Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 138

hypothalamus (hypocretin, histamine), and elsewhere in the brain (adeno-
sine, acetylcholine, GABA). There are dozens of other neuroactive sub-
stances (peptides, immune molecules, hormones) that influence sleep,
but significantly less is understood about their role. The functions of
neuromodulators are likely redundant for the experience of sleep and wake,
but they are also likely to have specific, nonoverlapping roles for specific
physiologic events associated with each state. A better understanding of
the physiology and neurochemistry of the systems underlying sleep and
wake can lead to a greater understanding of the manner in which disease
and its treatment can lead to reciprocal alterations in sleep and wake
( Fig. 6.1 ) .
1. THE BRAIN STEM
Seminal experiments done in the 1930s and 1940s 1,2 identified the
brain stem as an area of critical importance for occurrence of normal sleep
and wake. These early experiments “proved” the prevailing concept of sleep
as being a default brain state and wake being actively stimulated by sensory
input. Current scientific thought is that both sleep and wake are actively gen-
erated states. There are multiple discreet nuclei in the brain stem that con-
tribute to the generation of sleep and wake. These nuclei innervate both
cortical and subcortical structures and are primarily responsible for the syn-
chronization or desynchronization of electroencephalographic (EEG) activ-
ity. EEG synchrony is coordinated by the activity of thalamocortical neurons
that have two primary firing modes—single-spike firing and burst firing. 3
Single-spike firing occurs during wake and is permissive for independent
(i.e., nonsynchronized) cortical EEG activity. During single-spike firing,
the membrane potential of thalamocortical neurons is kept elevated by
the excitatory influences of a variety of neuromodulators. The excitatory
stimuli are primarily derived from nuclei in the basal forebrain (acetylcho-
line) and brain stem (noradrenaline, dopamine, serotonin, acetylcholine).
During nonrapid eye movement sleep (NREMS), there is a reduction in
the release of these excitatory transmitters, resulting in a decrease of
thalamocortical neuron membrane potential that leads to the expression
of T- and H-currents and a shift from single-spike firing to burst firing. 3 This
regular burst firing allows the thalamocortical neurons to synchronize the
firing of large numbers of cortical neurons, leading to the EEG synchroni-
zation that is indicative of NREMS. In rapid eye movement sleep (REMS),
there is a return of acetylcholinergic tone, which is sufficient to raise the