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The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.
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Role of Melatonin in the Regulation of Human Circadian
Rhythms and Sleep
C. Cajochen, K. Kra
¨uchi and A. Wirz-Justice
Center for Chronobiology, Psychiatric University Clinic, Basel, Switzerland.
Key words: chronobiotic, soporific, EEG power density, thermoregulation, sleepiness.
The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels.
The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of
the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans,
and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is
evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is
insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce
phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new,
desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a
chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous
melatonin to treat sleep or circadian rhythm disorders.
Endogenous melatonin and the circadian sleep–wake
cycle and thermoregulation
Under entrained conditions, the phase relationship between the
endogenous circadian rhythm of melatonin and the sleep–wake
cycle is such that during the usual 16-h waking day,stable levels of
neurobehavioural function can be maintained. This occurs
because the circadian pacemaker opposes the decrements in
neurobehavioural function associated with increased homeostatic
drive for sleep accumulating with sustained wakefulness. Exten-
sion of the wake episode into the biological night (i.e. past the
evening rise of melatonin) is associated with marked decrements
in neurobehavioural function, because the circadian pacemaker no
longer opposes the wake-dependent deterioration but, instead,
promotes sleep at this circadian phase (1). Thus, shortly after
habitual bedtime, a sharp increase in subjective sleepiness and its
electrophysiological correlates occurs (Fig. 1) (2). This latter
phenomenon has been referred to as ‘the opening of the sleep
gate’ (3). In parallel, the entire thermoregulatory cascade (i.e.
decrease in heat production and increase in heat loss leading to
decrease in core body temperature) starts with the rise in endo-
genous melatonin levels in the evening (Fig. 2) (4). Melatonin
onset seems to be the hormonal signal timing the rise in blood flow
in distal skin regions and hence heat loss, the degree of which
(measured by the distal–proximal skin temperature gradient) is the
best physiological predictor for the rapid onset of sleep (5).
The association of sleep with the melatonin rhythm has been
confirmed in blind people in whom the circadian pacemaker is not
entrained (6, 7) and in sighted subjects with non 24-sleep–wake
cycle syndrome (8, 9). Even more impressive are the results
obtained from studies using the forced desynchrony protocol to
separate out circadian- and wake-dependent components of beha-
viour. The daily circadian increase in melatonin secretion coin-
cides with a decrease in wake episodes during scheduled sleep
episodes (Fig. 3) (10). Sleep consolidation gradually deteriorates
during that phase of the circadian cycle with low melatonin
production. Electroencephalogram (EEG) activation during wake-
fulness is also timed at a specific phase relative to the circadian
melatonin rhythm (11).
These carefully controlled experiments clearly show that the
circadian pacemaker drives the rhythms of melatonin synthesis,
thermoregulation, sleep consolidation and EEG activation during
wakefulness. There may also be feedback from the pineal gland to
both the circadian pacemaker and thermoregulatory centres in the
hypothalamus. The interpretation is that melatonin weakens the
circadian signal from the suprachiasmatic nuclei (SCN), promot-
ing heat loss which induces sleepiness via the preoptic area of the
anterior hypothalamus. Any effect of melatonin on sleepiness and
sleep must be relative rather than absolute, however, because indi-
viduals who secrete no melatonin at all seem to sleep normally (12).
Effects of exogenous melatonin on sleep and
There is ample evidence for a close temporal relationship between
the melatonin secretory phase and thermoregulation and circadian
Journal of Neuroendocrinology, 2003, Vol. 15, 432–437
#2003 Blackwell Publishing Ltd
Correspondence to: Dr Christian Cajochen, Center for Chronobiology, Psychiatric University Clinic, Wilhelm Kleinstrasse 27, CH-4025 Basel, Switzerland
sleep propensity. However, is melatonin causally involved in sleep
and thermoregulatory mechanisms? Is it necessary, or sufcient?
Initially, the answer is no. The ability to sleep is still possible in the
absence of detectable endogenous melatonin during the day, or in
tetraplegic patients (13), and only a moderate incidence of sleep
disturbance has been reported in pinealectomized patients (14).
Absolute melatonin production (which varies enormously between
individuals) does not correlate with sleep quality in the elderly
(15) or elderly sleep-maintenance insomniacs (16). To our
knowledge, whether thermoregulatory mechanisms are changed
in low melatonin secretors, pinealectomized patients and in trau-
matic spinal cord injury subjects whose melatonin production is
absent, has not been investigated. At least in patients with spinal
injuries above T6, thermoregulation is impaired because of the
interruption of neuronal pathways to and from the hypothalamus
(17). By contrast, numerous laboratory studies under stringent
conditions clearly demonstrate that administration of melatonin
acutely affects sleep and thermoregulation in humans. Therefore,
on second glance, the answer to the question of the causal role of
melatonin would be yes. Exogenous melatonin elicits all the
physiological effects which occur in the evening during endogen-
ous melatonin secretion. Indeed, exogenous melatonin is most
effective when endogenous levels are low during the biological
day. It elicits time-dependent soporic effects, which have been
corroborated with electrophysiological measures of sleepiness
such as electroencephalographic theta activity during wakefulness
(18). The soporic effect is paralleled by a time- and dose-
dependent hypothermic action, mediated by an increase in heat loss
FIG. 1. Time courses of subjective sleepiness as assessed on the Karolinska
sleepiness scale (highest possible score ¼9, lowest possible score ¼1),
plasma melatonin, mean eye blink rate per 30-s epoch during the Karolinska
drowsiness test, incidence of slow eye movements (SEMs, percentage of 30-s
epochs containing at least 1 SEM per 5-min interval), and incidence of stage 1
sleep (percentage of 30-s epochs containing at least 15 s of stage 1 sleep per
5-min interval) are shown, averaged across 10 subjects (SE). All data were
binned in 2-h intervals and expressed with respect to elapsed time since
scheduled waketime. Vertical reference line indicates transition of subjects
habitual wake- and bedtime. Adapted with permission from Cajochen et al. (2).
FIG. 2. Time courses of subjective sleepiness (forinformation on the Karolinska
sleepiness scale, see Fig.1), core body temperature, distal and proximal
skin temperatures, the distal-to-proximal skin temperature gradient and sali-
vary melatonin in a baseline 7.5-h constant routine followed by a 7.5-h sleep
episode. Continuously measured data are plotted in 30-min bins. Mean values
of n ¼18 subjects (SE). Adapted with permission from Kra
¨uchi et al. (4).
Melatonin, sleep and circadian rhythms 433
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432437
(19, 20). In an experiment where we blocked this natural evening
increase in heat loss, subjective sleepiness, and melatonin secre-
tion by light exposure, we could show that melatonin replacement
(5 mg) acutely recovered the evening increase in heat loss, sub-
jective sleepiness and also theta activity in the waking EEG (21,
22). Together, these data suggest a causal relationship between
melatonin and sleepiness, probably mediated by thermoregulatory
mechanisms (4). This supports the hypothesis that the onset of
melatonin secretion might contribute to the rise in sleepiness and
sleep propensity that occurs in the evening. It remains to be
established whether exogenous melatonin acts via the SCN and
the thermoregulatory centres in the preoptic area of the anterior
hypothalamus, or whether it is a peripheral effect on receptors in
the arterio-venous anastomoses, or both.
Quantitative analysis of the sleep EEG based on the fast Fourier
transform (FFT) has revealed that 5 mg melatonin, given shortly
before a daytime sleep episode, suppresses low EEG components
and increases EEG activity in the sleep-spindle frequency range
(23). Interestingly, similar changes in the sleep EEG spectra occur
in sleep during the melatonin secretory phase (biological night)
when compared with sleep occurring outside the melatonin secre-
tory phase (biological day). Two different experimental paradigms
have revealed this: a forced desynchrony protocol (10) and a nap
protocol (24). The two top panels in Fig. 4 illustrate the similarity
in relative EEG power spectra during night-time sleep (high
endogenous melatonin levels) and during daytime sleep after
melatonin administration (5 mg). The bottom panel shows EEG
power density during night-time sleep after melatonin ingestion
(5 mg), which did not differ signicantly from a baseline placebo
night-time sleep recording (22). These studies suggest that as soon
melatonin is secreted (biological night), an extra dose of mela-
tonin (5 mg) has no further effect on the spectral composition of
the sleep EEG. Sleep spindles are presumably generated in the
nucleus reticularis of the thalamus (25) and are enhanced by
-receptor agonists (26). The effects of melatonin are, to
some extent, and to a much lower degree, similar to the changes
induced by GABA
agonists such as benzodiazepine hypnotics
(27). Both agents increase EEG activity in the frequency range of
sleep spindles. However, given that melatonins action (3 mg) on
sleep EEG spectra was not blocked by umanzenil (10 mg), a
antagonist which blocks benzodiazepine effects, the
mechanisms may be dissimilar (28).
Most studies on the role of melatonin in sleep have been
conned to classical sleep scoring analyses. Therefore, replication
of the above mentioned FFT ndings are required. The most
consistent effect found in those studies was that sleep latency was
shorter after melatonin, even at rather low doses (29). On the other
hand, sleep consolidation or sleep efciency was not affected by
night-time melatonin administration whereas, during daytime, an
improvement in sleep efciency could be found. Recent data from
a forced desynchrony protocol, where melatonin was given to
healthy young adults across a full range of circadian phases,
conrm that exogenous melatonin can only increase sleep ef-
ciency outside the time window of its normal production (30).
FIG. 3. Phase relationships between the circadian rhythms of plasma
melatonin and sleep consolidation. Data are plotted against circadian phase
of the plasma melatonin rhythm (08corresponds to the tted maximum,
bottom x-axis). To facilitate comparison with the situation in which the
circadian system is entrained to the 24-h day, the top x-axis indicates the
average clock time of the circadian melatonin rhythm during the rst day of
the forced desynchronization protocol (i.e. immediately upon release from
entrainment). Plasma melatonin data were expressed as Z-scores to correct for
interindividual differences in mean values. Wakefulness is expressed as a
percentage of recording time. Data are double-plotted (i.e. all data plotted left
from the dashed vertical line are repeated to the right of this vertical line)
(n ¼7) (SE). Adapted with permission from Dijk et al. (53).
FIG. 4. Effects of endogenous and exogenous melatonin on electroencepha-
logram power density in non-rapid eye movement sleep. For each frequency
bin and subject, the values were expressed either as a percentage of the
corresponding values during daytime naps (top panel) (24) or relative to the
corresponding placebo values (bottom panels) (22, 23). Top panel: adapted
with permission from Knoblauch et al. (24); middle panel: adapted with
permission from Dijk et al. (23); bottom panel: adapted with permission from
Cajochen et al. (22).
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432437
434 Melatonin, sleep and circadian rhythms
Similar ndings come from an extended sleep protocol. Chronic
administration of melatonin in a slow-release formulation during a
16-h sleep opportunity beginning at 16.00 h resulted in a redis-
tribution of sleep so that sleep efciency during the rst half of the
sleep opportunity was substantially higher during melatonin treat-
ment compared to placebo (31). These two recent studies provide
strong support for the hypothesis that exogenous melatonin
attenuates the wake-promoting signal of the endogenous circadian
pacemaker, allowing for increased sleep efciency at circadian
phases corresponding to the habitual wake episode. In summary,
endogenous melatonin has an important role in the circadian
regulation of sleep (sleep timing), and exogenous melatonin exerts
effects on the main characteristics of human sleep (i.e. slow
waves, sleep spindles, sleep latency and sleep consolidation).
Effects of exogenous melatonin on circadian rhythms
In a variety of animal species melatonin is a zeitgeber, which
induces phase shifts and entrainment of the circadian clock
underlying the expression of many 24-h rhythms (32). Melatonin
is also a major entraining signal for the circadian systems of fetal
and neonatal mammals (33). Daily exposure to circulating mel-
atonin allows fetuses to be synchronized with each other and with
their mother long before they can directly perceive the environ-
mental light/dark cycle on their own. Overall, the animal literature
clearly supports the role of melatonin as a chronobiotic.
In sighted humans, under real life conditions, exogenous mel-
atonin may not be able to sufciently override the most important
zeitgeberlight to produce a robust consistent, statistically sig-
nicant phase-shifting effect on the day after administration. An
elegant approach to elaborate phase-shifting capacities of mela-
tonin has been in totally blind people. In such individuals, light/
dark information fails to reach the endogenous circadian pace-
maker. In a proportion of these individuals, circadian rhythms (e.g.
melatonin and core body temperature) do not synchronize with the
environment and free run usually with a period length >24 h.
Recently, it was demonstrated that melatonin treatment (0.5
10 mg) can entrain the circadian system (melatonin or cortisol
rhythms) of some free-running blind people if initiated at an
appropriate time relative to internal time (34, 35). In addition,
melatonin can stabilize sleep/wake timing even without entraining
the circadian system (36). As for the zeitgeberlight, a number of
studies have begun to delineate a phaseresponse curve (PRC) for
melatonin. A classicPRC measures phase shifts following a
single exposure to a zeitgeberunder free-running conditions.
Repeated doses of melatonin do yield a PRC, with the direction of
the phase shift dependent on the time of administration (37, 38).
Unfortunately, in these studies, light, a much more powerful
zeitgeberon the human circadian pacemaker than melatonin,
was not controlled, or was of too high an intensity to provide
unmasked melatonin onset times. However, in a double-blind,
placebo-controlled, crossover study in which subjects were stu-
died under dim light and constant posture conditions, we and
others showed that a single melatonin dose at 18.00 h induced an
advance of the circadian nocturnal decline in core body tempera-
ture (19), heart rate and the dim-light melatonin onset as assessed
on the second day (more than 24 h) after melatonin administration
(39). In the same study, an earlier offset of sleep was observed in
the second night after melatonin administration. Because this
sleep episode was initiated 29 h after melatonin administration,
these effects have been interpreted as reecting a phase advance of
the circadian timing system similar to the effects of bright light
exposure in the morning hours (40). Interestingly, in our similarly
designed constant routine study of 5 mg melatonin given in the
morning (07.00 h), no evidence for a phase delay in the above
circadian rhythms was found (41). This means that either we have
missed the appropriate timing for a phase delay [selected accord-
ing to Zaidan et al. (37)] which might be later in the morning (i.e.
after endogenous melatonin levels had declined) or that the dose
was too high and overlapped into the phase advance portion of the
hypothetical PRC. To our knowledge, there is only one other
randomized, double-blind, placebo-controlled trial under con-
trolled light conditions that investigated the capacity of melatonin
to induce phase delays. The authors reported delays in the onset of
the melatonin secretory phase after administration of melatonin at
07.00 h; however, no signicant phase shift in the offset of
secretion could be determined (42). These data suggest that it
is difcult to phase delay human circadian rhythms by exogenous
melatonin. In fact, the evidence that melatonin has phase-delaying
effects (>30 min) in humans is based on very limited data (38). It
appears that the precise timing of melatonin administration is
crucial in order to exploit its chronobiotic properties. Therefore,
there is an urgent need for a complete PRC for a single dose of
melatonin carried out under stringently controlled laboratory
Implications for the treatment of insomnia and
circadian rhythms disorders
The soporic and chronobiotic properties of melatonin make it an
optimal candidate for treating sleep, in addition to circadian
rhythm disorders. In our view, the most successful attempt to
treat insomnia and changes in circadian phase position by mel-
atonin has been carried out in free-running blind people. Optimal
melatonin treatment in those people should utilize not only its
soporic effects by administration close to the desired bedtime,
but also its chronobiotic properties, in order to entrain sleep/wake
behaviour (43). Another promising patient group are elderly
patients with insomnia. However, compared to the excellent
studies in the blind, randomized, double-blind, placebo-controlled
trials are rare (n ¼6). In those six studies, the results of melatonin
treatment (0.56 mg) administered before bedtime were not con-
sistent: sleep latency decreased in four studies and sleep efciency
improved in three studies, whereas subjective sleep quality did not
improve in any of the studies (44). Reviewing 78 articles on
melatonin treatment in elderly insomniacs, Olde Rikkert and
Rigaud (44) concluded that melatonin is most effective in elderly
insomniacs who chronically use benzodiazepines and/or with
documented low melatonin secretion during sleep.
Abnormal timing of sleep with respect to circadian phase occurs
in the delayed sleep phase syndrome (DSPS), in which sleep
occurs at a delayed clock time relative to the light/dark cycle,
social, work, and family demands. In the rst use of melatonin in
patients with DSPS, it was found that, when administered 5 h
before sleep onset for a period of 4 weeks, melatonin (5 mg)
advanced sleep onset and wake times compared to placebo
(45). A more recent study conrmed this, showing that melatonin
induces an advance in sleep onset in patients with DSPS (46), and
is most effective in DSPS patients with shorter habitual sleep time
and later clinical onset (47).
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432437
Melatonin, sleep and circadian rhythms 435
The rst application of melatonin using chronobiological prin-
ciples was to alleviate the perceived effects of jet lag. There have
been many placebo-controlled and uncontrolled studies that have
recently been summarized by Cochrane (48). This stringent ana-
lysis concludes that nine of 10 trials of melatonin, taken close to
the target bedtime at destination, decreased jet lagsymptoms arising
after ights crossing ve or more time zones. One difculty in
using melatonin for jet lag is that its use may require adminis-
tration at times when it will have undesired soporic properties.
There is also a great interest in whether melatonin can facilitate
phase-shifting in night-shift workers; however, few studies have
measured such phase shifts. In two laboratory studies, circadian
rhythms were measured before and after a large shift in the sleep/
wake schedule (49, 50). Melatonin (5 mg) was administered
during the phase-advance portion of the PRC and produced larger
circadian phase shifts than placebo (49). In the other study,
subjects took 4 mg melatonin (or placebo) before and during their
daytime sleep (50) and melatonin did not produce a larger phase
delay than placebo. In a night-shift eld study, melatonin pro-
duced larger circadian phase shifts than placebo in only seven of
the rst 24 subjects studied (51). Overall, these studies do not
provide strong evidence that melatonin can help phase shift the
circadian rhythms of night-shift workers, in particular, when
comparing its action as being less strong than exposure to light.
One problem has been the lack of control over time of melatonin
administration, and of the subjectssleep schedules. In a recent
study where the timing of melatonin administration, the sleep/
wake schedule and, to some extent, the light/dark cycle could be
controlled in a eld setting, melatonin produced larger phase
advances than placebo in the circadian rhythms of melatonin and
core body temperature (52). Additional caution is required in this
setting to avoid the soporic effects of melatonin during work
requiring vigilance, or driving home after the shift.
A remarkably tight association between the circadian rhythms of
melatonin and sleep propensity and thermoregulation has been
described in humans. Together with the observation that daytime
administration of melatonin increases sleep propensity and
decreases core body temperature via heat loss induction, this
suggests that melatonin has direct effects on sleep-inducing
thermoregulatory mechanisms. The circadian rhythm of melato-
nin secretion may be part of the pathway by which the circadian
pacemaker drives the circadian rhythm of sleep propensity, sleep
structure and core body temperature.
There is clear evidence that melatonin induces phase shifts,
particularly phase advances, in human circadian rhythms, and pre-
cisely-timed melatonin can be useful for the treatment of insomnia
related to jet lag or shift work. However, there is the need for a
detailed PRC to single doses of melatonin in humans under
stringently-controlled laboratory conditions. Furthermore, further
studies are required using physiological doses and/or delivery
systems that generate naturalmelatonin proles, while at the
same time scheduling sleep at a variety of circadian phases to
establish the role of melatonin in the circadian regulation of sleep.
In summary, the combined circadian and soporic properties of
melatonin make it an attractive tool not only for basic circadian/
sleep research, but also as an attractive candidate for the treatment
of sleep disorders related to inappropriate circadian timing.
C.C. is supported by Swiss National Foundation Grants START # 3130-054991.98
and #3100-055385.98.
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#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432437
Melatonin, sleep and circadian rhythms 437
... It has been well-established that melatonin is a principal regulator of the circadian rhythm. 66 Melatonin also seems to play a role in numerous solid tumors, and investigations in terms of its role as a potential molecule that impedes the spread of cancer are ongoing. ...
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Circadian clock dysregulation has been implicated in various types of cancer and represents an area of growing research. However, the role of the circadian clock in prostate cancer has been relatively unexplored. This literature review will highlight the potential role of circadian clock dysregulation in prostate cancer by examining molecular, epidemiologic, and clinical data. The influence of melatonin, light, night shift work, chronotherapy, and androgen independence are discussed as they relate to the existing literature on their role in prostate cancer.
... A key output pathway of the SCN is its projection to the pineal gland where melatonin is produced (Cajochen et al., 2003). Therefore, these input and output pathways are reciprocal. ...
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Parkinson’s Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones – cortisol, melatonin, insulin, klotho, and vitamin D – that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease.
... Artificial light exposure also impacts this synchronization [11]. Light exposure regulates the production of the hormone melatonin, which is released with decreasing light and signals the transition from wakefulness to sleep [12]. The gold standard for determining an individuals' circadian timing is therefore to measure the time in the evening at which endogenous melatonin levels rise above a certain threshold (Dim Light Melatonin Onset) [13]. ...
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Objective To investigate behavioral sleep habits, self-perceived quality of sleep, and chronotype, and to examine their association with clinically relevant levels of depression in Swedish adolescents. Method Questionnaire data were obtained from a representative sample of Swedish adolescents (n = 8449; 50.8% girls; aged 12–16). Depression was defined as >13 BDI-II scores. Logistic regression modelling estimated the effects of sleep duration, sleep quality, and chronotype on depression, adjusted for socio-demographic factors. Results On weekdays, approximately 46% of adolescents slept less than the recommended length of eight hours per night (depressed: 68%, non-depressed: 40%). On weekends, however, only 17% slept shorter than recommended. Short weekday sleep duration was more common among girls than boys (53% vs. 38%) and girls reported worse sleep quality. The regression model showed that depression was predicted by weekday sleep duration (OR = 0.773, p < .0001), sleep quality (OR = 0.327, p < .0001), and late chronotype (OR = 1.126, p = .0017), but not by weekend sleep duration. A 30-minute increase in weekday sleep duration was associated with about 10% lower odds of depression. Conclusions A substantial proportion of Swedish adolescents do not seem to meet the sleep recommendations of eight hours per night. Short sleep duration on weekdays, poor sleep quality, and late chronotype were associated with increased risk of depression. Interventions promoting longer weekday sleep duration (e.g., later school start times) seem relevant in this context, but further research is needed to investigate the directionality and underlying mechanisms of these associations.
... The pineal gland is the most renowned source of melatonin and receives neural signals from the SCN (Tan et al. 2018). The pineal synthesis of melatonin is controlled via the nervous system and triggered by darkness 55 (Cajochen et al. 2003;Zawilska et al. 2009). On the other hand, peripheral secretion of melatonin is not controlled by any time cue (Zawilska et al. 2009). ...
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Chronobiological variations are in the fabric of life. The first ideas regarding the possible effects of circadian rhythm on surgical outcomes were published in the early 2000s. Some studies support and oppose this idea. The lack of experimental evidence in a controlled setting has led to this study. This study aimed to explore the chronobiological implications of surgical outcomes. The rats were divided into four groups. A random pattern dorsal skin flaps were elevated in all groups at six h intervals. Flap necrosis rates and melatonin, oxidant, and antioxidant factors were studied. Flap survival was better in the 06:00 h group. The flap necrosis was higher in the 18:00 h group. Some of the biochemical parameters displayed circadian variations. As an independent variable, the time of surgical intervention changed the flap survival rates. It should be noted that the study was held in a nocturnal animal model thus the pattern of flap survival can be in reversed fashion in a clinical scenario. This study is the first experimental evidence for "Chronosurgery" in a controlled setting. Further studies in all aspects of surgical disciplines are required.
... In adulthood, retinol metabolism and retinoic acid are critical for the regulation of both circadian and seasonal rhythms 66 . Melatonin also plays an essential role in circadian rhythms in the brain, and is one of the most reliable markers of the sleep-wake cycle 67 . Disruption of circadian rhythms and sleep are among the most common comorbidities in developmental disorders 68,69 . ...
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Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice causes male-biased changes in the brain and in NDD-relevant behaviors that persist into adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose developmental pyrethroid exposure. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. Disrupted folate metabolism was confirmed using perturbagen analysis on split-sample transcriptomics data from the same mice, which identified a folate inhibitor as the drug causing the most similar effect to DPE. These results suggest that DPE directly disrupts folate metabolism in the brain, which may inform both prevention and therapeutic strategies.
... To demonstrate that changes in oxidoreductase activity and ROS accumulation causally underpin the reduction in lifespan associated with social isolation we administered melatonin, a hormone primarily known for its regulation of vertebrate circadian rhythms 80 . In invertebrates, melatonin does not seem to regulate circadian rhythm, but has radical scavenger effects and antioxidant properties 81 . ...
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Social isolation negatively affects health, induces detrimental behaviors, and shortens lifespan in social species. Little is known about the mechanisms underpinning these effects because model species are typically short-lived and non-social. Using colonies of the carpenter ant Camponotus fellah, we show that social isolation induces hyperactivity, alters space-use, and reduces lifespan via changes in the expression of genes with key roles in oxidation-reduction and an associated accumulation of reactive oxygen species. These physiological effects are localized to the fat body and oenocytes, which perform liver-like functions in insects. We use pharmacological manipulations to demonstrate that the oxidation-reduction pathway causally underpins the detrimental effects of social isolation on behavior and lifespan. These findings have important implications for our understanding of how social isolation affects behavior and lifespan in general.
... In mammals, when falling asleep, ipRGC cells activate the SCN and its output neurohumoral signals switch the metabolic mode of the pineal gland [6,22,[33][34][35]. Increases in the blood and CSF, the content of melatonin, serotonin, norepinephrine and other neurotransmitters, provide switching the homeostasis of the cerebral cortex and hydrodynamics of CSF to the glymphatic system mode. ...
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The dynamics of hydrogen bonds in bulk and hydrated water affected the activation energies of temperature dependence of ion currents of voltage-dependent channels that regulate communication and trophic bonds in the neuropil of the cortical parenchyma. The physics of minimizing of isobaric heat capacity of water made it possible to explain stabilization and functional optimization of thermodynamics of eyeball fluids at 34.5 C and human brain during sleep at 36.5 C. At these temperatures, thermoreceptors of cornea and cells of ganglionic layer of the retina, through connections with suprachiasmatic nucleus and pineal gland, switch brain metabolism from daytime to nighttime modes. The phylogenesis of circadian rhythm was reflected in dependence of duration of nighttime sleep of mammals on diameter of eyeball, mass of pineal gland, and density of neurons in parenchyma of cortex. The activity of all nerves of eyeball led to division of nocturnal sleep into slow and fast phases. These phases correspond to two modes of glymphatic system - electrochemical and dynamic. The first is responsible for relaxation processes of synaptic plasticity and chemical neutralization of toxins with participation of water and melatonin. Rapid eye movement and an increase in cerebral blood flow in second mode increase water exchange in parenchyma and flush out toxins into venous system.
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Ferroptosis is a non-conventional cellular death caused by lipid peroxide induced iron deposition. Intracellular lipid accumulation followed by generation of lipid peroxides is an Hallmark of Non Alcoholic Fatty Liver Disease (NAFLD). Melatonin (MLT) is an important pineal hormone with tremendous antioxidant and anti-inflammatory properties. Various studies targeted ferroptosis in different diseases using melatonin. However, none of them focused the intrinsic mechanism of MLT’s action to counteract ferroptosis in NAFLD. Hence, the present study investigated the role of MLT in improvement of NAFLD induced ferroptosis. HepG2 cells were treated with Free Fatty Acids (FFAs) to induce in vitro NAFLD state and C57BL/6 mice were fed with HFD followed by MLT administration 1. The results indicated that MLT administration caused the recovery from both FFA and HFD induced ferroptotic state via increasing GSH and SOD level, decreasing lipid ROS and MDA (Malondialdehyde) level, increasing Nrf2 and HO-1 level to defend cells against an oxidative environment. MLT also altered the expression of two key proteins GPX4 and SLC7A11 back to their normal levels, which would otherwise cause ferroptosis. MLT also protected against histopathological damage of both liver tissue and HepG2 cells as depicted by Oil Red O, HE staining and immunofluorescence microscopy. MLT also had control over pAMPKα as well as PPARγ and PPARα responsible for lipid homeostasis and lipogenesis. In brief, MLT exerted its multifaceted effect in FFA and HFD induced NAFLD by retrieving cellular oxidative environment, reducing lipogenesis and lipid peroxidation and modulating Nrf2/HO-1 and GPX4/SLC7A11 axis to combat ferroptosis.
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There has been scant evidence for a phase-shifting effect of melatonin in shift-work or jet-lag protocols. This study tested whether melatonin can facilitate phase shifts in a simulated night-work protocol. Subjects (n = 32) slept in the afternoons/evenings before night work (a 7-h advance of the sleep schedule). They took melatonin (0.5 mg or 3.0 mg) or placebo before the first four of eight afternoon/evening sleep episodes at a time when melatonin has been shown to phase advance the circadian clock. Melatonin produced larger phase advances than placebo in the circadian rhythms of melatonin and temperature. Average phase advances (+/-SD) of the dim light melatonin onset were 1.7 +/- 1.2 h (placebo), 3.0 +/- 1.1 h (0.5 mg), and 3.9 +/- 0.5 h (3.0 mg). A measure of circadian adaptation, shifting the temperature minimum enough to occur within afternoon/evening sleep, showed that only subjects given melatonin achieved this goal (73% with 3.0 mg, 56% with 0.5 mg, and 0% with placebo). Melatonin could be used to promote adaptation to night work and jet travel.
Conference Paper
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Objectives: Elimination of endogenous melatonin by surgical removal of the pineal gland has been widely used in animal studies to examine the roles played by the hormone in physiology and behavior. In humans, pineal resection occurs during the removal of pineal neoplasms. It results in very low (<0.5 pg/ml plasma) or undetectable melatonin levels, generally without a discernible circadian rhythm. Pineal tumor resection thus provides a unique clinical model to assess the putative role of melatonin in sleep regulation, circadian rhythmicity and seasonality. We examined self-reported sleep characteristics, circadian chronotype, mood disturbance and seasonal variation in subjects who had undergone pineal tumor resection. Methods: Subjects (n=13; 62% male) ranged in age from 23.5 to 64.0 y (mean ± SD: 40.4 ± 12.2 y) and had undergone surgery 0.5 to 6.5 years earlier. Four patients had presented with pineal cysts and 9 with various tumors. Gross resection was performed in 11 cases, while 2 patients received an estimated 40% and 70-90% pineal excision, respectively. Seven did not require postoperative radiation or chemotherapy, while 4 received both, 1 received radiation treatment only, and 1 received chemotherapy without radiation. They received a battery of standardized self-assessment instruments including the Sleep Disorders Questionnaire (SDQ), the Morningness-Eveningness Questionnaire (MEQ), and the Personal Inventory for Depression and SAD (PIDS), which provides a global seasonality score and itemizes criteria for major depressive disorder in the past year. Overnight urine samples were collected to measure the concentration of 6-sulphatoxymelatonin (aMT6s) as an indicator of residual pineal function. Results: Three subjects were at high risk for sleep apnea (SA, n=2) or periodic leg movements (PLM, n=1), with scores above the 90 th %ile in the corresponding SDQ indices. Additionally, 10 SDQ items were extracted to obtain an estimate of insomnia (i.e., difficulty falling asleep, poor/disturbed sleep, and wakefulness during sleep) independent of other sleep disorders. Nine subjects (69%) reported at least one of these symptoms at least "sometimes", while 6 (46%) reported them at least "usually", and 5 (38%) "always". Four subjects (31%) reported sleeping less than 6 h (in one case, <5 h), while the longest wake episode during sleep was estimated at >20 min by 10 subjects (80%), >60 min by 7 (54%), and >120 min by 2 (15%). Two subjects used sleep medications, while 3 used melatonin supplements PRN (discontinued at least two days prior to urine collection). Seven subjects (58%) reported clinically significant symptoms of depression, although only 3 used antidepressants. The MEQ indicated that no one was an extreme circadian type: 6 subjects (46%) were rated as moderate morning types, 1 (8%) as a moderate evening type, and 6 (46%) as neither type. The global seasonality score averaged 5.0 ± 3.1, which indicates negligible seasonal mood variation similar to that of the nonseasonal subgroup of a random sample of New York City residents, and well below the overall population mean 1. In all subjects, nocturnal urinary concentration of aMT6s, assessed using the ELISA method (Bühlmann Laboratories, Switzerland), showed abnormally low nighttime levels of the metabolite, below the detection limit of the assay (0.3 ng/ml). Conclusions: These results suggest a moderate incidence of sleep and mood disturbance in pineal surgery patients, with little seasonal variation in mood and behavior and no extreme chronotypes. A larger sample, using direct measurement (polysomnography, psychiatric examination) of potential pathology or other abnormalities, and extra-pineal surgical controls, are needed to ascertain the reliability of these findings, the validity of the self-reports and their specificity to patients lacking endogenous melatonin.
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γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain, and it may play an important role in sleep regulation. The effects of GABA are mediated by activation of two classes of receptors, i.e. GABAA and GABAB receptors. GABAA receptors are assumed to have a pentameric glycoprotein structure, composed of different polypeptide subunits and, as a result, are highly heterogeneous. The GABAA1a receptor subclass (previously termed the benzodiazepine BDZ1 receptor) represents approximately half of all GABAA receptors. BDZ hypnotics exert their sleep-inducing action by increasing the GABAA receptor—mediated chloride ion (Cl−) current. Possibly due to their nonspecific effect at the different subtypes of GABAA receptors, these drugs can also induce daytime sedation, anterograde amnesia and rebound insomnia. Additionally, they affect the sleep EEG in a specific manner (the so-called ‘spectral GABA-BDZ signature’), and may lead to tolerance and dependence. Given the drawbacks of BDZs, newer compounds with a preferential selectivity for GABAA1a receptors were developed. It was hoped that they would have fewer adverse effects than nonspecific BDZs. The available data, however, do not support the notion that the pharmacodynamics of these newer agents result in markedly different clinical effects compared with the BDZ hypnotics. As with the BDZs, the pharmacokinetics are clinically more important than the pharmacodynamics. It is concluded that there are no major differences in hypnotic efficacy and safety between the newer, selective GABAA1a receptor agonists and the classical, nonselective BDZs.
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Even healthy people occasionally have difficulty falling asleep. Psychological relaxation techniques, hot baths, soothing infusions of plant extracts, melatonin and conventional hypnotics are all invoked in the search for a good night's sleep. Here we show that the degree of dilation of blood vessels in the skin of the hands and feet, which increases heat loss at these extremities, is the best physiological predictor for the rapid onset of sleep. Our findings provide further insight into the thermoregulatory cascade of events that precede the initiation of sleep.
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The effect of melatonin (5 mg, p.o.) on electroencephalographic (EEG) activity during sleep was investigated in eight men in a placebo-controlled cross-over design. Melatonin was administered immediately prior to a Ph daytime sleep episode (13-17 h) after a partial sleep deprivation. The non-REM sleep stages and REM sleep duration were not significantly affected. Melatonin enhanced EEG power density in non-REM sleep in the 13.75-14.0 Hz bin (i.e., within the frequency range of sleep spindles), and reduced activity in the 15.25-16.5 Hz band. In the first 2 h spectral values within the 2.25-5.0 Hz range were reduced. These changes in the EEG are to some extent similar to those induced by benzodiazepine hypnotics and to the contribution of the endogenous circadian pacemaker to the spectral composition of the sleep EEG when sleep occurs at night.
Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations