National Sleep Disorders Research Plan
 
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Section 1 Content:
Pharmacology and Pharmacogenetics of Sleep and Waking
Circadian Biology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








SECTION 1 - BASIC SLEEP SCIENCE

Sleep Neurobiology


Background

Sleep time is defended by an accumulation of "sleep debt", the need for more sleep that results from sleep restriction. Recent study findings in animals and humans suggest that a complete and sustained loss of sleep can, in rare and extreme cases, result in death. It is likely that an understanding of the effects of sleep loss will reveal basic principles of brain function relevant to a broad spectrum of neurological and behavioral disorders. Sleep is known to strongly affect the activity of most brain neurons.

Modern sleep neurobiology research has not yet achieved consensus as to the function of sleep. What determines the brain's memory for sleep loss? What is the neurological deficiency being regulated by the sleep debt memory? Does active (REM) sleep have different functions than quiet (nonREM) sleep?

Functional significance of the marked differences in amount of sleep within the animal kingdom is unknown. Similarly, the considerable variation in the duration of the sleep cycle (Wake-nonREM-REM) in different species of mammals from a high of 2 hours to as little as 15 minutes is poorly understood, as are the determinants and health significance of the variations of sleep duration within the human population.

Progress In The Last 5 Years

- Molecular biological approaches have contributed to understanding sleep control mechanisms. These approaches have led to one of the greatest achievements of sleep research since the discovery of REM sleep, the identification of the hypocretin (orexin) system and its central role in Narcolepsy and behavioral control.

- Genetic expression studies of sleep in drosophila (fruit flies) have produced important discoveries about the genetic basis of sleep. Moreover, they have established this species, with its well-documented and readily manipulated genome as a valid model of sleep genetics, making further rapid progress likely. Studies of murine mutants have progressed along the same lines. A better understanding of the populations of genes activated by sleep, waking and sleep deprivation and the time course of this activation has been made possible by the application of recent developments in simultaneous assessment of the activity of large numbers of genes.

- Studies using polymer-encapsulated suprachiasmatic nuclei (SCN) and related studies of diffusible factors released by the SCN have identified some of the major mediators of circadian-sleep relations.

- Less progress has been made in elucidating at a molecular level the phenomenon of sleep debt. The functional and biochemical regulation of changes in sleep time, REM and nonREM amounts and sleep morphology (e.g. delta power, eye movement intensity) with development remains mysterious, although some progress has been made in characterizing the neurophysiology and neurochemistry of sleep changes across the lifespan.

- Progress has been made in the electrophysiology of sleep at the neuronal level. The mechanisms responsible for generating and synchronizing rhythmic neuronal activity in nonREM sleep have been localized to thalamic regions and the ionic currents mediating rhythmic discharge have been identified. Cell groups in the hypothalamus and basal forebrain critical in the control of nonREM and REM sleep have been identified with anatomical and electrophysiological techniques. Some recent evidence suggests that localized brain mechanisms may mediate sleep debt.

- Important roles of amino acid and monoamine mechanisms in regulating muscle tone at the motor-neuronal level across the sleep cycle have been demonstrated. The circuitry controlling neurotransmitter release has been clarified. These advances are important in understanding numerous sleep disorders including Sleep-Disordered breathing (sleep apnea), cataplexy, REM sleep behavior disorder and other parasomnias.

- The neurochemical phenotypes of major groups of neurons contributing to REM and nonREM sleep regulation have been identified. Previously appreciated monoaminergic (serotonin, norepinephrine, epinephrine, dopamine, histamine) mechanisms have been shown to interact with amino acid (glutamate, GABA, glycine) neurotransmitter systems at forebrain and brainstem levels. Anatomical connections between the neurons critical to REM and nonREM sleep have been traced. Hypocretin/orexin has been identified as an important modulator of activity in sleep control systems. Other peptides important in the control of sleep states have been described and localized to brainstem and forebrain sleep control regions.

- Limited progress has been made in understanding the phylogeny of sleep. REM sleep has been found in primitive mammals. Some birds may show interhemispheric EEG asymmetry during sleep. Unihemispheric sleep and unihemispheric sleep debt has been found in marine mammals.

Research Recommendations

Determine the function of sleep as a whole and of the differential roles of REM and nonREM sleep. It will be helpful to study genetic mutant murine and invertebrate models with unusual sleep properties. An under-exploited resource is the variation in sleep time and quality in the animal kingdom. As the cost of sequencing continues to be reduced, it becomes practical to sequence the genomes of diverse species to determine the genetic basis of these differences. Advances in technology have made it practical to better record and characterize the great differences in sleep duration and quality between species. Recent work demonstrates that sleep is present unihemispherically in some mammals. In other animals, REM sleep appears to occur without the low voltage activity seen in most mammals. In still other mammals, blood pressure, heart rate, respiratory changes, eye movements, erections and other phenomena characteristic of human sleep do not occur. These variations in mammalian and in non-mammalian species, particularly if understood in an ecological context and at the cellular level, can provide a major insight into the functions of sleep.

- Bridge the gap between what is now known about the anatomy and neurochemistry of sleep, wake and waking arousal generating systems and the nature of the information processing that occurs at the synapses within these systems. Identification of the functional role played by each neurochemical link and the analysis of neurotransmitter interactions would, for example, facilitate the development of drugs to control muscle tone over the sleep-wake cycle.

- The pathophysiology and neurochemistry of sleep disorders needs to be better understood. How abnormal operation of sleep regulatory systems results in sleep disorders needs to be clarified. The anatomical and pathophysiologic causes of REM sleep behavior disorder, Sleep-Disordered Breathing (SDB), periodic limb movements during sleep, and parasomnias are poorly understood. Major advances have occurred in our understanding of Narcolepsy (Section V). Further work is needed, however, to clarify the cause of Narcolepsy without cataplexy and how disorders of the hypocretin/orexin system and other systems produce the multiple symptoms of narcolepsy. Work in this area represents a great opportunity for clarifying basic issues of sleep control and sleep pathology.

- An understanding of sleep debt at the biochemical and genetic level is needed, building on the new knowledge of sleep control at the neuronal level. The biochemical and genetic substrates of waking and arousal during waking and of REM sleep and nonREM sleep debt need to be understood.

- Interactions between sleep states and thermoregulatory, metabolic, cardiovascular and respiratory regulation at all levels of the neuroaxis need to be better described and understood. The role of sex, sex hormones, sexual maturity, pregnancy and lactation in sleep control needs to be investigated at a mechanistic level.

 
 
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National Heart Lung and Blood Institute (Click Here) National Center on Sleep Disorders Research (Click Here)