Annu. Rev. Med. 1997.

48:253–66
Copyright © 1996 by Annual Reviews Inc. All rights reserved

CIRCADIAN RHYTHMS: Basic

Neurobiology and Clinical Applications
Robert Y. Moore, MD
Departments of Psychiatry, Neurology, and Neuroscience, Center for Neuroscience and
Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsyl-
vania 15621

KEY WORDS: suprachiasmatic nucleus, retinohypothalamic tract, sleep disorders, affective dis-
orders, melatonin

ABSTRACT
Circadian rhythms are major features of adaptation to our environment. In
mammals, circadian rhythms are generated and regulated by a circadian timing
system. This system consists of entrainment pathways, pacemakers, and pace-
maker output to effector systems that are under circadian control. The primary
entrainment pathway is the retinohypothalamic tract, which terminates in the
circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The
output of the suprachiasmatic nuclei is principally to the hypothalamus, the
midline thalamus, and the basal forebrain. This provides a temporal organization
to the sleep-wake cycle, to many physiological and endocrine functions, and to
psychomotor performance functions. Disorders of circadian timing primarily
affect entrainment and pacemaker functions. The pineal hormone, melatonin,
appears to be a promising agent for therapy of some circadian timing disorders.

INTRODUCTION
As the earth rotates around the sun, it turns on its axis so that half of its surface
is continuously in light and half is continuously in darkness. These inexorable
cycles of light and dark provide the most pervasive recurring stimulus in our
environment, one to which virtually all eukaryotic organisms have evolved
adaptations. In mammals, the most evident manifestation of this adaptation is
the temporal organization of behavior into periods of rest and activity, sleep
and waking. Two patterns of mammalian behavior have evolved. Mammals
that utilize olfaction and audition as major senses for perceiving the environ-

0066-4219/97/0401-0253$08.00 253
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ment typically sleep during the day and are active at night, a nocturnal pattern.
In contrast, mammals that utilize vision as their primary sense are awake
during the day and sleep at night, a diurnal pattern. The diurnal pattern is
typical of primates, including humans. The generation and regulation of circa-
dian rhythms is a function of a specific neural system, the circadian timing
system (CTS). The CTS is responsible for providing not only a temporal
organization for behavior, but also for a large series of physiological and
endocrine functions that form a critical substrate for behavior. The ultimate
function of the CTS is to enhance the adaptive value of both sleep and waking
behavior to promote survival and reproduction.
To understand the neurobiology of normal and disordered circadian func-
tion, consider the two fundamental properties of circadian rhythms, generation
by endogenous pacemakers and entrainment by environmental stimuli. The
obvious explanation of a daily rhythm in sleep-wake behavior is that it repre-
sents a simple, passive response to the environmental light-dark cycle, but this
is not the case. When humans, or animals, are placed in temporal isolation, an
environment without time cues, the cycles of sleep and waking behavior
persist in what is termed a free-running state. That is, the rhythm persists but
with a period that differs from 24 h (Figure 1). The maintenance of free-run-
ning rhythms is accountable only by the action of an intrinsic clock, or pace-
maker. For the circadian clock in the organism to function properly in a normal
light-dark cycle, it must be reset regularly. This process is called entrainment.
The endogenous clock is reset predominantly by the major environmental
Zeitgeber (time giver), light. If we examine these fundamental properties of
circadian rhythms, endogenous generation and entrainment, it is obvious that a
CTS must have three basic components—photoreceptors and entrainment
pathways that provide photic information to the pacemakers, circadian pace-
makers, and efferent pathways that couple the pacemakers to effector sys-
tems—that are under circadian control. The intent of this article is to review
current understanding of the functional organization of the CTS and to use this
information as a basis for exploring some common disorders of circadian
function. Some aspects of circadian biology, particularly genetic and molecu-
lar ones, were covered recently (1) and are not considered here. Similarly, the
application of chronobiology to the design of optimal regimens of therapy (see
References 2 and 3 for reviews) is of considerable interest but beyond the
scope of this review.

NEUROBIOLOGY OF CIRCADIAN TIMING

The three aspects of circadian neurobiology—entrainment mechanisms and
pathways, pacemaker localization and function, and pacemaker projections
and coupling to effector systems—are discussed in that order.
 CIRCADIAN RHYTHMS 255

Figure 1 Free-running rhythm of waking (closed bars), sleep (open bars), and highest (up carats)
and lowest (down carats) body temperature in a young female subject maintained in temporal
isolation for one month. Although there is some day-to-day variation, the free-running period (t) of
her endogenous circadian pacemaker is 24.3 h. (From Reference 59, with permission.)

Entrainment Mechanisms and Pathways

Light is the principal Zeitgeber for the circadian system. Until recently, how-
ever, it was believed that light was not important in the entrainment of human
circadian rhythms and that social cues were more significant. This is not the
case. The function of light, in humans as in other mammals, is to establish the
period and phase of the circadian pacemaker. It accomplishes this through
256 MOORE

specific pathways and cellular mechanisms (see below). The effect of light is
dependent on time of day; that is, light alters pacemaker function in a time-de-
pendent manner. This process is described by the phase-response curve (PRC)
(Figure 2). If a nocturnal animal is placed in temporal isolation (constant
darkness or constant dim light), it exhibits a free-running rest-activity rhythm.
With the onset of the animal’s rest period designated circadian time (CT) 0 and
the onset of activity designated CT 12, light administered from CT 2 to CT 10
has no effect on the free-running rhythm. When light is administered from CT
10 to approximately CT 16, however, it delays the onset of activity. From
approximately CT 18 to CT 2, light advances the onset of activity. The phase
delays reflect the fact that the pacemaker views light in the CT 10 to CT 16
time period as a lengthening of day. Phase advances reflect the fact that the
pacemaker views light in the CT 18 to CT 2 period as advancing the onset of
day. The entire PRC describes the complex responses of the pacemaker to light
(Figure 2). Although there is less information about human than about animal
responses to light, available data show humans exhibiting a similar PRC (see
References 4–6 for reviews).

PHOTIC ENTRAINMENT PATHWAYS The investigation of neural mechanisms

of circadian timing was initiated by a search for the visual pathways that mediate
entrainment (see Reference 7 for review). It was found that transection of all
visual pathways leaving the optic chiasm, all of the then-known central retinal
projections, resulted in blind animals with no visual reflexes but with perfectly
normal entrainment of circadian rhythms. This led to a search for a new visual
pathway. It was found with the demonstration of direct projection from the retina
to the suprachiasmatic nucleus (SCN), a small hypothalamic cell group lying
just above the optic chiasm, lateral to the third ventricle (8, 9), a pathway
designated the retinohypothalamic tract (RHT). Because transection of all other
retinal projections does not affect entrainment, the RHT is sufficient for entrain-
ment. This is further corroborated by the demonstration that sectioning the RHT
abolishes entrainment without affecting other visual functions (10). Recent work
has focused on the retinal components of the photic entrainment pathway. The
RHT arises from a specific subset of retinal ganglion cells that are small with
sparse dendritic arbors, have a diffuse localization over the retina, and conform
to the “W-cell” class of ganglion cells (11). These cells project only to the CTS,
and they appear to be connected distally in the retina to cone bipolar cells and
cone photoreceptors (12). Available evidence suggests that the photoreceptors
are not specific to the CTS. The transmitter of the RHT is glutamate (13, 14).
Glutamate acts through NMDA and non-NMDA receptors to affect pacemaker
function, probably through intracellular mechanisms, including the immediate
early gene, cfos (15). The exact mechanisms by which a monophasic stimulus,
 CIRCADIAN RHYTHMS 257

Figure 2 The phase-response curve. The activity (horizontal bars) of animals maintained in
constant dark is recorded, with light pulses given as indicated before, during or after the period of
activity. Once the effects of light are determined, the PRC is constructed as shown.

light, produces either no response or a biphasic response in SCN neurons is

unclear, but recent work in Drosophila spp. provides a potential molecular basis
(16).

NONPHOTIC ENTRAINMENT PATHWAYS Although light serves as a primary

circadian Zeitgeber, it is not the only stimulus capable of resetting the SCN
pacemaker. In addition to projections to the SCN, the retinal ganglion cells that
give rise to the RHT also innervate a subdivision of the lateral geniculate
complex, the intergeniculate leaflet (IGL). The IGL projects back to the SCN in
a pathway in which GABA and neuropeptide Y are colocalized (17). Infusion
of neuropeptide Y into the SCN, both in vivo (18) and in vitro (19), and
stimulation of the IGL (20) produce phase changes with a distinctive PRC: phase
258 MOORE

advances during subjective day, and phase delays during subjective night.
Similar phase changes are observed in response to locomotor activity (21, 22),
and the activity-induced phase changes are blocked by lesions of the IGL (23).
Thus, it appears that the IGL integrates photic and nonphotic information to
provide entraining information to the SCN pacemaker (17). There are a number
of other afferent inputs to the SCN that are likely to provide further modulation
of pacemaker function (24).
Since locomotor activity is under circadian control, its effects on entrain-
ment can be interpreted as feedback effects on the pacemaker. Another exam-
ple of a feedback effect is the action of the pineal hormone, melatonin. In both
diurnal and nocturnal animals, the pineal gland synthesizes and releases mela-
tonin at night, a rhythm that is under the direct control of the SCN (24) via
pathways described below. Large numbers of melatonin receptors in nearly all
mammals, including man (25), are contained in the SCN, to which melatonin
is the mediator of feedback effects from the pineal gland. Melatonin can
entrain the SCN pacemaker under some conditions (26), and a PRC for mela-
tonin has been described for animals (27) and humans (28).

Pacemaker
EVIDENCE FOR SCN PACEMAKER FUNCTION Four lines of evidence establish
the SCN as the dominant mammalian circadian pacemaker. First, the SCN is the
major site of termination of the photic entrainment pathway, the RHT, and it
receives other entraining input as described above. Second, ablation of the SCN
results in a loss of nearly all circadian rhythms (see References 24 and 29 for
reviews). In each instance, the only effect of the SCN lesions is to alter the
temporal organization of the function studied. For example, SCN ablation
abolishes the sleep-wake rhythm, but the total amount of time spent awake and
asleep and the proportion of REM and slow-wave sleep are unaffected. Third,
the SCN exhibits a circadian rhythm in neuronal activity even when isolated
from the remainder of the brain in vivo (30) or in vitro (31). Fourth, transplan-
tation of fetal SCN into the brain of animals rendered arrhythmic by SCN lesions
restores rhythmicity (32), and the restored rhythm reflects the intrinsic rhyth-
micity of the donor tissue (33).
There is evidence that the eye contains an independent circadian oscillator
(34) in mammals but no indication that this has any effect on function outside
of the eye. Similarly, there may be local circadian oscillators in other tissues,
but the SCN appears to be the only brain circadian pacemaker that provides a
temporal organization for neural mechanisms of adaptation.

THE SCN IS MADE UP OF INDIVIDUAL NEURONAL OSCILLATORS The SCN has

two subdivisions in all mammals: a core that receives predominantly visual
 CIRCADIAN RHYTHMS 259

input, and a shell that receives input from other areas (35; see also 24). These
subdivisions are distinguishable both by the segregation of afferents and by the
peptide content of neurons that comprise them (24). Nevertheless, it appears that
all SCN neurons are GABA-producing in animals (36) and humans (37) so that
output is inhibitory. There are two potential principles of organization of the
SCN pacemaker: Circadian function could arise as an emergent property from
the coupling of a series of ultradian oscillators; or individual SCN neurons could
be born as circadian oscillators coupled by neural connections to form a
pacemaker (38). Recent data indicate that the latter organization is the one
employed. When SCN neurons are dissociated and maintained in tissue culture,
they retain individual patterns of firing that exhibit circadian rhythmicity (39).
It is not clear whether all SCN neurons are circadian oscillators or whether this
property is expressed only by neurons of the SCN core, or by some other
subpopulation.

SCN PACEMAKER OUTPUT

The SCN exhibits a rhythm in neuronal firing, with a discharge rate that is high
during the day and low during the night (30, 31). Thus, the signal transmitted
to other brain areas is simple. Similarly, the pattern of SCN efferent projec-
tions is limited. The major projections are to the hypothalamus, with lesser
ones to the basal forebrain and the midline thalamus (40). Although these
limited projections would not seem to account for the many functions under
circadian control, examining areas receiving secondary projections (Figure 3)
provides some insight. The information in primary projections to the basal
forebrain and midline thalamus is relayed to secondary forebrain areas in-
volved in a variety of higher functions. Primary projections to the hypothala-
mus result in circadian information being relayed to the anterior pituitary, the
hypothalamic, and the brainstem reticular formation regions involved in auto-
nomic regulation, control of metabolism and body temperature, and a temporal
organization of sleep-wake cycles. The control of pineal function is mediated
by direct SCN projections to the paraventricular hypothalamic nucleus, from
there to the upper thoracic intermediolateral cell column, and from there to the
superior cervical ganglion sympathetic neurons that project to the pineal (41).

DISORDERS OF CIRCADIAN FUNCTION

The function of the CTS is to provide a temporal organization of physiological
processes and behavior to promote effective adaptation to the environment. At
the behavioral level, this is expressed in regular cycles of sleep and waking,
and disorders of circadian function are typically characterized by disturbances
260 MOORE

Figure 3 Projections of the SCN pacemaker and functional correlations. The SCN has limited
primary projections but widespread secondary projections to areas involved in control of the many
functions regulated by the circadian system.

of sleep and waking and by other behavioral symptoms that reflect both the
sleep disturbances and alterations of circadian regulation of waking adaptive
behavior. From the organization of the CTS, we would expect three types of
circadian disorder: abnormalities of entrainment, pacemaker function, and
pacemaker coupling to effector systems.

Disorders of Entrainment

BLINDNESS (NON–24-HOUR SLEEP-WAKE SYNDROME) Congenital and acquired

blindness provide instances of pure disorders of entrainment. Individuals who
are blind typically attempt to adapt their behavior to that of their community.
For a number of years, it was believed that the blind accomplished this by
entraining their circadian system to the social cues of the environment, but it
now appears that most are not able to do so. In a recent study, Czeisler et al (42)
reported on two groups of blind subjects. One group had a free-running mela-
tonin rhythm, indicating that they were not entrained to the environmental
light-dark cycle. These individuals, however, did maintain 24-h sleep-wake
cycles. When their melatonin rhythm peaked during sleep, they reported sleep-
ing well and feeling well. When their melatonin and sleep periods were out of
phase, they experienced sleep disturbances and other symptoms indicative of
disturbed circadian regulation. Another blind group had entrained melatonin
rhythms and sleep-wake cycles and reported no symptoms. These individuals
showed a normal suppression of peak melatonin levels by light even though they
were totally blind. It must be concluded then that, because the nocturnal
 CIRCADIAN RHYTHMS 261

suppression of peak melatonin levels is a function of the RHT, in these individu-

als the retinal phototransduction mechanisms through the RHT are intact even
though all other retinal mechanisms are nonfunctional. Although it remains to
be established, it is presumed that individuals who are not blind but who exhibit
the symptoms of the non–24-h sleep-wake syndrome lack the RHT.

RAPID TIME-ZONE CHANGE SYNDROME (JET LAG) The jet lag syndrome is a
disorder of modern life. Symptoms of rapid time-zone change occur in some
individuals with changes of as little as 3 h, but at least a 5-h change is required
for most. The typical symptoms of jet lag include sleep disruption, fatigue,
difficulty concentrating, gastrointestinal distress, impaired psychomotor coor-
dination, reduced cognitive skills, and alterations of mood. The symptoms remit
spontaneously over days with their duration determined by the direction of
travel, west to east producing more impairment than east to west, and by the
number of time zones crossed. Measures to ameliorate jet lag are discussed by
Graeber (43). Recent studies indicate that melatonin is an effective treatment
(see Reference 44 for a review), presumably by acting on the SCN pacemaker.

WORK-SHIFT SYNDROME In industrialized countries, many occupations re-

quire unusual work hours. This is particularly true for health care workers, police
and security guards, truck drivers, and workers in heavy industry. The factors
involved in adjusting to shift work, discussed by Monk (45), are complex, and
disruption of circadian mechanisms is only one of many involved. The major
symptom of work-shift disorder is impaired sleep. There have been recent
descriptions of the use of bright light (46) and melatonin (47) to treat the
circadian abnormalities associated with shift work.

DELAYED PHASE SLEEP SYNDROME Delayed phase sleep syndrome is charac-

terized by a persistent inability to fall asleep and arise at conventional clock
times; the phase of the sleep-wake cycle is delayed. Sleep onset is usually
delayed until early morning, with a consequent delay in rising. Individuals
attempting to go to bed earlier are unable to fall asleep until their usual time,
and attempts to maintain a normal schedule cause insomnia and daytime fatigue.
This syndrome has customarily been viewed as a consequence of choice, or
lifestyle. It often occurs in teenagers, which has reinforced this view. Although
the symptoms clearly represent lifestyle in some individuals, in others it is
clearly a disorder of entrainment, a failure of pacemaker sensitivity to light in
the phase-advance portion of the PRC (48, 49) (Figure 4).

ADVANCED SLEEP PHASE SYNDROME In many respects, advanced sleep phase

syndrome is the mirror image of the delayed sleep phase syndrome. Individuals
262 MOORE

Figure 4 Phase-response curves in controls, in blind subjects, and in phase-delay and phase-ad-
vance sleep disorders.

with the advanced sleep phase syndrome have persistent early onset of sleep,
usually around 7–9 p.m., with a consequent awakening at 3–5 a.m. Such
individuals complain of an inability to stay awake for social events in the evening
and of being alone without companionship when they get up in the early
morning. Attempts to delay sleep onset result in severe evening fatigue and
usually fail. This syndrome is often found in the elderly, and it reflects a lack of
sensitivity in the delay portion of the PRC (Figure 4).

Disorders of Pacemaker Function and Pacemaker-Effector

Coupling
Two types of disorders are associated with pacemaker dysfunction. The first is
a loss of circadian function: arrhythmicity similar to that seen in animals with
SCN lesions. The second is an alteration of normal pacemaker output. A
diminution of the amplitude of circadian rhythms is characteristic of aging. In
this circumstance, however, it is unclear whether the problem is at the level of
 CIRCADIAN RHYTHMS 263

the pacemaker or whether it reflects a partial inability of effector systems to

respond to a normal pacemaker input.

IRREGULAR SLEEP-WAKE PATTERN SYNDROME In the relatively uncommon

irregular sleep-wake pattern syndrome, affected individuals have an irregular
distribution of sleep and wake with numerous interruptions. These individuals
complain both of their difficult schedule and insomnia and of daytime fatigue
and appear to be arrhythmic. In some instances in which 24-h recordings have
been made, there is no discernable rhythm in core body temperature. This may
occur in two situations: with evident hypothalamic pathology, such as a tumor
compressing the chiasmatic region of the hypothalamus (50); and spontaneously
without evident neuropathology.

SYNDROME ASSOCIATED WITH DECREASED AMPLITUDE In many elderly indi-

viduals, there is increased fragmentation of sleep and less sleep in the deeper
stages of slow-wave sleep (51), decreased amplitude of the body temperature
rhythm (52), and decreased amplitude of the cortisol and melatonin rhythms
(53), as well as the advance in phase described above. This is enhanced in many
individuals with Alzheimer’s disease (51, 52), where a decrease in cell number
in the SCN has been reported (54). These observations suggest that there is a
decrease in pacemaker output in aging and that the symptomatic expression of
this abnormality is insomnia (see Reference 55 for a review). Interestingly, it
has been reported recently that melatonin therapy, which should improve
pacemaker coupling, is significantly better than a placebo in treating sleep
disturbances in the elderly (56). It is not possible to state, however, that the sleep
disturbances of the elderly do not include problems of pacemaker coupling to
output systems. Indeed, it seems likely that a complex interaction of decreased
pacemaker output and decreased responsiveness of effector systems to pace-
maker output are operative in many of the circadian disturbances of the elderly.

AFFECTIVE DISORDERS
The affective disorders are a complex of diseases in which disturbances of
mood are prominent manifestations. There are also disturbances of sleep,
appetite, libido, cognition, and memory frequently reported. Although it has
long been thought that a disruption of circadian function may be a prominent
part of major depression, the most common of the affective disorders, this has
not been established. Two recent reviews (57, 58) concluded that there is no
primary disturbance of the circadian system in depression, but that circadian
function may be disrupted as part of the multiple manifestations of the primary
pathophysiology of these diseases. This is an area where much work still needs
264 MOORE
to be done. In particular, this area, and many others, would be well served if it
were possible to measure function of the CTS directly. It is quite likely,
though, that understanding the nature of circadian abnormalities in depression
should provide insight into its fundamental pathophysiology.
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