686 Biomed Environ Sci, 2018; 31(9): 686-699

Review

Interaction between the Circadian Clock and

Chronic Stress*

KUANG Xiao Dong1,^, YU Xin Bo2,^, CAO Yuan3, LI Dong Shui4,#, and ZHU Hai Yan5,#

Life on Earth, ranging from single-celled after the sympathetic-adrenomedullary system is

organisms to more complex mammals, has evolved stimulated, which prepares the organism for various
an internal circadian clock system that allows living challenges, such as by the increasing blood pressure,
organisms to coordinate their physiological heart rate, and glucose levels. Moreover, GCs
processes and biological activities with the participate in energy storage to optimize stress
environmental day-night cycle[1]. Therefore, the adaption via promoting lipolysis and hepatic
circadian clock system plays a critical role in glycogenolysis. However, an excessive level of GCs
maintaining internal physiological functions such as can cause many side effects, such as metabolic,
the immunity, metabolism, and mental health of immune, and mental disorders[8]. Undoubtedly,
mammals[2]. However, there is increasing evidence regulation of the HPA axis is essential for preventing
that circadian rhythm disorders can lead to a series the complications of chronic stress.
of related pathophysiological consequences for It has been verified that light can stimulate the
mammals[3-5]. secretion of GCs by the adrenal gland, which is
Stress refers to the method of protecting independently associated with activation of the HPA
organisms from any kind of stressors (including axis[9,12]. Additionally, light-induced GCs can
traumatic events, challenges, or demands), and is influence circadian gene expression in the peripheral
typically divided into two categories: acute stress tissues, suggesting that there is extensive crosstalk
and chronic stress. Acute stress can occur in an between GCs and the circadian clock[10,11].
organism due to exposure to a traumatic event for a In this paper, we review current studies on the
short period of time. Acute stress may induce a interaction of the circadian clock and chronic stress.
severe emotional response, but it is highly Finally, we critically discuss the consequences of this
manageable within the individual. In contrast, interaction on the HPA axis, immunity, metabolism,
chronic stress is defined as the response of an and mental disorders.
organism to a challenge for an extended period of A comprehensive search of the
time, which may cause serious medical MEDLINE/PubMED database was conducted in
consequences, and particularly contributes to January to March 2018 to identify related papers
nutritional imbalance, immunological diseases, and published in English. In electronic databases, we
depression. In general, stress exposure can lead to used the following key word combinations:
physiological changes that involve immediate ‘circadian clock’ AND ‘chronic stress’, ‘circadian clock’
activation of the sympathetic-adrenomedullary AND ‘HPA axis’, ‘HPA axis’ AND ‘chronic stress’,
system and delayed activation of the ‘chronic stress’ AND ‘immunity’, ‘circadian clock’
hypothalamic-pituitary-adrenal (HPA) axis[6]. The AND ‘immunity’, ‘chronic stress’ AND ‘metabolism’,
survival of the organism requires continuous ‘circadian clock’ AND ‘metabolism’, ‘chronic stress’
adaption to various challenges, and the secretion of AND ‘mental disorders’, ‘circadian clock’ AND
glucocorticoids (GCs) by the adrenal gland plays an ‘mental disorders’. To propose a successful review
important role in stress adaption[7]. Briefly, GCs for recent advancements, the publication date of the
facilitate the immediate response of catecholamines articles ranged from 2000 to 2018.

doi: 10.3967/bes2018.093
*
This study was funded by grants from the National Natural Science Foundation of China [No: 81670467].
1. Department of Pathology, Basic Medical College of Nanchang University, Nanchang 330006, Jiangxi, China; 2. Joint
programme of Nanchang University and Queen Mary University of London, Nanchang 330006, Jiangxi, China; 3. The First
Clinical Medical School of Nanchang University, Nanchang 330001, Jiangxi, China; 4. Department of Reproductive, The First
Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; 5. Emergency department of The General
Hospital of the People's Liberation Army, Beijing 100853, China
Interaction between the circadian clock and chronic stress 687

Primary studies were included in the review to zeitgebers, the subordinate clocks in the peripheral
demonstrate the latest work, and both narrative tissues are regulated by the master pacemaker via a
reviews and meta-analyses were selected for variety of autonomic signals and humoral factors to
full-text reading. In addition, genetic studies were anticipate the environmental day-night cycle and
included to explain the association of related prevent decreased expression of the subordinate
diseases and the HPA axis with core clock genes. We clock gene in the peripheral tissues. In the presence
used the reference management software, EndNote, of food cues, several subordinate clocks can be
to perform sorting and classification of related synchronized independently of the master
papers. pacemaker[17]. However, the regulatory mechanism
of the master pacemaker for subordinate clocks
The Circadian Clock remains unknown[18].
The term zeitgebers refers to external time cues, In general, the mammalian circadian system
such as light and food, that synchronize the internal consists of a central oscillator with a period of
clocks of organisms to the day-night cycle on Earth. approximately 24 h, input pathways conveying
However, the endogenous circadian rhythm is still external time cues to the central oscillator, and
present even in the absence of zeitgebers, output pathways synchronizing the circadian
free-running rhythms that last much longer, but they oscillators present in almost all cells of the body with
have a period of approximately 24 h[12]. The circadian environmental changes[19]. The molecular
clock system receives external zeitgebers and adjusts mechanism of the circadian clock is currently
the intrinsic circadian rhythm to correspond to described by transcriptional-translational feedback
environmental changes via phase resetting loops (TTLs)[20]. The major TTL is composed of the
effects[1,2]. The circadian system of an organism is circadian locomotor output cycle genes kaput (Clock),
mainly composed of the master pacemaker in the Casein kinase-1 δ/ε (CK1δ/ε), Cryptochrome (Cry1/2),
hypothalamic suprachiasmatic nucleus (SCN) and and Period (Per1-3) as well as the brain and muscle
subordinate clocks in the peripheral tissues. The SCN arnt-like (Bmal1) genes. Briefly, two transcription
is a tiny pacemaker neuron region of the anterior factors, CLOCK and BMAL1, form the heterodimers
hypothalamus, and is situated directly above the that bind to promoter element E-boxes to enhance
optic chiasm[13]. It is essential for coordinating the transcription of the Per and Cry genes. As their
circadian rhythm of physiological processes and transcripts are translated, PER and CRY proteins
biological behavior, including hormone levels, slowly accumulate in the cytoplasm throughout the
athletic performance, metabolism, and immune day. After reaching a certain concentration, they
function, throughout the entire body. The dominant interfere with each other and form complexes,
Zeitgeber for the master pacemaker of the SCN is the which in turn relocate to the nucleus to suppress the
light/dark cycle. SCN neurons receive direct photic activity of the CLOCK/BMAL1 heterodimers.
input from retinal ganglion cells, and the pineal However, the accumulated PER protein in the
gland then delays the transmission of temporal cytoplasm can be phosphorylated by CK1E; this
information to the peripheral tissue in the form of phosphorylation results in their ubiquitination and
melatonin secretion driven by the SCN. In mammals, degradation, which is accelerated by CK1δ. Similarly,
the final part of the neuronal route from the SCN to F-box/LRR-repeat protein 3 (FBXL3) is one
the pineal gland is the β1 adrenergic receptor, and component of the E3 ubiquitin ligase complex, which
the main neurotransmitter regulating melatonin mediates ubiquitination and subsequent
production is norepinephrine (NE). Therefore, the degradation of CRY1 and CRY2 proteins in the
SCN stimulates melatonin production via the release nucleus. As PER and CRY proteins are degraded, the
of NE for the duration of darkness. Upon exposure to repression of the CLOCK/BMAL1 heterodimers
light, melatonin production is suppressed due to lack disappears and the next cycle begins[21,23].
of NE stimulation[14]. The subordinate clocks in the Another type of TTL is the accessory feedback
peripheral tissues receive temporal information from loop, which is involved in the fine tuning of the
the master pacemaker via the melatonin rhythm, major loop. This feedback loop consists of reverse
which in turn coordinates the circadian rhythm of erythroblastoma (Rev-Erb-α) and the retinoic acid
the effective physiological system, such as the receptor-related orphan receptor (RORα).
immune system, blood pressure, bone metabolism, CLOCK/BMAL1 heterodimers can also drive the
and many others[15,16]. With the influence of other transcription of Rev-Erb-α and RORα. Rev-ErbA
688 Biomed Environ Sci, 2018; 31(9): 686-699

proteins are negative regulators of Bmal1 such as metabolic disorders, suppression of the
transcription, while RORA proteins play a critical role immune system, and deterioration of mental health.
in enhancing the transcription of Bmal1. Both are This phenomenon apparently has the potential to
[22] [30]
essential for the oscillation of BMAL1 proteins . induce damage across the entire lifespan .
The molecular pathways of the transcription and However, there are numerous defensive
translation feedback loops are presented in Figure 1. pathways driven by the HPA axis that prevent
In mammals, the formation of the biological organisms from experiencing chronic stress
circadian rhythm depends on the joint action of throughout their life.
clock genes and transcription factors. Our study The HPA axis is a neuroendocrine system that
demonstrated that core clock genes are rhythmically mainly consists of the hypothalamus, pituitary gland,
expressed not only in the SCN, but also in several and adrenal gland. It participates in the regulation of
central and peripheral tissues[23]. In vitro studies of neuroendocrine responses to stress stimuli. In the
peripheral tissues have also demonstrated that presence of chronic stress, the brainstem and limbic
almost all tissues express the core clock genes[24,25]. forebrain receive related stress signals from the
Subordinate clocks play a crucial role in individual sensory system across the entire body and relay
peripheral tissues, as they drive the rhythmic these signals to the paraventricular nucleus (PVN) of
expression of specific genes involved in many the hypothalamus to stimulate corticotrophin-
physiological functions[26]. Several studies have releasing hormone (CRH) and arginine vasopressin
revealed that the subordinate clocks in peripheral (AVP) secretion. These signals are essential for
tissues are not SCN-independent and require signal activation of the HPA axis[29-31]. CRH is the major
output from the SCN to become entrained to the regulator and AVP strengthens the positive
rhythmicity[27,28]. stimulatory effect of CRH on the secretion of
HPA AXIS-Mediated Regulation of Chronic Stress adrenocorticotrophic hormone (ACTH). Both CRH
Prolonged external or internal challenges that and AVP are transported to the related receptors in
continually disrupt the homeostasis of organisms the posterior pituitary corticotrophs via the
cause chronic stress. Exposure to chronic stress hypophyseal portal system to promote the secretion
yields a wide variety of adverse medical outcomes, of ACTH[33]. ACTH is then transported by the blood to

Figure 1. Schematic of the transcriptional-translational feedback loops. The transcriptional-translational

feedback loops constitute the molecular circadian clock. In the major loop, CLOCK and BMAL1 form the
heterodimers that bind to promoter element E-boxes to enhance the transcription of the Per and Cry
genes. Excessive CRY/PER protein complexes can inhibit CLOCK/BMAL1-mediated transcription in the
nucleus and CK1E, leading to the degradation of PER proteins. In the accessory feedback loop,
CLOCK/BMAL1 heterodimers promote the transcription of Rev-Erb-α and RORα. Rev-ErbA proteins
suppress the transcription of bmal1, while RORA proteins enhance it.
Interaction between the circadian clock and chronic stress 689

bind to the melanocortin type-2 receptors (MC2Rs) aggravates the chronic inflammatory states of
in the zona fasciculata of the adrenal cortex in the chronic stress-related diseases including rheumatoid
adrenal gland, where the secretion of GCs is arthritis (RA), allergy diseases, obesity, diabetes
stimulated. GCs are characterized by negative mellitus, and depression[41]. The GC resistance linking
feedback that inhibits the secretion of CRH and to each disease will be fully described later in this
[32]
ACTH . GCs mediate their biological effects via review. In the following, we will discuss the interaction
mineralocorticoid receptors (MRs) or glucocorticoid of GCs and the circadian clock in mammals.
receptors (GRs), which are widely expressed in
almost all cells in the body with the exception of the GCS and the Circadian Clock
SCN[33]. Briefly, the intracellular glucocorticoid It is well known that the secretory rates of GCs
receptor (iGR) is a ligand-dependent transcription are high in the early morning but low at midnight.
factor. After a specific ligand binds to iGRs, the This biological behavior results from cyclical
activated iGRs bind to glucocorticoid response fluctuations in the signals from the master
elements in the nucleus to regulate the transcription pacemaker in the SCN that stimulates GC secretion.
of target genes[35,36]. Moreover, the activation of iGRs is accompanied by
In mammals, acute stress-induced activation of the peak level of GCs[42]. These phenomena indicate
the HPA axis plays an important role in resisting that there is a relationship between iGR activation
destructive stimuli. Briefly, high levels of GCs lead to and the circadian rhythm. In contrast, MRs can be
an increased availability of glucose, a stable constantly activated by GCs even at low circulation
lysosomal membrane, and suppressed activation of levels due to the higher affinity. This comparison
neutrophils to facilitate the ‘fight or flight’ means the circadian rhythm of GCs is predominantly
response[34]. Experiments in mammals have mediated by GRs. Studies in humans have
demonstrated that even minimally destructive demonstrated that GCs can influence the output
stimuli can cause the death of mammals without a signals of the master pacemaker by markedly
bilateral adrenal gland, while mammals with the inhibiting the expression of the core clock gene of
adrenal cortex of an adrenal gland can survive for a the master pacemaker in the SCN and subordinate
long time[8]. For instance, previous studies have clocks in the peripheral tissues[43]. For example,
demonstrated that adrenalectomized mice exhibit Balsalobre et al. have confirmed that injection of
an enhanced susceptibility to organ injury, dexamethasone as a GC agonist at different times
endotoxemia, and even sleep deprivation[37-39]. induces a phase shift of the subordinate clocks in
Currently, stress-induced death in patients with mice, such that GC signaling can modify the internal
cortisol replacement remains a problem. This circadian clock network. In addition, dynamic
evidence supports the notion that GCs are necessary feeding times uncoupled the subordinate clocks
for stress resistance. In addition, some hormones, from the master clock in wild-type mice, while this
including catecholamines, maintain homeostasis of phenomenon disappeared in dexamethasone-
mammals only in the presence of GCs, the so-called injected mice[44]. In summary, GCs facilitate the
permissive action of GCs. coupling of the subordinate clocks and master clock
In addition to the activation of the HPA axis, the and stabilize the rhythm of the subordinate clocks
ultimate biological effect is commonly associated against external perturbation.
with GC sensitivity. GC sensitivity can reflect the A circadian oscillation with a peak in the GC
tissue responsiveness to GCs, which is determined by circadian rhythm before the active phase is displayed
multiple factors including the expression and affinity during the day in humans and, conversely, during the
of GRs. On exposure to chronic stress, persistently night in rodents[45]. Furthermore, this rhythm
elevated circulating GCs can result in reduced GC overlays a stronger ultradian pattern for the
sensitivity or even resistance. GC resistance refers to secretion of GCs and ACTH driven by a negative
the inability of the tissue to respond to the limited feedback loop. All components of the HPA axis,
GC response, consequently resulting in excess including CRH, ACTH, and GCs, can detect the
secretion of GCs via constant activation of the HPA appearance of a circadian oscillation[47]. Therefore,
axis to maintain the balance between the biological the secretion of GCs is typically episodic rather than
effect and secretion[40]. It is well known that GCs are smoothly continuous, and is regulated by the SCN via
highly effective in inhibiting inflammatory responses the HPA axis or alternative pathways. Briefly, the
and immune disorders. Therefore, GC resistance SCN activates the ANS to alter the ACTH sensitivity of
690 Biomed Environ Sci, 2018; 31(9): 686-699

the zona fasciculata, which coordinates the secretion of the immune system to protect the body from
of GCs with the environmental day-night cycle. In pathogens by stimulating immunological cells. In
addition, the adrenal peripheral clock participates in contrast, chronic stress participates in the inhibition
the ACTH signal pathway and subsequent GC of immune system via activation of the HPA axis.
secretion via circadian expression of the related core Therefore, there is a strong connection between
[46]
clock genes . The core clock genes Per, Bmal1, and immunity and the HPA axis, which involves the
Cry play a critical role in maintaining the clock process of maintaining homeostasis of the internal
rhythm in the negative feedback loop. This notion is environment. It is well established that an immune
supported by the evidence of an abnormal circadian challenge can stimulate activation of the HPA axis via
[50]
rhythm in the biological behavior of mice deficient of multiple pathways . When an immune insult
Bmal1 and Cry. Time-independent and low ACTH occurs in the body, the rapid production of
sensitivity occurred in the Bmal1 knockout mice but numerous inflammatory mediators, including tumor
not in the wild-type mice throughout the day. It is necrosis factor-alpha (TNF-α), interleukins (IL-1/2/6),
well established that GR sensitivity is necessary for and interferons (IFN-α/β/γ), may trigger activation of
negative feedback of the HPA axis. However, CRY1 the HPA axis[51,52]. Briefly, inflammatory mediators
and CRY2 predominantly occupy the ligand binding are transported by the peripheral circulation system
sites of the GR during its peak at night in order to to regulate neuronal circuits that project to the PVN
inhibit GC activation. As a result of this specificity, via an impaired blood-brain barrier in order to
Cry-knockout mice are characterized by impaired stimulate the release of CRH[53].
negative feedback and constantly elevated levels of During activation of the HPA axis, high levels of
GCs[48]. In addition, the circadian rhythms of Per1 GCs are released into the body to exert
knockout mice cannot be induced by light, and the anti-inflammatory and immunosuppressive effects.
accuracy and stability of the circadian rhythm of GC GCs can block the progression of inflammation and
secretion are significantly suppressed. Genetic are responsible for rapid resolution of the
deletion of both Per1 and Per2 leads to the inflammation[54]. During the early stage of
disappearance of the circadian rhythm of GC inflammation, GCs stabilize the lysosomal membrane,
secretion[49]. In summary, the integrity of the decrease the permeability of capillaries, and
circadian clock is necessary for the circadian rhythm decrease the migration of white blood cells into the
of GC secretion. inflamed area. When inflammation has been well
The literature review on the core genes and GC established, GCs enhance the rate of healing.
secretion is presented in Table 1. Despite the phase of inflammation, the primary
anti-inflammatory mechanism suppresses the
Circadian Interaction with HPA AXIS-Immunity
Crosstalk synthesis of inflammatory mediators and enhances
the anti-inflammatory cytokines of multiple types of
In mammals, the immune system may be largely immune cells, including both T lymphocytes and
influenced by stress. Acute stress strengthens the ability B cells; this process is termed immunosuppression[55].
Table 1. Summary of Studies on Clock Genes and Glucocorticoid Secretion
Studies Participants Measure Results
Gómez-Abellán Human adipose tissue Rhythm calculation and analysis Circadian pattern of Clock, Bmal1, and Per2
[43] treated with dexamethasone of gene expression expression is altered by dexamethasone
et al.
(n = 6) and control adipose exposure
tissue (n = 6)
[44]
Balsalobre et al. Dexamethasone-phosphate Expression level of Per1 Dexamethasone led to phase shifts in
injected and wild-type mice circadian gene expression in the peripheral
tissue, aside from the SCN
[48]
Lamis et al. Cry-deficient and wild-type Corticosterone and ACTH Genetic deletion of Cry resulted in reduced
mice measurements suppression of the HPA axis
[49]
Yang et al. mPer2−/− mice (n = 4) and Locomotor activity and Abnormal circadian rhythm of activity and
wild-type mice (n = 4) corticosterone measurements corticosterone production in mPer2−/− mice

Note. SCN: suprachiasmatic nucleus, ACTH: adrenocorticotrophic hormone, HPA: hypothalamic-pituitary-

adrenal.
Interaction between the circadian clock and chronic stress 691

When GCs adhere to immune cells, they suppress the chronic inflammatory states. For instance, RA
the expression of nuclear factor patients exhibit a reduced expression of GR and
kappa-light-chain-enhancer of activated B cells increased level of inflammatory cytokines such as
(NF-κB cells), which is an important regulator TNF-α, thus causing GC resistance[59,60].
involved in the release of proinflammatory There is considerable evidence in the literature
[56]
mediators that promote the immune response . indicating that the circadian clock is essential for
Therefore, the level of proinflammatory cytokines regulation of the immune system and allows the
that stimulate the HPA axis is markedly decreased[58]. organism to adapt to daily environment-induced
Among them, the most important mediator is IL-2, changes in the immune response. The major
which promotes the proliferation of T helper cell regulatory mechanism of the circadian clock with
type 1 (Th1), which is essential for cell-mediated respect to the immune system is influenced by the
[61]
immunity. In addition, GCs regulate the adaptive function of immune cells . The secretion of
immune responses by inducing a shift in T helper (Th) proinflammatory cytokines by macrophages follows
cell differentiation toward a predominance of T helper a circadian rhythm, whereas this circadian secretion
cell type 2 (Th2) (Figure 2). This biological behavior of was disrupted in core clock gene (Bmal1, Cry,
[64]
GCs inhibits the release of proinflammatory cytokines Rev-Erb-α) knockout mice . Several studies have
and increases the synthesis of anti-inflammatory demonstrated that both BMAL1/CLOCK and
cytokines, including IL-4, IL-10, and IL-13. Regardless of Rev-ErbA proteins enhance the migration of
the precise mechanism by which the macrophages to infectious and inflammatory sites by
anti-inflammatory and immunosuppressive effects promoting or inhibiting the expression of chemokine
occur, GCs play a crucial role in combating certain ligand 2 (CCL2)[62,63,65]. In addition, CLOCK proteins
types of disease, such as graft-versus-host disease, RA, regulate the activity of NF-κB, which is supported by
and allergy diseases[57]. These diseases are the evidence that inhibition of human CLOCK proteins
characterized by chronic inflammation and a severe deactivates the NF-κB signal pathway[66,68]. However,
immune response. However, prolonged use of GCs subjects who have experienced long-term sleep
may not treat these diseases, but instead exacerbate deprivation have been reported to possess a larger

Figure 2. Cross-interaction between the hypothalamic-pituitary-adrenal axis and the immune system.
Immune cells release proinflammatory cytokines (TNF-α, IL-1/2/6, IFN-α/β/γ) via the innate immune
response and adaptive immune response, which activate three levels of the
hypothalamic-pituitary-adrenal axis to secrete glucocorticoids (GCs). Conversely, GCs bind to specific GC
receptors on immune cells to suppress the release of proinflammatory cytokines and enhance a shift in
T helper (Th) cell differentiation toward a predominance of T helper (Th2) cells. This biological behavior
stimulates the production of anti-inflammatory cytokines (IL-4, IL-10, IL-13) to prevent damage due to
serious inflammatory reactions[49]. ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CRH,
corticotropin-releasing factor; PVN, paraventricular nucleus of the hypothalamus; M, macrophage; NK,
natural killer cells; DC, dendritic cells.
692 Biomed Environ Sci, 2018; 31(9): 686-699

number of immune cells (monocytes, NK cells, and IL6 has been identified as strongly rhythmic in
lymphocytes) at night and higher levels of patients with RA, with peak values in the morning.
proinflammatory cytokines (IL-6 and TNF-α) during Studies have demonstrated that the circadian
the day than healthy individuals[67]. The above rhythm of IL-6 may explain the specific diurnal
studies revealed that the immune responses in variation of RA symptoms, along with the
[73]
organisms are characterized by the circadian rhythm, inadequate circadian secretion of cortisol .
and, thus, disruption of the circadian clock is Interestingly, the circadian expression of Per2 in
associated with immune disorders and chronic synovial cells in RA patients changed significantly,
inflammatory diseases. In turn, the severity of the with high levels expressed in the morning, whereas
immune response also influences the circadian rhythm. healthy individual exhibited peak values at night[74].
It has been reported that the circadian rhythm of mice It is believed that the inflammation associated with
was altered in response to lipopolysaccharide RA cross-interacts with the circadian clock. The
treatment[69]. For instance, expression of the Per2 gene circadian clock controls the pathological rhythms by
was suppressed in the livers of rats with turpentine regulating the expression of inflammatory mediators,
oil-induced inflammation[70]. which play a critical role in the inflammation of RA.
The immune system protects organisms from This regulation is supported by evidence indicating
diseases via recognition of foreign pathogens and that both the number of activated T lymphocytes
induces immune resistance; therefore, it can lead to and the release of TNF-α are increased in Cry1/2
an immune disease when the immune balance is off knockout mice[75]. However, related inflammatory
or the immune system is compromised[71]. The mediators can also provide feedback on the
circadian clock plays a crucial role in the homeostatic expression of core clock genes. Recent studies have
maintenance of the immune system; thus, there is a revealed that TNF-α can upregulate the
cross-interaction between circadian clock disorders expression of Bmal1 and Cry1, while downregulating
and immune diseases, particularly for RA and allergy the expression of Per2[76]. Several allergic
diseases. RA is a long-term autoimmune disorder of diseases, including allergic rhinitis, exhibit
unknown etiology, which typically results in circadian rhythm variations. Nakamura et al. found
nonspecific inflammation of the peripheral joints[72]. that Clock mutations in mast cells lead to circadian
The symptoms of RA, namely, pain and stiffness, variation in immunoglobulin E-mediated allergic
follow a circadian rhythm and are more severe in the reactions[77].
early morning than at other times of the day. In The literature review on core genes and
addition, the level of the proinflammatory cytokine immunity is presented in Table 2.
Table 2. Summary for Studies Included for Clock Genes and Immunity
Studies Participants Measure Results
[62]
Sato et al. Murine macrophage cell line Chemotaxis assay of migratory activity Rev-Erb-α inhibits the inflammatory
RAW264 and relative expression of the infiltration of macrophages by
inflammatory molecular element, CCL2 suppressing CCL2 expression
[68]
Tang et al. HUVECs Western blot analysis of hCLOCK Inhibition of hCLOCK deactivates the
knockdown HUVECs NF-κB signal pathway
[70]
Susan et al. Rat treated with TURP (n = 4) Relative expression of Per2 in the liver TURP suppress the expression of
and healthy controls (n = 4) peripheral clock gene Per2
[74]
Yoshida et al. RA patient synovial cells Relative expression of Per2 TNF-α alters
the Per2 circadian rhythm by
suppressing the expression of Per2.

Hashiramoto et Cry1/2 knockdown mice (n = Relative expression of TNF-α The expression of TNF-α is under
[75]
al. 12) and wild-type mice (n = 12) control of Cry in RA

Nakamura et Wild-type and Clock-mutated Quantitative analysis of IgE/mast Clock mutations in mast cells lead to
[76]
al. BMCMCs cell-mediated allergic reactions circadian variation in IgE-mediated
allergic reactions

Note. HUVECS: Human Umbilical Vein Endothelial Cells, BMCMCs: bone marrow-derived cultured mast
cells, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, TURP: turpentine oil, TNF-α: tumor
necrosis factor α, RA: rheumatoid arthritis, IgE: immunoglobulin E.
Interaction between the circadian clock and chronic stress 693

Crosstalk Between the Circadian Clock and elevated plasma GC concentrations compared to
Metabolism in Chronic Stress healthy rats[83]. Additionally, GC resistance also
occurs in obese patients via reduced expression of
It has been previous described that acute stress GRs in adipose tissue compared to that in skeletal
can induce immediate emotional response, and thus muscle .
[84]
cause anorexia in humans. In contrast, studies in
It is likely that the circadian clock of organisms is
mammals strongly support the notion of chronic
involved in most metabolic processes during periods
stress having non-negligible undesirable effects in
of chronic stress. The circadian system is essential
humans consuming constant high calorie food, and
for maintaining the balance of glucose metabolism
one well-documented consequence is that
at multiple levels[85]. Bmal1 knockout mice are
hyperphagia may contribute to the development of
[78] characterized by impaired insulin secretion and
obesity and diabetes mellitus . The main
insulin resistance during the fasting phase. Once
regulatory mechanism is the HPA axis, which
supplanted with the exogenous Bmal1 gene, the
regulates appetite in humans and animals during [86]
dysregulated insulin action is restored to normal .
stress. It has been demonstrated that stress causes
Both the PER and CRY proteins are negative
anorexia if high calorie food is not available, while
feedback elements of the circadian system, and CRY
inducing hyperphagia if high calorie food is
regulates fasting glucose levels via the induction of
available[79]. Under normal physiological conditions,
gluconeogenesis[87]. Stamenkovic et al. found that
GCs participate in the stimulation of gluconeogenesis
the expression of Per2/3 and Cry circadian genes
in the liver, where there is a marked increase in
was reduced in diabetes mellitus patients[88].
glycogen storage. In addition, GCs also reduce the
The clock gene, Rev-Erb-α, regulates islet β cell
rate of glucose utilization in the peripheral tissues[80].
Both increased rates of gluconeogenesis and function. In the impaired glucose-induced insulin
decreased rates of glucose utilization result in secretion of the murine model, the expression of
elevated blood glucose levels and stimulate insulin REV-ERBα was significantly reduced, resulting in
secretion. On exposure to stress, excessive GCs are suppressed proliferation of β cells. A high fat diet
released throughout the body and alter homeostasis, influences the expression level of Rev-ErbA and
resulting in multiple metabolic diseases. Acute stress disrupts the diurnal secretion of insulin. This
causes a temporary elevation in blood glucose levels experiment indicated that Rev-ErbA can facilitate the
in order to suppress the appetite, which leads to adaption of β-cells to different challenges[89].
weight loss in humans who do not consume constant Furthermore, the core clock genes, Bmal1 and clock,
high calorie food. In contrast, chronic stress modulate the expression of liver enzymes, thereby
enhancement of the appetite in humans to achieve affecting the homeostasis of glucose and lipid
prolonged high calorie food intake may lead to metabolism. Mice with a liver-specific genetic
hyperglycemia[79]. Moreover, it has been reported deletion of Bmal1 tended to appear hypoglycemic in
that an increased level of plasma insulin is the fasting phase[90]. In type II diabetes mellitus and
ineffective in maintaining blood glucose levels under hyperlipidemic mouse models, BMAL1 and CLOCK
GC resistance-induced high levels of circulating GCs may directly participate in the regulation of
due to the reduced sensitivity of many tissues, and phosphoryl carboxykinase activity in the liver, thus
so-called insulin resistance is responsible for yielding circadian rhythmic changes[91].
[81] Ubiquitin-specific protein is activated by
diabetes mellitus . Reagan et al. confirmed that
diabetes may also serve as a metabolic model of 11β-hydroxysteroid dehydrogenase 1 to regulate
[82] liver gluconeogenesis. The activation of the liver
chronic stress . This research further demonstrated
the view that there is a close relationship between peroxisome proliferator-activated receptor (PPARγ)
chronic stress and the metabolic pathway of glucose. in aromatics receptor-mediated insulin resistance is
[92]
Another physiological effect of GCs on adipose tissue an important pathway . Studies have indicated
involves the mobilization of fatty acids via lipolysis. that the PPARγ is also involved in the association
Chronic stress induces excessive GC secretion and between the circadian system and lipid metabolism.
hyperphagia, thereby leading to an increase in the Briefly, the PPAR-α binds to the Bmal1 promoter to
concentration of free fatty acids in the plasma and improve its expression, while PPARγ function is
[93,94]
excess deposition of fat in the chest and head regulated by PER2 .
regions of the body, which may cause obesity. This is The literature review on core genes and
supported by evidence from obese rats with metabolism is presented in Table 3.
694 Biomed Environ Sci, 2018; 31(9): 686-699

Disrupted Circadian Rhythm and Mental Disorders hippocampus)[98]. Whether a disrupted circadian
rhythm leads to depression, or whether depression
Both stress and the circadian rhythm play a can cause a disruption in the circadian rhythm,
critical role in daily alterations of the light-dark cycle, remains unknown[99]. The symptoms of depression
lifecycle, and emergence of psychological diseases, include a disrupted circadian rhythm and early
namely, major depressive disorder (MDD), morning awakening, which suggests an alteration in
posttraumatic stress disorder (PTSD), schizophrenia the time phase of the circadian system
(SCZ), anxiety disorder, and attention deficit pacemaker[100]. It is common that circadian rhythm
hyperactivity disorder (ADHD)[95]. The HPA axis is not disorders are accompanied by depression, but the
only stimulated in response to stress, but also in etiology remains unclear. Bahk et al. confirmed that
response to negative feedback regulated by limbic the circadian rhythm closely interacts with suicide in
structures including the amygdala and hippocampus. depressed patients. Significantly more suicidal
Both the amygdala and the hippocampus express thoughts are reported by evening-type depressed
GRs; thus, GC feedback acts on these regions to [102]
patients than by morning-type patients . In
participate in the inhibition of stress responses, addition, depressed patients expressed markedly
formation of memories, or even structural changes. higher mRNA levels of Bmal1, Clock, and Per1 than
Acute stress, such as a traumatic event, promotes did non-depressed people[101]. Recent
memory formation accompanied by high circulating neuroendocrinology findings suggested that
GC levels. For chronic stress, the prolonged increase abnormalities followed the onset of depression and
in GCs ultimately led to neuronal atrophy and that patients manifested abnormal secretion of
impaired memory[96]. An important experimental melatonin[103]. Furthermore, the literature also
study has demonstrated that a disrupted circadian indicates that there is no significant difference in the
rhythm and delayed sleep time can have level of plasma melatonin in depression patients
significant impact on mood, cognitive function, and without circadian rhythm disorders compared to
behavior[97]. those of normal people, while depressed patients
MDD is characterized by the presence of with circadian rhythm disorders express a
depression that persists for at least 2 weeks. significantly higher level of plasma melatonin than
Depressed patients exhibit a disrupted circadian do normal people[104]. These results demonstrate
rhythm and GC resistance due to impaired HPA axis that a reduced level of plasma melatonin is the
feedback, which often lead to abnormalities in physiological basis for depression in patients with an
related brain regions (the amygdala and altered circadian rhythm.

Table 3. Summary of Studies on Clock Genes and Metabolism

Studies Participants Measure Results
[86]
Sadacca et al. Wild-type mice (n = 9) and Glucose and insulin tolerance Severe glucose intolerance and
Bmal1 knockout mice (n = 9) tests, measurement of defective insulin production
glucose-stimulated insulin occur in the Bmal1 knockout
secretion mice
[88]
Stamenkovic et al. Islets from type II diabetes Expression analysis of the Type II diabetes mellitus led to
mellitus patients (n = 9) and core clock genes Per2, Per3, reduced expression level of the
healthy Individuals (n = 50) and Cry2 clock genes Per2, Per3, and
Cry2
[89]
Vieira et al. Mice were fed with a chow diet Relative expression of Leptin up-regulates Rev-Erb-α
(n = 4) and a high fat diet (n = 4) Rev-Erb-α in pancreatic -cells expression whereas a high fat
diet disrupts Rev-Erb-α
expression
[94]
Grimaldi et al. Per2 knockout and wild-type Lipidomic analyses of mice, Per2 alters lipid metabolism by
mice relative expression of PPAR-α suppressing PPARγ to inhibit
in mouse embryo fibroblasts adipogenesis

Note. PPARγ: peroxisome proliferator-activated receptor.

Interaction between the circadian clock and chronic stress 695

Experiencing a traumatic event or chronic may cause anxiety disorder co-occurring with
exposure to abuse may facilitate the development of disruption of the circadian rhythm. Furthermore,
long-term mental disorders, namely, PTSD. Previous clinical data have indicated that variants in the
research has demonstrated a relationship between expression of the circadian clock-related gene, Per3,
[106] [117]
hippocampal atrophy and PTSD . Briefly, the might contribute to human anxiety disorder .
hippocampus is a rich region of GRs that are Beyond this study, Cissé et al. have evaluated the
sensitive to the damaging effects of secreted GCs in anxiety-like behavior of mice when exposure to dim
the presence of circadian rhythm alterations and light at night (dLAN) is associated with two core
chronic stress[105]. Therefore, there is an interaction clock genes, Clock and Rev-Erb. Chronic exposure to
between the circadian rhythm and PTSD. It has been dLAN induces anxiety-like behavior in mice, which
reported that irregular rhythmicity of the HPA axis enhances Clock gene expression in the
and the autonomic and immune systems results in hypothalamus, whereas Rev-Erb gene expression is
circadian disruption in PTSD[107]. Circadian disruption suppressed[118]. Additionally, Cry1/2 deficient mice
in PTSD was also supported by evidence in rats exhibited increased anxiety behavior compared to
exposed to chronic stressors, which led to rhythm wild-type mice[119].
dysregulation of core body temperatures[108]. ADHD is a common childhood onset mental
Interestingly, genome-wide association studies disorder with symptoms of impulsivity, inattention,
(GWASs) have identified a correlation between PTSD and hyperactivity, which may extend into adulthood.
and the core clock gene, RORα[109]. The protein RORA In addition to these symptoms, ADHD patients
protects the hippocampus and other sensitive frequently experience sleep disturbances, both
tissues against the damaging effects of GCs, thus children and adults[120]. A recent study reported a
changes in RORA levels may confer a risk for greater occurrence of insomnia during the night and
PTSD[110]. In contrast, animal model studies have sleepiness in the morning in ADHD children than in
demonstrated that PTSD also alters the expression of healthy children[121]. This phenomenon has also has
core clock genes such as Per1 and Per2 in central been found in adults using functional linear
clock tissues, including the SCN[111]. modeling, suggesting that adults with ADHD have
A recent study revealed that all patients with lower sleep quality than do normal adults[122]. Given
SCZ exhibited disrupted circadian rhythms compared that ADHD is strongly heritable, these results
to those of healthy controls, particularly with respect indicate that ADHD may involve the circadian clock
to alterations of sleep-wake and melatonin or clock gene variants. For instance, many studies
cycles[112,113]. Genetic studies have identified have advocated that an SNP (rs1801260) at the
numerous proteins associated with SCZ risk. Even 3’-untranslated region (3’-UTR) region of the Clock
common single nucleotide polymorphisms (SNPs) gene has been identified as a predisposing risk factor
may result in SCZ, which has been confirmed by for adult ADHD patients[123,124]. This polymorphism is
GWASs with large patient samples. For example, also associated with ADHD-related traits in healthy
Neuregulin 1 (Nrg1) has been identified as an SCZ adults without evening preference, particularly in
risk gene. The protein Nrg1 is involved in a series of the male population[125]. It is well known that both
neural processes, such as synapse formation. core clock genes, Bmal1 and Per2, are linked to the
Therefore, Nrg1-deficient mice can be used as internal circadian rhythm; Baird et al. conducted a
SCZ-relevant mouse models, which exhibit significant case-control study and found decreased rhythmic
[114]
circadian abnormalities . In contrast to GWASs, expression of the Bmal1 and Per2 genes in ADHD
copy number variant studies have identified risk patients compared to that in healthy individuals[126].
genes that contribute to SCZ via deleted or The literature review on core genes and mental
duplicated DNA[115]. It has been well documented disorders is presented in Table 4.
that duplication of the vasoactive intestinal peptide
receptor 2 (Vipr2) gene may lead to SCZ. The Vipr2 Conclusion
gene is involved in the stability of circadian The significance of the interplay between the
rhythmicity in the SCN. Moreover, disrupted circadian clock and chronic stress is an important
rest/activity patterns were observed in Vipr2 topic. Understandably, it is difficult to fully describe
knockout mice[116]. this interaction, but an increasing number of studies
Anxiety is the normal response in individuals have revealed that the circadian clock regulates
faced with stress, but an excessive stress response chronic stress via the HPA axis, while chronic stress
696 Biomed Environ Sci, 2018; 31(9): 686-699

Table 4. Summary of Studies on Clock Genes and Mental Disorders

Studies Participants Measure Results
[101]
Gouin et al. Individuals with a history of Relative expression of clock gene Individuals with a history of
depression (n = 30), non-depressed mRNA: Clock, Bmal1, Per1, and depression were associated with
individuals (n = 30) Per2 in peripheral blood higher Clock, Bmal1, Per1, and
leukocytes Per2 mRNA levels
[110]
Logue et al. Individuals with PTSD (n = 295), Genotyping and statistical RORα is significantly associated
healthy controls (n = 196) analysis of the core clock gene, with PTSD
RORα
[111]
Koresh et al. Individuals with PTSD (n = 8), Relative expression of clock gene PTSD may alter the circadian
healthy controls (n = 8) mRNA: Per1 and Per2 pattern of Per1 and Per2
expression in the SCN
[112]
Johansson et al. Schizophrenia patients (n = 11) and Relative expression of clock Schizophrenia patients exhibit a
healthy controls (n = 11) genes: Clock, Bmal1, Per1, Per2, loss of the rhythmic expression of
Cry1, Cry2, Rev-Erbα Cry1 and Per2, and decreased
expression of Clock, Per2, and Cry1
[117]
Liberman et al. Individuals with anxiety disorder (n Genotyping of SNPs of the Per3 Per3 SNP (rs228697) is significantly
= 310) and healthy controls (n = 70) gene associated with anxiety
[118]
Cissé et al. Adult mice with dLAN-induced Relative expression of clock Adult mice with dLAN-induced
anxiety (n = 63) and healthy control genes: Clock and Rev-Erbα anxiety had increased levels of
(n = 60) Clock gene expression and
decreased levels of Rev-Erb gene
expression in the hypothalamus
[123]
Kissling et al. Individuals with ADHD (n = 143), Genotyping and analysis of SNPs The Clock SNP (rs1801260) is
healthy individuals (n = 143) (rs1801260) of the Clock gene significantly associated with ADHD
[126]
Baird et al. Adult ADHD patients (n = 13) and Clock gene analysis of Bmal1 and ADHD patients exhibited
healthy controls (n = 19) Per2 decreased rhythmic expression of
the Bmal1 and Per2 genes

Note. PTSD: posttraumatic stress disorder, SCN: suprachiasmatic nucleus, dLAN: dim light at night, SNP:
single nucleotide polymorphism.

affects the regulation of the circadian clock. Yu, ZHU Hai Yan; Provided final approval of
Accordingly, this interaction extends to multiple manuscript to be published: LI Dong Shui, ZHU Hai
physiological aspects of the body, such as immunity, Yan.
metabolism, and mental health. The molecular Competing Interests None of the authors have
components of the circadian clock also participate in competing interests to declare.
^
these interactions. Unfortunately, in modern These authors contribute equally to this article.
#
societies, prolonged high levels of stress result in Correspondence should be addressed to LI Dong Shui,
numerous people developing an irregular work-rest Professor, Chief Physician, PhD, E-mail: [email protected];
ZHU Hai Yan, Professor, Chief Physician, PhD, E-mail:
schedule. Therefore, a disrupted circadian rhythm
[email protected]
leads to a variety of further diseases.
Biographical notes of the first authors: KUANG Xiao
Future studies should provide a more complete Dong, male, born in 1976, PhD, associate professor,
assessment of the common regulatory mechanism of majoring in pathology; YU Xin Bo, male, born in 1996,
both the circadian clock and chronic stress. We bachelor degree, majoring in clinical medicine and
anticipate that these studies targeting circadian HPA biomedical science.
axis regulation will provide a broader perspective for Received: April 12, 2018;
the development of successful therapeutic Accepted: August 30, 2018
interventions for clinical diseases associated with
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