Abstract
Being awake, alert, and able to function in our 24-7 world is a challenge in the face
of the fatigue and sleepiness engendered by long work hours, unusual work schedules,
sickness, and other factors. Development of effective treatments to combat fatigue
and sleepiness requires an understanding of the neurobiology of wakefulness. In this
brief review, we examine the neuroanatomical, neurochemical, and molecular basis of
the wakeful state to provide a framework for understanding current and future pharmacologic
approaches to modification of wakefulness. The spontaneously awake state can be defined
as a natural state of vigilance or arousal differing from natural sleep in both behavior
and neural activity. These differences have long intrigued researchers and largely
have been characterized in the brain areas and neurochemical systems affecting the
sleep and wake states. Many of the strategies for promoting the awake condition involve
manipulation or modulation of specific neurochemical systems with the ultimate goal
of enhancing wakefulness, diminishing sleepiness, or both. Wakefulness is an important
cortical function that depends on the coordinated effort of multiple brain areas including
the thalamus, hypothalamus, and basal forebrain to integrate and relay information
from the brainstem to the cortex. Norepinephrine and serotonin—long considered arousal-enhancing
transmitters as well as glutamate, acetylcholine, histamine, and the neuromodulators
hypocretin-orexins and adenosine, are known to affect the signal transduction in these
brain areas and initiate, promote, or enhance wakefulness. Use of molecular tools
to evaluate the awake, asleep, and sleep-deprived state has revealed novel insights
concerning the gene expression events associated with wakefulness. Understanding wakefulness
at this level undoubtedly will contribute to the development of pharmacologic approaches
to promote or enhance the wakeful state. We caution, however, that sleep may have
a necessary, restorative function for the brain; therefore, prolonging wakefulness
for long periods through artificial means could have unexpected and perhaps detrimental
consequences on brain health.
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© 2006 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
