Sleep loss leads to impaired cognitive performance and excessive daytime sleepiness. These symptoms of sleep loss are now recognized as major contributors to accident rates and decreased workplace productivity. Mice will be used to model two types of human sleep loss that produce daytime sleepiness and cognitive impairments: 1) Total sleep deprivation, which can occur due to vocational demands such as shift work or emergency work, and, 2) Sleep fragmentation, a pattern of sleep disturbance seen in many clinical disorders including sleep apnea. Sleep fragmentation disrupts the continuity of sleep and interferes with the restorative effects of sleep. Despite the fact that total sleep time is not greatly reduced by sleep fragmentation, we hypothesize that the physiological and behavioral consequences of sleep fragmentation will be similar to those of total sleep deprivation. The overall goal of this proposa is to understand the role of basal forebrain (BF) neurons in sleep loss induced deficits in wakefulness and vigilance. To accomplish this goal, mice will be used to test the hypothesis that BF GABAergic parvalbumin (PV) and cholinergic - positive neurons enhance wakefulness/alertness, attention, and cortical activation. Both BF PV and cholinergic neurons are hypothesized to be arousal promoting via their cortical projections. Hence, we predict that activation of these arousal promoting BF neurons can reduce sleep-loss induced impairments. Based on preliminary data, we further hypothesize that BF PV neurons will more potently enhance wakefulness, attention, and cortical activation relative to BF cholinergic neurons; PV neurons are also predicted to more effectively reduce the impairments in these measures observed in sleep deprived mice. Abundant evidence indicates that the BF contains cortically projecting and wakefulness promoting neurons that are important for cortical activation and wakefulness (e.g., large non-specific cell body lesions in BF produce a coma-like state). However, only recently have optogenetic methods been available to precisely determine the role of neurotransmitter specific neurons in the brain. Optogenetic inhibition of BF neurons in Aim 1 is predicted to simulate the effects of sleep loss, demonstrating the necessity of BF PV and cholinergic neurons in the sleep loss induced impairments.
Aim 2 will determine if: a) excitation of BF neurons is sufficient to enhance wakefulness, attention, and cortical activation in non sleep deprived mice, and, b) excitation of BF neurons will reduce sleep loss induced impairments in wakefulness, attention, and cortical activation.
Aim 3 will measure the single unit activity of optogenetically identified BF neurons to confirm that their discharge pattern is consistent with their proposed physiological role in the regulation of natural sleep and wakefulness, and in the mediation of the cortical activity responses to sensory stimuli. The following preliminary data support these hypotheses and predictions: 1. Inhibition of PV neurons reduces measures of wakefulness, attention in the novel object recognition task, and evoked cortical activation; thus, the effects of inhibition of BF PV neurons closely resemble the effects f sleep loss on these measures. 2. Excitation of BF PV neurons produces wakefulness and cortical activation and BF PV unit activity is increased during wakefulness. Compared to BF PV neurons, excitation of cholinergic neurons appears to produce a more modulatory, slower and less powerful behavioral and physiological response. If successful, the experiments proposed will demonstrate mechanistic links between BF unit activity, cortical activation, wakefulness/arousal, and attention. Thus, these findings will guide the development of therapeutic interventions targeting the subcortical arousal promoting neurons to treat the consequences of sleep disorders which are prevalent in the Veteran population.

Public Health Relevance

The basic research proposed will guide the development of therapeutic interventions to treat sleep disturbances and their side effects in order to improve the health and safety of Veterans. Veterans have a very high incidence of sleep problems, with sleep apnea and chronic insomnia being the most common. Veterans with PTSD or TBI have even higher incidences of these and other sleep disorders. The most common symptoms of insomnia and sleep apnea are excessive daytime sleepiness and cognitive impairments, which are now recognized to contribute to accidents (e.g., over 5,000 fatal traffic accidents per year), and to decreases in workplace productivity. 50 to 70 million Americans have a chronic sleep disorder and many others lose sleep due to vocational demands (e.g., shift workers, emergency/military workers). Once sleep problems arise they also aggravate a variety of mental and medical health conditions which affect US Veterans, including psychiatric disorders, diabetes, chronic pain, and heart disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology R (NURR)
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VA Boston Health Care System
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