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Adenosine and the Basal Forebrain in the Control of Behavioral State


Many people reduce their sleep due to medical and non-medical reasons, a pattern that is called chronic sleep restriction (CSR). Reducing sleep for as little as 2 h for several days can impair cardiovascular, immune, and endocrine functions, as well as cognition and daytime vigilance. Sleep disturbances, such as CSR, accompany and aggravate many medical conditions affecting US veterans including PTSD, heart disease, psychiatric disorders, and chronic pain. In experiments, humans report a normalization of subjective sleepiness after as little as 2 or 3 days of CSR (i.e., 3 nights of sleeping only 4h or 6h/night); however, objective sleep onset latency measures indicate that sleepiness increases steadily. Cognitive performance also declines steadily over 14 days of CSR. Thus, humans adapt to some of the perceptual and neurophysiological consequences of CSR, whereas other effects do not adapt. Similar CSR results in rats are described in Aim 1. The biological consequences of CSR have been little investigated due to the relative lack of animal models of CSR. The overall goal of this proposal is to understand the neurobiology underlying the behavioral/physiological consequences of CSR using a rat model. Male rats will be allowed 4, 6, 14, or 24h/day of sleep opportunity for up to 10 days, followed by 5 recovery days. Cage motion is used to produce the periods of wakefulness. Rats adapt readily to this procedure and show no signs of discomfort or stress. The overarching neurobiological hypothesis is that the inhibitory neuromodulator adenosine (AD) mediates the sleepiness and cognitive impairments associated with CSR. The previous findings of this VA merit grant support the hypothesis that AD is a mediator of the sleepiness that follows short periods of sleep loss, a role in which its inhibitory action on the basal forebrain wakefulness-promoting neurons appears especially important. Short periods of sleep loss also increase AD A1 receptor mRNA, supporting our prediction that CSR will increase A1 receptor number in order to maintain elevated levels AD inhibitory tone (i.e., positive feedback). The proposed aims will answer the following questions: Aim 1. What are the effects of CSR on sleepiness and vigilance performance? (using sleep recordings, sleep latency tests, and operant tests of sustained attention). CSR is predicted to produce sleepiness and cognitive impairments in rats (like in humans). Aim 2. What is the effect of CSR on spatial learning and memory (water maze), and on long term potentiation (LTP; a measure of synaptic plasticity important for memory formation). We predict that the CSR-induced spatial memory impairments are mediated by an increase in hippocampal AD tone which reduces LTP. Aim 3. What is the effect of CSR on brain AD tone? (measuring brain extracellular AD levels; AD A1 & A2a receptor mRNA, A1 density & binding). Do the predicted increases in AD receptors alter the behavioral & physiological response to AD drugs? On the first day of CSR, we predict that the behavioral symptoms will correlate with an elevation of BF AD levels, whereas on CSR days 3-10, changes in A1 & A2a receptors maintain elevated levels of AD inhibition in the brain. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance to Veterans' health and/or healthcare issues. All human life, and indeed the life of all mammals, is shaped by periods of wakefulness and sleep, and thus knowledge of the underlying mechanisms is of great biological, social and medical significance. An understanding of how the brain regulates natural sleep holds the promise of providing a basis for the rational development of treatments for sleep disorders affecting the veteran population, such as sleep apnea, narcolepsy, insomnia, and sleep disturbance related to PTSD and traumatic brain injury. Basic research on endogenous neural sleep factors, such as adenosine, could lead to a new generation of medications to both treat insomnia and, conversely, promote attention & vigilance. The significance of this line of research is underscored by the fact that Robert W. McCarley, Director of the Lab of Neuroscience, received the Middleton Award in 2000 based on the adenosine work of the laboratory. The rat model of chronic sleep restriction proposed has high external validity, as many people in our society habitually reduce the amount of sleep they obtain. The recent establishment of an animal model of chronic sleep restriction will provide opportunities for studies aimed at all levels of investigation (from molecular events to behavioral effects). Excessive daytime sleepiness and difficulty maintaining alertness are very common medical complaints, with even greater prevalence in older males, such as the population of US veterans. Chronic sleep restriction can cause or aggravate the symptoms of sleepiness leading to impaired occupational performance and safety, as well as impacting on general health and quality of life. The ability to perform at a high level under the condition of limited sleep is also very important to active military personnel, doctors in residency training, and emergency & transportation workers, just to name a few. Hence, a better understanding of the behavioral and neurobiological consequences of chronic sleep restriction is important for the health care of the veteran population. Recognizing the importance sleep hygiene for the VA healthcare system, we recently began work on an animal model of chronic sleep restriction. This research can be expected to benefit the VA population rather quickly. For example, within 2 yr, the rat models we have developed will be available for testing drugs influencing alertness and sleep. Clinical trials of experimental medications or interventions could follow shortly thereafter via our collaborators doing human research. In conclusion, there is a direct path from our studies on animal models to related clinical research, which could lead to improved medical care of veterans.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.