cholinergic and PARV-pos GABAergic neuronal activation in homeostatic sleep regulation. Using the state-of-the-art optogenetic technology to selectively manipulate the activities of cholinergic and PARV-GABA neurons combined with simultaneous polysomnographic recordings to monitor changes in cortical EEG and in vivo microdialysis for measuring extracellular neurochemical changes we will test the following model: Prolonged SD->BF cholinergic neuronal activation->increase extracellular NO and adenosine->inhibition of wake active cholinergic and non-cholinergic neurons->increased sleepiness. Successful completion of these exploratory studies will (1) validate a novel combinatorial method of performing optogenetics with in vivo microdialysis, (2) extend our understanding of the causal role of specific BF neuronal subtypes in modulating cortical EEG and homeostatic sleep response.

Public Health Relevance

Sleep deprivation is a wide spread problem with negative impacts on performance efficiency, health and cognition. The current application proposes to use in vivo microdialysis with the state-of-the-art method of optogenetics to selectively manipulate two major wake-active neuronal cell types to discern their role in modulating the homeostatic sleep factors that increase the propensity to sleep and decrease attention and cognition. Understanding the neuronal components involved in mediating neurochemical changes is important towards designing targeted treatment plans to counteract the effects of sleep deprivation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Gnadt, James W
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Harvard University
Schools of Medicine
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