J. Pineal Res.

2008; 44:341–347 Ó 2007 The Authors

Journal compilation Ó 2007 Blackwell Munksgaard
Doi:10.1111/j.1600-079X.2007.00540.x
Journal of Pineal Research

MINI REVIEW
Melatonin, consciousness, and traumatic stress

Abstract: Descartes intuitively anticipated the so-called Ôbinding problemÕ of Petr Bob1 and Peter
consciousness and thought that the pineal gland enables spatio-temporal Fedor-Freybergh1,2
integration in cognitive processing. Recent findings indicate that a major role 1
Center for Neuropsychiatric Research of
in the process of temporal integration and binding involve neurons in Traumatic Stress & Department of Psychiatry,
suprachiasmatic nuclei, specifically targeting the pineal gland and other First Faculty of Medicine, Charles University,
Prague, Czech Republic; 2St. Elisabeth
structures, and control the neuroendocrine rhythms. Melatonin is an University College of Health and Social Work,
endocrine output signal of the clock and provides circadian information as Bratislava, Slovakia
an endogenous synchronizer which stabilizes and reinforces circadian
rhythms. This integrative process occurs at the different levels of the
circadian network via gene expression in some brain regions and peripheral
structures that enables integration of circadian, hormonal, and metabolic
information and creating temporal order of bodily and mental experience.
This specific temporal order is reflected in associative sequentiality that is
necessary for cognition, behavior and all processes of memory consolidation
that must preserve all information in the temporal causal order and
synchrony. In this context, recent findings suggest that melatonin could be a
potential regulator in the processes that contribute to memory formation,
long-term potentiation, and synaptic plasticity in the hippocampus and other Key words: consciousness, dissociation,
brain regions. There is evidence that stress disrupts normal activity and melatonin, memory, pineal gland, stress
memory consolidation in the hippocampus and prefrontal cortex, and this Address reprint requests to Petr Bob, Depart-
process leads to memories that are stored without a contextual or ment of Psychiatry, First Faculty of Medicine of
Charles University, Ke Karlovu 11, 128 00
spatiotemporal frame. These findings emphasize a specific role of melatonin
Prague, Czech Republic.
in mechanisms of consciousness, memory and stress and are also consistent E-mail: petrbob@netscape.net
with reported studies that indicate melatonin alterations under stressful Received October 23, 2007;
conditions and in mental disorders. accepted October 31, 2007.

Melatonin responds to direct signals from the SCN and

Introduction
Melatonin is a molecule widely distributed in nature that
occurs as an important signal molecule in unicellular
organisms, plants, fungi and also in animals and humans
[1–4]. Roughly 50 years ago it was found in bovine pineal
tissue as a major secretory product of the pineal gland and
identified as the indole molecule, N-acetyl-5-methoxytryp-
tamine [5]. Melatonin is a small lipid and water-soluble
indoleamine that can easily diffuse through cell membranes.
A major site of melatonin biosynthesis in vertebrates is the
pineal gland but its production also occurs in retina,
gastrointestinal tract, skin, bone marrow cells (in human
and mouse), and lymphocytes, among other organs [6–14].
Pineal melatonin secretion mainly occurs at night and its
synthesis is in close relationship with sleep regulation (with
nocturnal maximum) and other cyclic metabolic activities.
During light exposure, information from specialized retinal
ganglion cells is send to the suprachiasmatic nuclei (SCN)
of the hypothalamus and subsequently via the sympathetic
pathways to the pineal gland. In addition to the retina, the
SCN also receive numerous inputs from other brain areas
[15, 16].
its secretion is essential for biologic clock regulation, which
enables order and temporal relationships in the normal
interactions of various bodily processes. The circadian
SCN clock is composed of thousands of oscillating
neurons depending on the cell autonomous action of
circadian clock genes that produces a coherent output
capable of creating temporal order in physiology and
behavior [17]. Additionally, there is growing evidence
suggesting that circulating hormones and other metabolic
signals may modulate circadian oscillations via clock gene
expression in some brain regions and peripheral structures
[18]. For example, melatonin modulates the rhythm of the
clock gene Per1 in the pituitary gland, striatum, and
adrenal cortex [19–22]. This specific ability to modulate
clock gene expression via the circulating hormones pro-
vides a means for integration of circadian, hormonal, and
metabolic information. These findings suggest that various
brain area projections to the SCN as well as neuroendo-
crine influences on circadian oscillations may affect
biologic rhythms. These inner clocks are also neces-
sary for collecting information and creating temporal
order of mental experiences. Disruption of this temporal

341
Bob and Fedor-Freybergh
integration may occur in circadian rhythm disturbances
and also in mental disorders.
Melatonin and cognitive function
More than three centuries ago, Rene Descartes described the
pineal gland as Ôthe seat of the soul.Õ In his ÔPassions of
the SoulÕ he thought that ÔÔ. . . although the soul is joined to
the whole body there is a certain part where it exercises its
functions more than all the othersÕ. Descartes thought that
time is a basic mechanisms of the universe and used the
ÔclockÕ metaphor as an explanation for basic mechanism of
the brain and other physiologic functions [23, 24]. He
thought that when we sense only one image with two eyes,
only one sound with two ears or only one object by two
hands, the sensations from two sources must be fused
somewhere. Descartes intuitively postulated that this infor-
mation is fused and governed by clock mechanisms in the
pineal gland. He believed that the pineal gland is involved in
sensation, imagination, memory, and the causation of
bodily movements, and described the mind as an extracor-
poreal entity that is expressed through the pineal gland [23,
24]. Descartes intuitively anticipated the so-called Ôbinding
problemÕ of consciousness which means the neural correlate
of consciousness as a part of the nervous system that
transforms neural activity in reportable subjective experi-
ences.
A major hypothesis is that this neural correlate of
consciousness can compare and bind activity patterns only
if they arrive simultaneously at the neural correlate of a
conscious experience [25]. Consciousness combines the
present multimodal sensory information with relevant
elements of the past and creates spatio-temporal memory.
Information from each modality is continuously distributed
into distinct features and locally processed in different
relatively specialized brain regions and globally integrated
by interactions among these regions. Information is repre-
sented by integration through levels of synchronization
within neuronal populations and of coherence among
multiple brain regions that facilitate large-scale integration,
or ÔbindingÕ [26–29].
Recent data suggest that SCN neurons play a major role
in this process of temporal integration and binding.
Contrary to earlier views of the SCN as composed of
identical resettable oscillators, recent rapidly accumulating
evidence is that rhythmicity in the SCN is the product of a
highly organized network of heterogeneous cells [30–32].
Present results indicate that specialized network organiza-
tion of SCN oscillators presents a unique opportunity to
understand the relationship between cellular, intercellular,
and molecular functions. These individual neural oscillators
with the temporal patterns of rhythmicity are organized
into a coherent activity of biologic clock and facilitate
temporal synchronization that produces differentially timed
waves specifically targeting the pineal gland and other
structures, and control neuroendocrine rhythms [30–32].
Melatonin as one of the endocrine output signals by
which the clock provides circadian information as an
endogenous synchronizer is able to stabilize and reinforce
circadian rhythms and to maintain their mutual phase-
relationship. This integrative process occurs at the different
342
levels of the circadian network via gene expression in some
brain regions and peripheral structures that enables inte-
gration of circadian, hormonal, and metabolic information
and creating temporal order of bodily and mental experi-
ence [18, 33, 34]. This specific temporal order is reflected in
associative process that is necessary for cognition, behavior
and all processes of memory consolidation that must
preserve all the information in the temporal causal order
and synchrony or sequentiality of the internal cognitive
maps.
In this context, recent findings suggest that melatonin
could be a potential regulator in the processes that
contribute to memory formation, long-term potentiation
(LTP) and synaptic plasticity in the hippocampus and other
brain regions [35–40]. A basic mechanism of melatonin
action is that it may interact with both excitatory and
inhibitory neurotransmitter systems [38, 41, 42]. A mech-
anism probably underlying the effects of melatonin on
synaptic plasticity is a modulation of the intrinsic excit-
ability of hippocampal neurons. Hyperpolarizaton induced
by melatonin might reduce LTP by inhibiting NMDA
receptor activation during high frequency stimulation [39].
Melatonin application decreases membrane excitability in
other regions of the nervous system in part via an
enhancement of potassium currents [39]. Melatonin also
may decrease spontaneous action potential generation in
the SCN [39, 43–45] through an increase in a potassium
conductance and a decrease in a hyperpolarization-acti-
vated current [46, 47]. Melatonin may also reduce LTP
induction through a regulation of signaling pathways
downstream of the membrane and NMDA receptor acti-
vation and outside of the hippocampus; thus, melatonin
may influence rhythms in gene expression and second
messenger systems [21, 39, 48]. Electrophysiologic studies
also have reported that melatonin may regulate the
electrical activity of hippocampal neurons [39, 49, 50] and
alter synaptic transmission between hippocampal neurons
[51–53]. These findings indicate that melatonin may regu-
late learning and memory through its influence on synaptic
connections within the hippocampus undergoing activity-
dependent changes in synaptic strength including enhance-
ments in the strength of excitatory synaptic transmission
that regulate LTP.
Melatonin, spatio-temporal memory, and
stress
Historical and recent findings indicate that repeated stress
and especially traumatic stress experiences may disturb
mental integrity and lead to dissociation of memory and
mental experience [54–57]. This clinical experience of
psychologic fragmentation of memory contents is in agree-
ment with experimental evidence of the neural dissociability
of the memory processes [58–61]. The evidence supports the
view that memory systems concerned with encoding emo-
tion and context are dissociable at psychologic, physiologic,
and anatomic levels [62]. There is evidence that stress
disrupts normal activity and memory consolidation in the
hippocampus and prefrontal cortex [63–65]. This process
leads to memories that are stored without a contextual or
spatiotemporal frame. Neurophysiologic processes that

lead to consolidation of stressful emotional experiences
therefore produce memories, which are often fragmentary,
temporally, and spatially disorganized, mainly because they
originate from entirely unrelated events [66].
Disturbed temporal memory related to stress conditions
is evident from studies focused on episodic and autobio-
graphical memories. For example, results in group of 87
children aged 7–15 years, who were exposed to a traumatic
event requiring hospitalization, indicate that specifically
children, who showed temporal disorganization, but not
absence of emotion or dissociative amnesia, in narrative
themes were more likely to report concurrent subsyndromal
PTSD symptoms at 4–7 wk post-trauma [67]. Similarly
other results provide evidence demonstrating that exposure
to a significant psychological stressor preserves or even
enhances memory for emotional aspects of an event, and
simultaneously disrupts memory for non-emotional aspects
of the same event [65]. These results are consistent with
other findings of differential effects of stress on brain
systems responsible for encoding and retrieving emotional
memories in the amygdala and non-emotional memories in
the hippocampal formation, and consistent with the view
that memories formed under high levels of stress are not
qualitatively the same as those formed under ordinary
emotional circumstances but display typical forms of
spatiotemporal disorganization, fragmentation, and incom-
pleteness [65, 68].
According to recent experimental findings, stress-related
events are also related to melatonin alterations in animals
and in humans. For example, repeated maternal separation
and deprivation caused low blood melatonin levels and a
significant negative correlation between blood melatonin
levels and spatial memory performance in both male and
female adolescent rats, which suggest an association
between melatonin production and neurodevelopment
[69]. Further studies also found the interactions among
stress, melatonin and the pineal gland [70–75]. Electron
microscopy studies have found that immobilization stress
induces pinealocyte degeneration [76–78]. Physical-immo-
bilization stress in laboratory rats led to a significant
increase of pineal melatonin levels [79–81]. Psychosocial
stress also may induce a robust increase of the melatonin
metabolite 6-sulfatoxymelatonin in subordinate animals
[82, 83]. In humans, stress may cause sleep disturbances,
such as insomnia, and reduced nocturnal peak of pineal
melatonin secretion that is often present in depressed
patients [84–87].
These studies suggest that the pineal gland may be
significantly affected by stress, which is consistent with
findings that the pineal expresses a high density of the
glucocorticoid receptor [88–90]. Melatonin receptors are
also present in regions that participate in the stress
response, such as the hippocampus and the adrenal gland
[50, 91]. Recent data also show that rhythmic secretion of
melatonin from the pineal gland is related to the modula-
tion of neurotransmitter release, especially serotonin and
dopamine [70]. These data are in agreement with findings
that pineal gland expresses a high density of glucocorticoid
receptors, which suggest that the gland may be a target site
for glucocorticoid damage during stress and it is similar as
other regions, such as the hippocampus, which is highly
Melatonin, consciousness, and traumatic stress
sensitive to stress and prolonged glucocorticoid secretion
during chronic stress may have deleterious effects to the
pineal gland [81]. Prolonged glucocorticoid secretion during
chronic stress may lead to deleterious effects in the pineal by
inhibition of glucose transport, and a faster decline of ATP
concentrations and metabolism in pinealocytes, similar to
that proposed in hippocampal stress damage [81, 92]. Stress
may impair the sympathetic innervation to the pineal and
also the rhythmic secretion of melatonin which may
influence the information transmitted to other brain areas
because the hippocampus has high levels of melatonin
receptors and regulate the limbic-HPA and sympathetic-
adrenergic–noradrenergic systems [50, 81].
Collectively, these findings suggest that melatonin prob-
ably is significantly associated with the regulation of
memory, cognition, and also involved in emotional pro-
cesses [93–95]. These findings emphasize a specific role for
melatonin in mechanisms of consciousness, memory, and
stress are also consistent with reported studies that indicate
melatonin alterations in psychopathology mainly in
patients with depression, schizophrenia, anxiety disorders,
eating disorders and also in other mental disorders [87, 96].
For example, in many studies decreased melatonin levels in
patients with depressive disorder were reported although
melatonin increase has also been documented [87, 97–100].
Typical melatonin alterations have also been found in
schizophrenia and suggest that diminished melatonin
secretion may be associated with the pathophysiology of a
subgroup of schizophrenic patients, and that a subnormal
plasma melatonin level may be a marker of a subgroup
of schizophrenic patients [87, 101–105]. As characteristic
alterations in rhythm of melatonin secretion have been
found in various mental disorders [87, 106–110], further
investigation is needed to assess the specific relationship
between melatonin and stress-related dysfunctions in var-
ious types of mental disorders that could illuminate
etiologic mechanisms and treatment perspectives.
Conclusion
Because stress and especially traumatic stress has been
identified a significant factor in pathogenesis of mental
disorders [111–114], together these findings suggest that
melatonin alterations represent an important neuroendo-
crinologic marker of psychopathological processes and
stress-related cognitive dysfunctions. Melatonin represents
the biological clock which significantly influences encoding
and contextual binding in memory processes and cognition.
This integrative function of melatonin on many levels of
living organisms represents an embodied time that is a
major factor of bodily and mental functioning.
Stress presents a moment of cognitive conflict associated
with spatio-temporal disorganization and lack of order in
mental experience including its temporal-episodic character
that causes dissociation of mental experience. At this point,
melatonin disturbances may reflect also specific changes in
temporal binding and encoding episodic memory related to
traumatic stress and dissociation. It is well documented that
stress exposure in childhood may determine developmental
abnormalities in the amygdala, hippocampus, cerebellum,
anterior cingulate cortex, corpus callosum, and other brain
343
Bob and Fedor-Freybergh
structures that play a critical role in mediating the response
to stress [111, 112, 115, 116].
Stress also significantly influences the HPA axis and
causes disturbances in neuroendocrinological balance,
control hormonal levels, energetic metabolism and neuro-
immunomodulation during stress reaction [65, 111, 117–
123]. The most serious disturbances of HPA axis are
caused by traumatic events, such as childhood abuse or
neglect in the first years of life and they often have long-
term impact on emotional, behavioral, cognitive, social,
and physiological functions; also love and social care may
influence these functions and improve dissociative distur-
bances [111, 124–127]. Stress also significantly causes a
decrease in brain-derived neurotrophic factor in the
hippocampus that may determine neurodegenerative pro-
cess [128, 129].
Recent accumulating evidence also indicates that mela-
tonin and/or its metabolites may slow neurodegenerative
processes and show protective effects against stress [130–
136]. Although at this time the relationship between stress
and melatonin is only partially understood, the positive
influence of melatonin to memory and cognition seems to
be particularly promising for further research that may well
determine basic relationships and consequences for treat-
ment of mental disorders.
Acknowledgments
This work was supported by research grants
MSM0021620849, MSM0021622404, and support of
research project of Centre for Neuropsychiatric Research
of Traumatic Stress 1M06039 by Czech Ministry of
Education.
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