1 - BASIC SLEEP SCIENCE
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?
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
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.
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.