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Current Understanding of the Circadian Clock and the Clinical Implications for Neurological Disorders
Fred W. Turek, PhD;
Christine Dugovic, PhD;
Phyllis C. Zee, MD, PhD
Arch Neurol. 2001;58:1781-1787.
ABSTRACT
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The changes in behavior that occur
on a 24-hour basis to match the 24-hour changes in the physical
environment due to the rotation of the earth on its axis are a hallmark
of life on the planet Earth.1 The nervous system of both
lower and higher organisms has evolved over millions of years to meet
the demands of the dramatic changes in the physical environment that
occur in relation to the changes in the light-dark cycle, optimizing
the survival and reproductive success of the organism. During the past
50 years, it has been clearly established that the 24-hour nature of
life was not simply a response to the 24-hour changes in the physical
environment imposed by celestial mechanics, but instead was due to an
internal time-keeping system in the brain. Many neurological disorders
are associated with abnormal 24-hour rhythms, including the sleep-wake
cycle. The recent discovery of the molecular basis of the neural clock
in animals offers neurologists new avenues for studying the
pathophysiology of neurological disorders.
INTRODUCTION
The internal nature of the 24-hour timing system
becomes apparent when an animal is placed in an environment devoid of
all external 24-hour signals; under these conditions, diurnal rhythms
persist with a free-running period of about 24 hours and are thus
called "circadian" (ie, approximately 1 day) rhythms.1
The most obvious 24-hour rhythm in most animals is the sleep-wake
cycle, in which sleep and wake occur at specific times of the day
and/or night.2 In mammals, the central circadian clock that
regulates the timing of sleep and wake, as well as most if not all
24-hour rhythms, is located in a small region of the hypothalamus
called the suprachiasmatic nucleus (SCN). While the
expression of many 24-hour rhythms may be primarily under the control
of the circadian clock in the SCN, many other rhythms are largely
dependent on whether the organism is asleep or awake, regardless of the
circadian time.3 Thus, the expression of most 24-hour
rhythms at the behavioral, physiological, and biochemical levels
depends on the integration of inputs from the circadian clock and the
sleep-wake systems of the animal.
Sleep and the expression of many metabolic and endocrine
circadian rhythms are often disrupted in people with neurological
disorders.4 Indeed, the symptoms associated with various
neurological diseases may be due in part to disruption of the
sleep-wake cycle. In addition, various neurological disorders may
themselves disrupt the sleep-wake cycle, resulting in a positive
feedback loop whereby disrupted sleep and wake exacerbate the
neurological disorders while the disease itself has a negative effect
on the sleep-wake states. After first reviewing what is known about the
circadian clock underlying the timing of the sleep-wake cycle, as well
as other 24-hour rhythms in mammals, this article will focus on the
relevance of sleep and circadian rhythmicity for the practice of
neurology as well as for the study of neuroscience in general.
WHERE IS THE
CIRCADIAN CLOCK, AND
HOW DOES IT TICK?
Neuronal Perspective
The finding in the early 1970s that lesions on a small region of the
hypothalamus in rodents led to a disruption of endocrine and behavioral
circadian rhythms was the first step in the ultimate demonstration that
the bilaterally paired SCN was the location of a master central
circadian pacemaker, or clock, which regulated most if not all
circadian rhythms in mammals.5 During the following 3
decades, many elegant studies were performed in mammals (mainly
rodents), which in aggregate demonstrated that:
- Total destruction of the SCN abolishes many behavioral, endocrine, and
metabolic circadian rhythms.
- Isolated SCN tissue in vivo and in vitro could maintain 24-hour neural
firing and/or neurosecretory rhythms.
- Transplantation of fetal SCN tissue into the brains of arrhythmic
SCN-lesioned animals could restore circadian rhythmicity, and the
restored rhythm in some studies was shown to have genetically defined
characteristics specific to the donor and not the SCN-recipient
animals.
- Cultures of individual dissociated SCN neurons continue to express
circadian oscillations in firing rates that differ from cell to cell.
This latter finding is particularly noteworthy because it
demonstrates that the expression of circadian rhythms by a complex
neural structure is not a property of a network of neurons that depend
on their interaction with one another.6 Instead, individual
SCN neurons have intrinsic 24-hour oscillatory properties; thus the
ultimate underlying clock mechanism is within the neuron. Nevertheless,
clearly the thousands of neurons in the SCN are not each keeping their
own time independent of one another. Instead, they must somehow be
coupled to one another such that, ultimately, a single coordinated
circadian signal(s) is generated and conveyed to the rest of the brain
and the peripheral organs of the body.
Although the SCN-driven circadian rhythms can be expressed in the
absence of any 24-hour changes in the physical environment, under
normal conditions the SCN circadian clock must be entrained to the
24-hour day. For most organisms, the light-dark cycle is the major
environmental synchronizing agent, and in mammals, a special retinal
hypothalamic tract connects the photoreceptors in the eye to the
SCN.7 In addition to the retinal hypothalamic tract input
to the SCN, the circadian clock receives neural inputs from a variety
of neural areas in the brain.8 Of particular note are the
serotonergic (5-HT) projections from the brainstem raphe nuclei that
project both directly and indirectly to the SCN. In view of the central
role of the 5-HT system in the causes of many neurological and
psychiatric disorders, the 5-HT system may be involved in the
disregulation of circadian rhythms that are often associated with these
disorders.
Molecular Perspective
Since the circadian clock in mammals resides in the SCN, and individual
SCN cells can maintain circadian rhythmicity, the molecular mechanisms
by which 24-hour rhythms can be generated must reside within the SCN
cells. This molecular machinery remained a complete mystery until just
a few years ago when the first mammalian circadian clock gene, called
Clock, was discovered.9 Prior to the discovery and
cloning of the Clock gene in 1997,9 many genes and
their protein products were known to be expressed in the SCN on a
rhythmic basis, and protein synthesis was clearly important for the
expression of circadian timing.10 The core elements of the
molecular mammalian circadian clock, however, remained
unknown despite the fact that molecular components of the
Clock in the fruit fly, Drosophila, and the
filamentous fungi, Neurospora, had been identified in the
1980s.11
Because no mammalian orthologs to per or tim had been identified in the
early 1990s, and no other genes in mammals were even possible candidate
circadian genes, a team of investigators at Northwestern University
(Evanston, Ill) applied a directed "forward genetic" approach in
mice to identify the first circadian clock genes in mammals. The
approach involved using a chemical mutagen to induce a high random
mutation rate in the germ line of mice. The offspring of these animals
were then screened for an abnormal circadian phenotype that would be
due to a dominant or semidominant random mutation of a gene involved in
the generation of circadian rhythms.12 One such animal was
identified early in the screen. This founder animal had a free-running
period of the activity rhythm in constant darkness that was an hour
longer (~24.7 hours) and 6 SD from the mean period observed in
wild-type mice (Figure
1). Breeding of this putative
mutant animal and its offspring established that the change in
phenotype was due to a mutation that was inherited in a classical
mendelian fashion. In mice carrying 2 copies of the mutated gene, the
period of the activity rhythm was initially 27 to 28 hours under
free-running conditions, and quite often the activity rhythm became
arrhythmic after extended exposure to constant darkness (Figure
1). The gene responsible for the altered phenotype has been
mapped and cloned.9, 13
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Figure 1.
Activity records of 3 mice. Each day's activity data are presented
beneath the preceding day. For the first part of each record, the
animals were maintained on a 12-hour light/12-hour dark cycle (LD),
with darkness represented by the black bar at the top of each record.
On the days noted, the animals were transferred from the LD cycle to
constant darkness (DD). A, the activity record of a normal
C57BL/6J mouse. Note that the free-running period in DD is
approximately 23.7 hours. B, The activity record of a C57BL/6J mouse
carrying 1 copy of a mutant Clock gene. Note that the
free-running period in DD is approximately 24.8 hours. C, The activity
record of a C57BL/6J mouse that is carrying 2 copies of the mutated
Clock gene. Note the very long (~28 hours) free-running
rhythm during the first few days in DD before the rhythm becomes
chaotic after extended exposure to DD.
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Soon after the Clock gene was discovered, there
were many rapid advances that integrated the mouse and fly molecular
circadian clock gene stories.14 Until recently, no specific
gene had been identified as a component of the molecular circadian
clock in humans. However, the discovery of the genes in mice ensured
that it was only a matter of time before the presently known (and
unknown) clock genes would be implicated in human circadian function.
Indeed, the recent report that a missense mutation in the human
per2 gene underlines advanced sleep phase syndrome in at
least some humans15 indicates that other abnormal clock
gene alleles will be discovered to underlie unusual circadian
phenotypes in humans.
RELEVANCY OF THE CIRCADIAN CLOCK TO THE PRACTICE OF NEUROLOGY
As noted earlier in this review, the circadian clock can influence the
24-hour overall temporal organization in a direct as well as indirect
fashion by controlling the timing of the rhythm of sleep and wake that
in turn has a strong influence on the timing of many
rhythms.3 Furthermore, changes in the sleep-wake and
activity-rest cycle itself can influence the circadian clock; thus, it
is often difficult to separate the influence of the circadian and
sleep-wake system in contributing to various disorders. Indeed, the
highly integrated nature of these 2 systems suggests that they should
be considered in combination when trying to relate temporal
disorganization to various disease states, including neurological
disorders.
Disorders of circadian temporal organization come in 2
general varieties: those imposed by the lifestyle of the individual
(eg, in shift workers or in individuals moving rapidly across time
zones [the jet-lag syndrome]), and those that arise from endogenous
alterations in normal rhythmicity. Disturbed sleep and circadian
rhythms are apparent in many neurological disorders. Briefly reviewed
in this section are the sleep and circadian rhythm disturbances
that have been associated with the most common neurological disorders,
including epilepsy, dementia, cerebrovascular disease, movement
disorders, neuromuscular disorders, demyelinating disease, and
headache. A more extensive coverage of this subject can be found in a
recent review by Zee and Grujic.4
Epilepsy
It has been known for more than a century that seizures occur
preferentially in most patients at particular times of the day or
night, with some patients expressing seizures during the day and others
during sleep. In general, primary generalized seizures occur during the
day, while secondary generalized convulsions occur most often during
sleep. The time of day dependency of seizures tends to disappear with
aging, although it is not known if age-related changes in the
sleep-wake and circadian clock systems influence age-related changes in
the daily temporal control of seizures.
Just as sleep and arousal states influence the occurrence and
expression of seizures, seizures in turn affect sleep; poor sleep is
associated with many neurological disorders, which may contribute
to the pathological symptoms of the primary disorders. For
example, the severity of neurological
abnormalities in patients with epilepsy is positively correlated
with the degree of sleep disturbance. In addition to sleep, other
circadian rhythms (eg, endocrine and neuroendocrine) often show
abnormal phasing and/or amplitude in epileptic patients.
Dementia
A wide variety of diurnal rhythm disturbances have been associated with
Alzheimer disease (AD), the most common dementia in most industrialized
countries.16 Disruption of nocturnal sleep with nocturnal
wanderings, which may be due to a disruption of
circadian rhythmicity, is one of the major problems that precipitates
nursing home institutionalization of patients with AD. In addition to
alterations in the sleep-wake and rest-activity cycles, changes in body
temperature and various endocrine and physiological rhythms have been
noted in patients with AD, with the severity and nature of the rhythm
disruption often being associated with the severity of the disease. Of
particular importance for the care of AD patients is the high incidence
of "sundowning," during which patients with dementia show highly
agitated and disrupted behaviors near the end of the day. These
behaviors are difficult to manage and can be overwhelming for the
caretaker, whether in the home or an institution.
Of particular interest to circadian neurobiologists is the finding that
aging is associated not only with a decreased amplitude of many
behavioral and metabolic rhythms, but also with the expression or
number of neuropeptide cells in the SCN. While there are reports that
the SCNs of patients with AD at autopsy show a decrease in vasopressin
cell number and peptide levels, the functional significance of these
changes is unknown.
In addition to AD, other disorders that induce dementia, such as
Huntington disease and the various prion diseases, are associated with
disturbed sleep-wake cycles. Interestingly, mice with a deletion of the
prion protein exhibit prominent sleep fragmentation and an alteration
in circadian period, indicating that the prion protein is somehow
involved in the regulation of sleep and circadian
rhythms.17 In addition to the pronounced sleep
abnormalities that are the hallmark of the prion disease,
fatal familial insomnia, circadian rhythmicity in various endocrine
rhythms are abnormal or absent in patients with this disease,
suggesting that the central circadian pacemaker itself may be
affected.
Dementia owing to hepatic encephalopathy is also associated with
disturbance of the sleep-wake cycle and circadian rhythmicity. Indeed,
animal studies involving a surgical induction of
hepatic encephalopathy have demonstrated that such a procedure results
in abnormal endocrine and behavior rhythms.18 These rhythm
disturbances can be reversed or attenuated with a low-protein
diet or neomycin, indicating that altered circadian rhythmicity is
caused by the effects of liver dysfunction on the circadian clock
system.4 In humans, hepatic failure results in a
variety of circadian abnormalities,19 including both an
increased amplitude and a phase delay in the onset and offset of the
nocturnal melatonin rhythm (Figure
2). The question of whether
sleep and circadian rhythm abnormalities in humans with liver
dysfunction are due to a direct effect on the circadian clock and/or
sleep regulatory mechanisms or are a consequence of alteration in
hepatic metabolism of hormones such as melatonin remains unanswered.
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Figure 2.
Mean ± SE plasma melatonin levels in a group of control
subjects and in a group of patients with liver disease. Blood samples
were collected at 30-minute intervals for 24 hours. Patients with liver
disease showed not only elevated plasma levels of melatonin, but also a
delay in both the onset of the rising and declining phase of the
melatonin rhythm when compared with controls. The vertical dashed line
denotes midnight.20
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Cerebrovascular Disease
Sleep disturbances are common in people who have had stroke. This
may not only decrease the quality of life, but also lead to an increase
in morbidity. Quite often, the type of sleep disturbance is related to
the location and size of the stroke. Because the brainstem and the
thalamus are important in the regulation of sleep, strokes in these
areas commonly affect sleep.
The circadian variation in the time of the onset of ischemic
stroke is a good example of how the overall temporal organization of
many physiological systems can effect human health and disease.
Ischemic strokes (as well as myocardial infarction) most often occur in
the morning during the first few hours of wakefulness. In the morning,
upon awakening and moving to an upright posture, there is an increase
in blood pressure and heart rate. In addition,
there is an increase in platelet aggregability, catacholamine
levels, and plasma renin activity. All these rhythmic changes interact
to promote changes in vascular tone, which can increase the risk of
ischemia.
Movement Disorders
Abnormal motor activity during wake and sleep is often
associated with a disruption of sleep. Several movement disorders are
specific to sleep, including periodic leg movement syndrome, rapid eye
movement (REM) sleep behavior disorder, and nocturnal dystonia. In
periodic leg movement syndrome, movements are followed by changes in
the electroencephalogram that are suggestive of arousal from sleep; the
resultant sleep fragmentation can lead to severe insomnia and excessive
daytime sleepiness. The distinguishing feature of REM behavior sleep
disorders is the loss of motor inhibition during REM sleep, which can
result in increased and often dangerous motor activity during REM
sleep, as the patient appears to be enacting events associated with
dreaming. In contrast, nocturnal paroxysmal dystonia involves
stereotypic body movements during non-REM sleep, particularly during
slow-wave sleep. The debate as to whether nocturnal paroxysmal dystonia
is a sleep or seizure disorder only highlights the fact that the sleep
and wake states can influence seizure in the
way that they affect activity in the brain.
Sleep abnormalities are often associated with waking movement
disorders, including Parkinson disease, progressive supranuclear palsy,
and the Shy-Drager syndrome. The finding of sleep difficulties in the
majority of patients with Parkinson disease is perhaps not surprising
since the disease is caused by a loss of function in brainstem nuclei
that are also involved in the control of sleep. Various hormonal and
physiological circadian rhythm abnormalities have been reported in
patients with Parkinson disease, and this may be due to an altered
input of brainstem nuclei to the SCN.
Neuromuscular Disorders
Frequent complaints among patients with neuromuscular disorders include
daytime sleepiness and fatigue. Both motor and respiratory disturbances
during sleep undoubtedly contribute to daytime fatigue in patients with
the most common neuromuscular disorders, including muscular dystrophy,
amyotrophic lateral sclerosis, postpolio syndrome, and myasthenia
gravis. In myotonic dystrophy, the most common form of muscular
dystrophy, excessive sleepiness is quite often observed. Such
hypersomnia could be due to neuronal damage in areas of the thalamus
that are known to be involved in the regulation of the sleep-wake
cycle, again highlighting the interdependence of sleep and neurological
disorders.
Multiple Sclerosis
Multiple sclerosis, a demyelinating disorder that affects multiple
central nervous system white matter tracts, is associated with
prolonged sleep latency, frequent nocturnal awakenings, nonrestorative
sleep, and early-morning awakenings. It is not surprising that sleep is
affected in such a diverse manner since patients with multiple
sclerosis have a diverse set of abnormalities that can affect the
quality and quantity of sleep, including immobility, spasticity,
urinary problems, respiratory control, and periodic leg movements.
Headaches
The most common types of headaches that are associated with sleep and
circadian rhythmicity are migraine, cluster, and chronic paroxysmal
hemicrania. Headache and sleep disorder frequently occur in the same
patient, which may be due to the fact that some neurotransmitters that
regulate sleep, such as serotonin and histamine, have also been
implicated in some types of headaches. Both cluster and migraine
headaches have a strong circadian component to their occurrence.
Interestingly, cluster headaches occur most often in the spring and
fall, when day lengths are changing the most rapidly. In mammals, the
circadian clock in the SCN plays a central role in measuring the
seasonal change in day length, which can in turn influence a wide
variety of physiological systems. The finding of a seasonal change in
headache occurrence is a reminder that we have just begun to understand
the many ways in which the circadian clock system may affect and
modulate neurological disorders.
RELEVANCE OF THE CIRCADIAN CLOCK TO NEUROSCIENCE
A few years ago a "birthday party" was held at Harvard Medical
School to celebrate the 25th anniversary of the discovery that
lesioning of the SCN abolished circadian rhythmicity in rats. This was
the first clear experimental result that eventually led to the
demonstration that the SCN was the site of the master circadian
pacemaker in mammals.20 One of the themes of the
party/symposium was that discoveries about SCN function were often at
the forefront in terms of the use of new neuroscience approaches and
techniques. Perhaps the main reasons for this were the "simple"
nature of the circadian clock and the "simple" method for
monitoring clock functions in mammals. The first simplicity was the
relatively basic anatomical location (the SCN) of a neural center
regulating complex behavioral and physiological rhythms. Whereas other
behaviors such as reproduction, feeding, sleep, and learning
involve many and diffuse areas of the brain, the generation of
circadian rhythms could be located to a few thousand neurons in close
proximity to one another. The second simplicity was the use of an
elementary and inexpensive method for monitoring a "reporter output
rhythm" of the central circadian clock: the rhythm of wheel-running
behavior to assay the state of the circadian clock on a continuous
basis for essentially the lifetime of the organism. At Northwestern
University, for example, for many years we have been able to monitor
the rhythm of wheel-running behavior of more than 1500 rodents, 365
days per year, with minimal disturbance to animals housed under
different lighting and other environmental conditions. The
justification for using this simple rhythmic behavior as a surrogate
marker of the state of the circadian clock was the demonstration
throughout the years that the same circadian clock that regulates the
rhythm of wheel-running and locomotor activity regulates most if not
all behavioral, physiological, and cellular rhythms.
This anatomically defined structure with an easily measured behavioral
output allowed circadian rhythm researchers to use powerful new
neuroscience approaches over time to study brain function at many
different levels. These approaches include:
- The use of specific lesions and knife cuts to discover functionally
important components and pathways of the circadian clock system;
- The use of the newly developed 2-deoxyglucose technique to link brain
energy usages with function (the neurons of the SCN are more active
during the day than during the night, in both diurnal and nocturnal
species—a finding that allowed investigators to demonstrate SCN
rhythmicity in fetal and neonatal animals long before any physiological
and behavioral rhythms are expressed);
- The use of the expression of immediate early genes to map
the molecular cascade of events that occur in neural tissue between
stimulation and a change in brain function;
- The use of transplanted neural tissue (the SCN) to restore a behavior
after that behavior had been abolished or changed by experimental
(lesions) or natural (aging) means.
Perhaps the most significant advancement for
the neurosciences that has come from the circadian clock field is still
ongoing. While the mutagenesis and phenotypic screening approach had
been used for many years to find interesting mutant animals in lower
organisms, particularly in Drosophila, mammalian behavior was
thought to be too complex and/or regulated by too many genes for the
mutation of a single gene to have an input that would be of any
significance. The discovery of the animal with mutated Clock
was a "proof of principle" that the mutagenesis and phenotypic
screening approach could indeed lead to the discovery of single gene
mutations that could have dramatic effects on a complex behavior.
Furthermore, the use of this approach, in combination with the genetic
markers on the mouse genome and modern molecular biology techniques,
led to the identification of a totally novel gene involved in the
regulation of a complex behavior arising from a complex neuronal
system. To date, no other novel genes regulating a complex behavior
have been found using this approach, but many centers are now being set
up or are in the process of generating mutant animals with the ultimate
goal of discovering genes and understanding their functions in the
regulation of many different behaviors. Nevertheless, there are still
many investigators who study complex behaviors who are still not
convinced that their behavior can be dissected by a forward genetic
approach that mutates one gene at a time. A legacy that we believe the
circadian field will leave to the neuroscience community is that it
will indeed be possible to mutate single genes that will ultimately
lead to the discovery of complex cellular and system levels processes
that together regulate even the most complex of mammalian behaviors.
FUTURE CLINICAL DIRECTIONS
We take the position that the field of neurology has not paid
sufficient attention to the importance of sleep and circadian rhythms
in the etiology and/or treatment of neurological disorders. Of course
as sleep and circadian rhythm researchers, we obviously have a biased
perspective. Nevertheless, as discussed in this review, sleep and
rhythm disorders are characteristic of many neurological disorders, and
these temporal disturbances may in themselves be responsible for some
of the symptoms that are a part of neurological diseases. In addition,
it is likely that associated sleep and rhythm disturbances will have a
negative effect on the quality of life of the patients and their
caregivers, and thus, for optimal treatment of the neurological
disorder, improving sleep and circadian organization should be of high
priority.
In the 1970s and 1980s, the discovery and the discovery process that
the SCN was the site of the master circadian clock in mammals ushered
in an era during which the study of circadian rhythms became one of the
subdivisions of the neurosciences. Indeed, except for meetings at which
the central focus is biological rhythms (such as the meeting of the
Society for Research on Biological Rhythms), it is likely that more
papers are presented on circadian rhythms at the Annual Meeting of the
American Neuroscience Society than at any other broad-based biomedical
scientific meeting. Given that the "home" basic science discipline
of the field of biological rhythms is the neurosciences, one might
expect that the "home" clinical discipline for the clinical
components of the field of circadian rhythms would be neurology.
Despite neurology being the natural clinical and intellectual base for
the field of rhythms, this has not occurred in practice. While there
are certainly many historical reasons for this, perhaps an overriding
one has to do with the position of sleep clinics in the United States.
Since the majority of patients visiting at sleep clinics are diagnosed
and treated for sleep apnea, sleep clinics have commonly been dominated
by clinicians interested and focused on respiratory problems. With
sleep disorders being one of the most obvious links between the neural
circadian clock and human health and disease, the clear clinical
connection for circadian biomedical researchers is with those
clinicians interested in the neural basis of sleep and its neuronal
interactions with the circadian system. Thus, there is a disconnect
between the home of the basic researchers and the clinical
practitioners. The study of the central mechanisms underlying sleep and
rhythmicity is in the neurosciences, while the clinical home for sleep
disorders (and the revenues generated by the treatment of these
disorders) is often in the field of pulmonary physiology. However, the
central nervous system control of the sleep-wake and circadian clock
systems is rarely the intellectual focus of respiratory physiologists.
We hope and anticipate that greater awareness of the important role
played by sleep and circadian disturbances in the causes and treatment
of neurological disorders will lead to a heightened interest in the
discipline of neurology for the study of sleep and circadian rhythms
that matches that found today in the neurosciences.
AUTHOR INFORMATION
Accepted for publication May 14, 2001.
The preparation of this review was supported by grants
RO1-AG-18200 and PO1-AG-11412 from the National Institute of Aging, and
grant RO1-HL-59598 from the National Health and Lung Blood Institute,
National Institutes of Health, Bethesda, Md.
From the Center for Sleep and Circadian Biology, Department of
Neurobiology and Physiology, Department of Neurology, Northwestern
University, Evanston, Ill.
Corresponding author: Fred W. Turek, PhD, Center for Circadian
Biology and Medicine, Northwestern University, 2153 N Campus Dr,
Evanston, IL 60208-3520 (e-mail: turek{at}northwestern.edu).
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ABSTRACT
SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD
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