Biology Reference
In-Depth Information
recordings in SWS, referred to as '
d
power' are hypothe-
sized to be a direct readout of the 'sleep pressure', or our
intrinsic drive to get sleep (more on the 'sleep homeostat'
later). Hence, when sleep-deprived one experiences an
increased 'need' for sleep which correlates with a corre-
sponding increase in
d
power for that
sleep were observed, indicating relative independence of
NREM sleep from Process-C
[39,43]
. However, these
studies and others
[44]
have also shown a strong correlation
of the circadian phase with the onset/density of REM and
wake-promoting signals.
Another facet uncovered in these studies is the
involvement of melatonin, a hormone secreted rhythmi-
cally by the pineal gland, in modulating sleep efficiency
[43]
. In the absence of photic entrainment, completely
blind patients often exhibit drastic circadian-rhythm irreg-
ularities and poor sleep
individual (also
referred to as 'rebound sleep';
[36]
).
As discussed above, our
d
power reflects our 'sleep
pressure', but what gates the onset of sleep? In answering
this question we arrive at the relationship between the
circadian system and the sleep
wake pathways. In 1982
Borb
ยด
rly proposed the two-process model, which in simple
terms proposes the presence of a circadian component or
'Process-C' that gates the onset of sleep/wake to an
ecologically relevant time, while a 'Process-S' acts as
a sleep homeostat to determine the duration, quality, and
depth of sleep
[37]
. It
wake rhythms
[45]
. Circadian re-
entrainment and enhanced sleep consolidation are observed
after scheduled, long-term administration of melatonin in
these blind patients
[46,47]
. Melatonin is observed to
phase-shift the circadian sleep
e
e
wake cycle, and although
the mode of action is not completely understood, studies
suggest that melatonin inhibits neuronal firing by acting
through its cognate receptors in the master-clock, the SCN
[48
e
is known that under a normal
sleep
wake cycle the homeostatic drive or Process-S
builds up in phase with the circadian-active phase or
Process-C. But during sleep Process-S is dissipated in an
exponential manner, with mammals spending about one-
third of a given 24-hour day resting or inactive. In corollary,
Process-C enables
e
51]
. Taken together, behavioral disentanglement
protocols have not only helped identify Process-C-inde-
pendent variables but also have definitively validated the
presence of a cross-talk between Process-C and Process-S.
Although the anatomical location of the sleep homeo-
stat is not known, the central oscillator governing the body
clock is located in the suprachiasmatic nuclei (SCN) of the
hypothalamus. Thus surgical removal of the SCN followed
by perturbation of sleep
e
wake
episodes by counteracting the increasing homeostatic
pressure of Process-S during the rest and wake phases,
respectively
[38
the consolidation of
sleep
e
40]
.
The existence of the two oscillating processes, Process-
C and Process-S, is now widely accepted. However, the
extent of the interdependence or independence of these two
processes remains contentious. Behavioral, surgical, and
genetic perturbation protocols have been utilized in an
effort to disentangle the contributions of these two oscil-
lating systems. Behavioral disentanglement protocols, for
example the 'forced desynchrony' and 'spontaneous
internal desynchrony' protocols, involve the complete
removal of the subject from the environmental and social
cues required for the normal circadian entrainment to the
24-hour day. Under the 'spontaneous internal desynchrony'
protocol, the subjects self-select their light
e
wake states has been performed
to disentangle the physiological role of sleep from circa-
dian functions. A classic study involving lesions of the SCN
in diurnal squirrel monkeys found a dramatic 4-hour overall
increase in the total sleep time in the lesioned monkeys
compared to their control counterparts
[52]
. Therefore, this
study suggested that the circadian pathways were involved
mainly in wake-promoting pathways. However, subsequent
studies using nocturnal rats, mice, hamsters and others
indicated a more complex role of SCN involving both
sleep- and wake-promoting functions (
[53,54]
; also see
review by Ralph Mistelberger
[55]
for extensive discussion
on this topic). Pleiotropic roles of any anatomical loci in the
brain, along with technical challenges of these studies, have
been a major limitation, making it difficult to reproduce and
compare the different studies. Two brain regions, the
ventrolateral preoptic nucleus (VLPO) and the lateral
hypothalamic area (LHA; see
Figure 21.1
), have been
unequivocally associated with sleep- and wake-promoting
centers, respectively. However, a detailed study on the
circadian output following VLPO or LHA lesions remains
to be performed.
Mechanistic understanding of the clock has proved
useful in uncovering its relationship to sleep. Molecular,
cellular, and behavioral studies have revealed a basic
mechanism of clock function in insects and mammals. The
molecular clock is made of interlocking feedback loops
governed by two families of transactivators (Bmal1/2 and
e
dark cycles;
under these 'free running' conditions, the homeostatic drive
and consolidation of sleep were found to remain intact.
However, dramatic differences in the phase relationship
between the two processes were observed: the onset of the
NREM sleep phase advanced by 6 hours to overlap the
nadir of core-body temperature rhythms, which oscillates
in a circadian fashion
[41,42]
. In 'forced desynchrony',
instead of a normal 24-hour day, the subjects are exposed to
a sleep
e
wake schedule imitating either very short (20 hr)
or long (28 hr) days. Such schedules are beyond the
entrainment limits, causing the biological clock to 'free-
run' and desynchronize with the sleep
e
wake cycle. Thus,
under forced desynchrony, sleep episodes occur at all
phases of the endogenous circadian cycle. But unlike sleep-
deprivation protocols, only minor changes in slow-wave
e
