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Circadian rhythm stress

Circadian rhythm stress

Sleep 26 2 wtress PubMed Cirfadian Scholar Viswanathan AN, Schernhammer ES Circulating Hydration for staying hydrated during sports events and the risk Circadisn breast and endometrial cancer in women. Yamamoto T, Hydration for staying hydrated during sports events Y, Tanaka M, Yoshida Glutathione production, Soma H, Shinohara K, et al. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. J Clin Endocrinol Metab 95 5 — In mice, neurogenesis in the developing SCN primarily occurs between embryonic days 10 and 15 E10 and 15and intra-SCN circuits are formed during the following days Circadian disruption in psychiatric disorders. Sorry, a shareable link is not currently available for this article.

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The PNS generally predominates during resting conditions towards conserving and storing energy or regulating basic body functions e. Through its tonic properties, the PNS is vital especially under resting conditions, and is, therefore, particularly implicated in the development of cardiovascular diseases and other comorbidities 27 , CRH and AVP are released from the PVN into the hypophyseal system in response to stimulatory signals from higher regulatory centers e.

ACTH reaches the cortex of the adrenal glands through release in the systemic circulation and stimulates both production and secretion of GCs. Systemically released GCs, in turn, besides their major actions, close a negative feedback loop by suppressing the activation of the PVN and the pituitary gland 6 , GCs influence a myriad of physiologic functions and are essential for the activation, maintenance, and downregulation of the stress response.

GCs mainly exert their pleiotropic effects through genomic, nongenomic, and mitochondrial actions of the intracellular cognate GC and mineralocorticoid receptors GR, MR , which function as a ligand-activated transcription factors 4 — 9 , 52 — GR and MR are evolutionarily close, showing large homologies at their DNA-binding domain and sharing many responsive genes.

Upon ligand-binding, the receptors dissociate from the interacting proteins i. GR and MR have complementary actions with respect to HPA axis activity and reactivity In humans, the glucocorticoid receptor hGR is encoded by the NR3C1 gene, which is located in the long arm of chromo-some 5 and consists of 10 exons.

The alternative usage of exon 9α or 9β gives rise to the two main receptor isoforms, the classic hGRα and the hGRβ 8 , 52 , 54 — Ubiquitarilly expressed in every tissue except the suprachiasmatic nucleus SCN of the hypothalamus, the hGRα is primarily localized in the cytoplasm of glucocorticoid target cells 57 , hGRβ, exclusively localized in the nucleus of certain cells e.

A growing body of evidence suggests that hGRβ has its own, hGRα-independent transcriptional activity and plays an important role in insulin signalling, inflammation, and carcinogenesis The MR is encoded by the NR3C2 gene, is located on chromosome 4 and also consisting of 10 exons MR is peripherally expressed in several tissues e.

Of particular importance are the GR and MR effects in the CNS. While GR are expressed throughout the brain, MR are abundantly expressed in limbic brain structures involved in emotional processing, arousal and memory i. Interestingly, the MRs show a tenfold higher affinity to cortisol than GRs and are largely already occupied under basal cortisol levels, while GRs become gradually occupied through cortisol peak levels e.

Thus, depending on receptor type, cell topology, tissue-specific expression, their specific ligands e. In addition, GC may also signal through protein-protein interactions between receptors and other important transcription factors, including the nuclear factor-κB NF-κB , the activator protein-1 AP-1 , and the signal transducers and activators of transcription STATs.

However, perhaps even more importantly, GC exert also rapid, nongenomic actions, mediated by membrane-bound MRs and GRs that trigger the activation of kinase signal transduction pathways 8 , 52 , 54 — 57 , Membrane-bound MRs and GRs show lower GC affinity than intracellular receptors and are increasingly occupied only through higher cortisol concentrations, thus mainly playing a crucial role in translation of rapid GC pulses in the initial phase of HPA axis activation 70 — Circadian molecular oscillations are independently generated in virtually every cell of living organisms, thus influencing molecular biological processes over the course of the day.

However, it is the orchestration of these innumerable, diverging and tissue-specific peripheral oscillations into a main rhythmic symphony that is of vital importance for the promotion of homeostasis in higher organisms.

The CS represents an extensive network of time-keeping mechanisms that creates and maintains this cellular and systemic rhythmicity, through temporal organization and coordination of many physiological and transcriptional oscillating processes throughout several structural levels in the organism 17 , In order to stay adjusted to the geophysical time, the CS receives continuously input by behavioral, hormonal, and environmental signals, a process called entrainment.

The CS has three main functions as a pacemaker through intrinsic and self-sustainable rhythm generation, b internal Zeitgeber germ. time-giver with a distinct rhythm output for peripheral synchronization, and c Zeitnehmer germ. g, nutrition, light, sleep, social activity for proper time entrainment of the intrinsic period to the environmental cycle The central mammalian CS includes specialized signal transduction mechanisms in the retina, the retinohypothalamic tract RHT , the suprachiasmatic nucleus SCN , the superior cervical ganglia, the pineal gland PGL , the thalamic intergeniculate leaflet IGL , and the raphe nuclei 18 , 77 , 78 cf.

Figures 1 and 2. The SCN is a bilateral paired structure with high cell density, consisting of 50, neurons in humans displaying a synchronised rhythmic metabolic and electrical activity, and is located in the anterior hypothalamus directly over of the optic chiasm, next to the third ventricle.

The most important Zeitgeber is light. These melanopsin-containing cells have been shown to be sensitive to light wavelengths — nm, i. blue light different from the classical visual system i. The photic input transmitted from the ipRGC through the retinohypothalamic tract to the SCN 88 and from there to the upper part of the thoracic spinal cord, the superior cervical ganglia and the PGL gland The NPY-containing pathway from the IGL and the serotonergic pathway from the median raphe represent the two other main afferent projections to the SCN Taken together, anatomical routes directly involved with the SCN are numerous, with up to 15 efferent and 35 afferent projections This synchrony gets mostly lost without an input from the SCN 91 , although other Zeitgebers , such as nutrient, temperature, and social cues, can also entrain peripheral clocks In the past decades, mounting evidence has evolved our understanding from the first discovered clock gene Period or PER conserved from fruit flies to humans 93 to a complex molecular clockwork generated at the cellular level by molecular oscillators in all nucleus-containing cells of an organism 15 , 74 , Figure 3 ].

Besides this core negative feedback loop, there are also auxiliary feedback loops that stabilize the transcriptional activity of the core regulatory loop 94 , — REV-ERBα, reverse viral erythroblastosis oncogene product alpha.

These regulatory loops, receive adjustive input from related influencing systems. Besides the strongest circadian entrainment by light, other biological cues, such as nutrition and temperature, can also influence the activity of the clock system.

Similarly, temperature decrease can represent a strong circadian cue, as the cold-inducible RNA-binding protein CRBP accumulates under lower body temperature in peripheral clocks but not in the SCN and influences circadian gene expression The superior robustness and resilience of the distinct intrinsic activity rhythm of the SCN is mainly preserved by the synchronization of SCN neurons through intercellular coupling to its neighbour cells in an action-potential-dependent manner There are different kinds of SCN neurons containing different neuropeptides, such as arginin-vasopressin AVP , vasoactive intestinal peptide VIP , γ-amino-butyric-acid GABA , glutamate, gastrin-releasing peptide, and somatostatin.

This large variety of neuropeptides within the SCN ensures a rich diversity in signalling properties to effector targets According to its neurocircuit topology, the SCN can be functionally divided into two subregions. The dorsomedial shell region primarily produces AVP and gets mainly innervated by the hypothalamus, while the ventrolateral core region primarily produces VIP and receives photic input [cf.

SCN output projections target many different brain regions and modulate the activity of downstream neurohumoral pathways in a rhythmic manner, herewith influencing a plethora of physiological processes 14 , 16 , The most important effector targets of the SCN include: i hypothalamic centers associated with activity, temperature, and sleep regulation, such as the subparaventricular area subPVN and the dorsomedial nucleus of the hypothalamus DMH , ii preautonomic hypothalamic neurons, affecting vagal and sympathetic autonomic centers in brain stem and spinal cord and, thus, exerting circadian control throughout the body via ANS activity 80 , and iii neuroendocrine hypothalamic centers responsible for hormone secretion e.

Figures 2 and 5 ]. The PVN is a significant integrating center for energy homeostasis and distribution center of circadian rhythmicity to the body, as its parvocellular neurons project to the median eminence to control the release of ACTH and thyroid-stimulating hormone TSH in the anterior pituitary i.

In addition, the central CS, exerts its synchronizing effects also through humoral i. The main effector of the central CS and essential synchronizing hormone is pineal melatonin MLT — , whose secretion is strictly modulated by the SCN and sympathetic fibers originating from the superior cervical ganglia , , — MLT modulates central and peripheral oscillators and related secondary molecular pathways mainly by cell-specific control through G-protein-coupled MLT membrane receptors MT 1 and MT 2 and GABAergic mechanisms , , [cf.

Figure 4 ]. MT is broadly distributed in the body and are vital for immunomodulation, endocrine, reproductive and cardiovascular regulation, cancerogenesis, and aging.

Additionally, MLT interacts with cytoplasmic factors i. retinoid acid receptor related orphan and Z receptors, ROR, RZR , while numerous other actions of MLT are receptor independent e.

MLT concentration reaches high levels at night plasma peak between h and h , overlapping with decreases in core body temperature, alertness, and performance , The sharp elevation of nocturnal cerebrospinal fluid CSF MLT exerts substantial protective effects and is responsible for nocturnal tissue recovery after the daily free radical brain damage due to high oxygen utilization These multifaceted chronobiotic regulatory actions have led to the recognition of MLT as one of the most pleiotropic biological signals in photoperiodic species , On the other hand, it is important to note that the majority of laboratory mouse strains do not produce melatonin and thus challenge the importance of MLT in related animal findings Figure 4 Multilevel interactions between the circadian system and the hypothalamic-pituitary-adrenal HPA axis.

AC, adrenal cortex; CRH, corticotropin releasing hormone; GCs, glucocorticoids; ipRGC, intrinsically photosensitive retinal ganglion cells; MT, melatonin receptor; PVN, paraventricular nucleus; RHT, retinohypothalamic tract; RNS, reactive nitrogen species; RORα, retinoic acid receptor-related orphan receptor α; ROS, radical oxygen species; RZRβ, retinoid acid receptor related Z receptor β; SCN, suprachiasmatic nucleus; SCG, superior cervical ganlia.

Finally, sleep acts restorative in concert with the CS, but also independently, towards optimizing the internal temporal order Sleep propensity and sleep stage timing, regulated through the subPVN and DMH, are bidirectionally associated with circadian gene expression in the SCN , but also strongly modulated by MLT levels , — The human CS and SS are closely and bidirectionally interconnected at multiple central and peripheral functional levels 19 , 22 , 23 , — The circadian properties of the HPA axis are so distinct, that, along with MLT, GCs have been established as a robust measure of CS output activity.

Additionally, MLT and GCs can also feedback at various levels and influence the main circadian rhythm themselves. Interestingly, the phase angle between CORT and MLT onset, the two major hormonal output signals of the CS and the HPA axis, has been identified as a potential useful biomarker in human stress-related research The HPA axis shows distinct circadian activity at rest with a robust diurnal oscillation of circulating GCs i.

SCN ablation completely abolishes the GC circadian rhythm, suggesting that HPA axis activity is driven by the central CS In addition, the CS has a major influence on the ANS.

Major human cardiovascular markers, such as heart rate, blood pressure, baroreflex, heart rate variability vagal measure , plasma epinephrine, and norepinephrine levels sympathetic measure and their response to stressors exhibit robust circadian variations with a distinct peak of sympathetic activity and nadir of parasympathetic activity in the morning hours — By doing so, the HPA axis and SNS activity are believed to prepare the organism for the higher energetic demand associated with typical external and internal stressors of the waking phase The CS orchestrates the circadian activity and reactivity of the HPA axis through both hormonal and neuronal pathways.

There are three main pathways of CS influence on the HPA axis: i direct SCN influence on HPA axis at the hypothalamic level, ii SCN innervation of the adrenal glands through indirect, multisynaptic autonomic innervation, and iii peripheral rhythms of local adrenal clocks, all three involved in the steroidogenic pathway and the ACTH-dependent transduction cascade in the zona glomerulosa and zona fasciculata of the adrenal gland [cf.

Through the second pathway, the SCN transmits photic information via multisynaptic autonomic innervation i. Interestingly, SCN neurons display connections to SNS and PNS, indicating that the SCN is not only essential for the physiologic autonomic diurnal fluctuations seen in humans , , , but also involved in both activation and deactivation of neuronal innervation of the adrenal in a circadian circle The intrinsic circadian rhythm of adrenal glands in metabolic activity and GC release even in culture has been shown very early in literature , while clock genes expression was repeatedly reported in the following years , , , , However, additional adrenal-intrinsic mechanisms depending on systemic cues, such as food-entrainable oscillators of the gland, could influence the diurnal rhythms of GC secretion , Another very important mechanism for shaping the GC circadian rhythm is their own systemic levels, exerting a negative feedback regulation of ACTH release The sensitivity of this feedback mechanism is highest during the trough point of the circadian glucocorticoid rhythm depending only MR at this time, while both MR and GR are involved at the GC peak-point lowest sensitivity Finally, MLT, apart from its direct modulating effect on the SCN , has been also shown to directly influence GC production and release by the adrenal gland, as well as acetylation rhythms of GR, GR translocation to the nuclei and transcriptional activity , , , Figure 5 Multilevel interactions between the circadian system and the hypothalamic-pituitary-adrenal HPA axis.

ACTH, adrenocorticotropic hormone; APG, anterior pituitary gland; AVP, arginine vasopressin; BMAL1, brain-muscle-arnt-like protein 1; CA, catecholamines; CLOCK, circadian locomotor output cycle kaput; CRH, corticotropin releasing hormone; CRYs, cryptochromes; HSD, hydroxysteroid dehydrogenase; ipRGC, intrinsically photosensitive retinal ganglion cells; GCs, glucocorticoids; GR, glucocorticoid receptor; PERs, periods; PVN, paraventricular nucleus; REV-ERBα, reverse viral erythroblastosis oncogene product alpha; RHT, retinohypothalamic tract; RORα, retinoic acid receptor-related orphan nuclear receptor alpha SCN, suprachiasmatic nucleus.

proteasome TTFL in the SCN, thus being crucial for circadian entrainment in photoperiodic species The neurohumoral interactions between CS and SS described above, have further molecular underpinnings at the cellular level, where the GR plays a fundamental role. In addition, a CLOCK-mediated posttranslational modification of hGRα is involved with the nuclear localization signal 1 NL1 , altering the cytoplasm-to-nucleus translocation of the receptor following ligand-induced activation, and indicates that the hGRα acetylation by CLOCK is linked to several molecular mechanisms Interestingly, the effect of a specific clock gene deletion on circulating GCs seems to depend on the specific TTFL missing member, suggesting that alteration of the positive or negative limb of the core clock feedback loop may have opposing effects on stress regulation.

Accordingly, BMAL1 TTFL positive limb gene deletion leads to low adrenal ACTH sensitivity throughout the circadian circle, supporting constant low GC levels and insensitivity to acute stress Furthermore, CHRONO ChIP-derived repressor of network oscillator , which is encoded by a BMAL-target gene, interacted with BMAL1, CRY2 and DEC2 and recruited the histone deacetylase 1 HDAC1 to the transcriptional machinery, ultimately repressing the principal transcriptional loop CHRONO is also able to acetylate the hinge region lysine cluster of GR, reducing its DNA-binding and thus indicating that this protein might play a fundamental role in the interaction of the CS with the SS , , More recent in vitro and in vivo studies also showed that REVERBa, in interaction with heat-shock-protein HSP 90, influences the stability and nuclear localization of GR in the liver and provides another link between the CS, metabolism and glucocorticoid actions , In addition, transcriptional cofactors of nuclear receptors e.

Similarly, HSP, forming a dynamic complex with the GR in the cytoplasm i. Finally, FKBP5, a chaperone protein of particular interest involved in directing activated GRs to the nucleus and implicated in a number of stress related psychiatric disorders, is also rhythmically expressed in most tissues , suggesting its involvement in circadian gating of GC signals.

Apart from the influence on many important biological processes, the rhythmic oscillations of the SS activity and especially the HPA axis and GC rhythmicity exert a vital synchronizing effect on the central and peripheral CS activity 19 , 23 , GCs, through binding to the hGRα, can efficiently reset the activity of peripheral clocks — , while they spare the SCN, which maintains its master intrinsic circadian rhythm, as it does not express GRs , The attenuation of the peripheral clocks by the phase-shifting effects of the GCs is then normally restored by the influence of the SCN.

However, the SS has to directly influence the SCN through an alternative pathway, as both stress exposure and exogenous GC application enhances AVP and VIP mRNA expression and release in the SCN , , while acute stress exposure also leads to an upregulation of Per1 and Per2 protein expression in the SCN In addition, GCs play an important role in the adjustment of nutrition-related uncoupling between the central and peripheral CS, as their high secretion after feeding slows down the circadian uncoupling and restores proper phasing , GCs are, thus, not just a downstreal hormonal output of central and peripheral clocks, but can also influence the CS itself and interact with other clock outputs toward a harmonious circadian regulation , , adding another interaction level between the stress and the circadian clock system.

Alteration of the GC rhythm e. Taken together, the SS through its effectors efficiently adjusts the circadian rhythm-linked output pathways of the body to properly respond to stressors, providing resistance to stress challenges in order to evade uncordinated circadian shifts Diurnally circulating GCs vitally contribute to the development of the CS activity by adjusting the phase of peripheral oscillators 19 , GCs synchronizing effects mainly involve GR-related phase shifting of peripheral circadian expression of several clock-related genes , — All peripheral clocks express GR, which translocate into the nucleus after activation and modulate transcriptional activity of several clock genes e.

PER1 contains GRs in its regulatory sequences, while GRs influence the expression of PER2 through binding to an intronic domain GCs lead herewith to upregulation of these genes, causing a phase delay of peripheral clocks with respect to the SCN master clock A genetically, functionally e.

externally administered corticosteroids attenuated GC diurnal rhythm has been shown to be associated with abolished or shifted circadian clock gene e. Even externally applied corticosteroids can entrain molecular oscillation in peripheral clocks , and have been shown, for example, to speed up or slow down adaptation to a new light-dark schedule after jetlag-induced circadian desynchrony However, rhythmic GC signaling is also required for periodic clock gene expression in certain brain regions outside the SCN, suggesting an important role of the adrenal rhythm also for higher brain functions in key stress-system-related regions Indeed, GR-mediated GC signaling is, for example, fundamental for the rhythmic expression of PER2 in the amygdala , , while adrenalectomy is shown to supress and extended GC exposure to increase PER gene expression in the PVN, bed nucleus of stria terminalis BNST and other limbic areas , , — GC-dependent circadian gene expression could even be indirectly involved in a GC feedback pathway to the SCN For example, serotonergic projections of the raphe nucleus to the SCN involved in light entrainment show a GC-dependent circadian transcription of tryptophan hydroxylase-2 TH-2 , an enzyme involved in serotonin synthesis Furthermore, GR-related GC effects and clock machinery also interact through a modulation of catecholamine biosynthesis and degradation, thus influencing time-of-day-dependent stress responses and further reinforcing the interaction between the CS and the SS 94 , , Catecholamine biosynthesis is both GC- and clock-regulated, as TH i.

Taken together, GC rhythms exert an accompanying circadian signal which consitutes an additional level of security to ensure proper circadian signalling input to the cell cycle oscillating machinery, while, on the other hand, peripheral clocks might gate this GR-specific input.

The human CS enables the nyctohemeral organization and coordination of many temporal physiologic processes promoting homeostasis and environmental adaptation A misalignment of the human circadian rhythm is associated with a critical loss of this harmonious biological timed order at different organizational levels, which is defined as chronodisruption — Chronodisruption-related cacostatic load with short- and long-term pathophysiologic and epigenetic consequences — can lead to a wide range of biological consequences in the organism , — Chronodisruption may gradually change the fundamental properties of brain systems regulating neuroendocrine, immune, and autonomic function and denotes a breakdown of appropriate biobehavioral adaptations to challenges with increased stress sensitivity and vulnerability to stress-related disorders 20 , , Sleep acts in concert with the central CS, but also independently towards an optimal internal temporal order Specific sleep stages are closely related with specific clock gene expression in the SCN and are tightly ruled by the CS 81 , , SD has been associated with circadian-related gene expression alterations in humans — In addition, SD also relates to various HPA axis dysregulations e.

Accordingly, chronodisruption in humans has been associated with increased risk for cardiovascular morbidity, metabolic consequences, inflammation, immune dysregulation, psychiatric disorders and even elevated cancer risk , , — Interestingly, even circadian gene polymorphisms have been associated with some similar consequences , In addition to other crucial circadian cues that can dysregulate circadian rhythms e.

Normally, after exposure to stressors, the SS can transiently override the CS creating a transient uncoupling of the central and peripheral circadian rhythm, through a hGR-related phase shift of peripheral clock-related genes , , , , , , Thereby, the SCN is only indirectly influenced and is, thus, able to maintain its master rhythm and restore its initial main phase to the periphery after stress termination , Indeed, subacute stressors have been experimentally shown to have only transient impact on SCN-regulated rhythms in animal research , However, the stability of the SCN clock appears to fade away after extensive acute or chronic physical, psychological, inflammatory, or metabolic stress For example, in a study comparing single versus chronic social defeat across two weeks, single stress exposure advanced only the adrenal peripheral clock, while chronic stress also clocks in the CNS Animal research provides additional evidence that chronic mild stress disrupts the regulated gene expression of several clock genes in several peripheral , , but also CNS tissues, including the hippocampus, amygdala, PFC , , , and the SCN , , , Chronic stress exposure in mice has been shown to alter the circadian properties of the HPA axis , , while extensive physical stress after surgery in humans leads to disturbances in MLT, CORT and core body temperature rhythms In addition, numerous human and animal studies suggest that acute extensive and chronic stress can affect major sleep centers of the brain , , , , — and, thus, influence sleep physiology leading to both immediate and long-lasting sleep disruption — Apart from the physiological circadian activity of the SS, the stress responsiveness also displays diurnal sensitivity changes, probably through differential interference of the SCN to different brain areas , , For example, acute psychological stress, involving higher brain areas and the limbic system, as well as acute physical external stress i.

This appears reasonable, as acute physiological internal stress represents a greater threat during the active phase of animals, while acute external physical stressors e.

Interestingly, further experimental findings in animals suggest that repeated external stress exposure i. social-defeat paradigm shows inverse effects and exerts more detrimental effects during the active phase , in animal research.

These results jointly suggest that the effect of a stressor depends not only on the circadian phase of exposure, but also on the interaction of the circadian phase with the stressor type, as well as with the chronicity of the stressor 25 , For example, both physical and psychological stress at the beginning of the light phase leads to a phase advance, while at the beginning of the dark phase to a phase delay of PER2 expression in mice The stress-related effects on internal rhythms described above have supported a recent research focus on the potential causal role of SD and chronodisruption in the acute pathophysiology and the development of long-term effects of traumatic stress exposure, suggesting that chronodisruption may represent a potential underlying neurobiologic link — The association between sleep and circadian disruption and psychopathology was first officially noted by Emil Kreapelin in and has evolved through the years by numerous biological findings Traumatic stress exposure may cause both immediate and long-lasting SD — , which may represent a central pathway mediating the enduring neurobiological correlates of trauma , , , — [cf.

Figure 6 ]. For example, several human cohort studies have repeatedly suggested that early-life traumatic stress exposure is related to adult SD years later, including global i.

Such sleep dysregulation could further enhance maladaptive stress regulation and precipitate the neurobiological correlates of traumatic stress through impaired homeodynamic balance, resulting in the extensive symptomatology and comorbidity of trauma-related disorders , — Figure 6 Schematic model of trauma-related chronodisruption as underlying biological pathway leading to posttraumatic stress disorder PTSD and PTSD-related comorbidities.

Posttraumatic stress disorder PTSD is classified in DSM-5 as a trauma- and stress-related disorder following a psychologically distressing event outside the range of usual human experience Evidence of circadian dysregulation in PTSD mostly originates from sleep research findings.

According to DSM-5, SD represents prominent clinical feature of the disorder with very high prevalence , , , and is often closely related to severity of PTSD psychopathology , and resistant to first-line treatments — SD in PTSD is associated with sleep-related arousal dysregulation and include sleep avoidance, insomnia, nightmares, hyperarousal states, sleep terrors and nocturnal anxiety attacks, body-movement and breathing-related sleep disorders , , — , with increased sympathovagal tone during rapid-eye-movement REM sleep, fragmented REM sleep patterns, and reduced REM theta activity — , , — Similar findings have been in animal and human SD studies , Interestingly, REM sleep disruption in the immediate aftermath of a trauma , , , as well as sleep impairment prior to traumatic stress exposure could represent risk factors for PTSD development , SD prior to trauma have been specifically shown to be associated with a 2.

SD after trauma thus represents a rather core than secondary feature of PTSD , , , — , and may be both a precipitating and perpetuating factor of the disorder — Besides SD, traumatic stress also affects neural correlates of memory formation — Memory processing, formation and consolidation are directly influenced by sleep — Sleep promotes memory consolidation, particularly for emotionally salient information , while SD reduces the connectivity between amygdala and PFC thus disrupting memory consolidation — , as repeatedly shown in PTSD.

In addition to SD studies in PTSD, additional CS-related evidence on chronodisruption in PTSD originates from genetic, neuroendocrine, autonomic, and immune findings. For example, genome-wide association studies have also implicated to core circadian genes as PTSD candidate risk genes: pituitary adenylate cyclase-activating polypeptide PACAP and retinoid-related orphan receptor alpha RORA-α gene.

PACAP is involved in phase resetting in response to light — and RORA-α is rhythmically expressed and regulates BMAL activity , Furthermore, as immune system activity tightly follows circadian rhythms imposed by the SCN synchronisation , — , our recent first report on the loss of the typical peripheral biphasic rhythm of IL-6 in combat stress exposed individuals , is of particular importance.

Further neuroendocrine findings in PTSD repeatedly show increased central CRH levels, altered HPA axis reactivity with enhanced negative feedback inhibition and blunted circadian CORT rhythm and CAR, while some studies—but not all—have shown decreased circulating concentrations of CORT — Similarly, patients with PTSD exhibit increased autonomic reactivity, elevated central and peripheral norepinephrine concentrations, higher basal heart rate, increased sympathovagal balance, blunted salivary alpha-amylase awakening response and, most importantly, blunted diurnal autonomic differences , , — , suggesting central neuroautonomic dysregulation leading to higher cardiovascular risk in PTSD , , In addition, disrupted MLT levels in the first 48 h after traumatic stress exposure were shown to be associated with a higher PTSD development risk Finally, PTSD has been frequently related to several other comorbidities, such as chronic fatigue syndrome CFS — , fibromyalgia — , rheumatoid arthritis , which all share a very similar underlying neuroendocrinological profile to PTSD e.

Current evidence suggests that SD and CD may have a vital predispositional role in PTSD development , while their effective treatment could be associated with substantial improvement of overall PTSD symptomology , — Nevertheless, SD is still often clinically addressed as a secondary symptom in PTSD.

Careful assessment and treatment of SD and CD should therefore be an integral part in PTSD management , , — Cognitive-behavioral sleep management in PTSD constitutes a widely acceptable and effective treatment option with durable gains and beneficial effects , — In addition, the antihypertensives α-1 adrenoreceptor antagonist prazosin and α-2 adrenoreceptor agonist clonidine, the synthetic cannabinoid receptor 1 and 2 agonist nabilone and the multilemodal antidepressant trazodone i.

Standard pharmacological sleep management in PTSD, however, may treat sleep quantity sufficiently, but often fail to improve daytime functioning and restore CD in PTSD , Therefore, development of chronopharmacological interventions that would restore CS-related alterations and herethrough counteract changes in PTSD-related neurocircuitry could represent interesting novel therapeutic strategies — Recent experimental findings emphasize on a pleiotropic, but crucial role of MLT in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress, and epigenetics, thus suggesting a potentially beneficiary effect of an add-on melatonergic treatment in PTSD , Numerous studies have repeatedly confirmed the efficacy of melatonergic treatment on almost every aspect of sleep disturbance, while preserving a benign side-effect profile and safety in both short- and long-term administration, with no efficacy wear-off, withdrawal effects or dependence risk , — In addition, MLT is known to adjust and reset amplitude and phase of CNS e.

MLT also decreases hypothalamic CRH levels and inhibit the ACTH-stimulated CORT production in the primate and human adrenal gland , — , — , thus attenuating the adrenocortical secretory response in acute and chronic stress models — With respect to the ANS, MLT entrain disrupted autonomic rhythmicity by inhibiting central sympatho-adreno-medullary SAM outflow and shifting autonomic balance in favour of vagal activity , — Interestingly, research findings suggest a direct enhancing effect of melatonergic transmission in stimulus processing, memory consolidation, and conditional cued fear extinction, especially under stress — Finally, immediate melatonergic treatment directly after exposure to stress, normalizes the altered expression of Per 1 and Per 2 genes in hippocampal regions of rats, thus suggesting a possible immediate preventing properties MLT has been shown to protect these hippocampal neurons from oxidative stress, by preventing GC-related toxicity through decrease of receptor translocation to nuclei in models of sleep deprivation and chronic stress — Taken together, MLT and melatonergic agents could therefore represent a promising adjuvant contribution to the clinical treatment and perhaps prevention of stress-related syndromes and comorbidities in mental disorders in general and PTSD in particular , , , — Further options for a pharmacological or nonpharmacological manipulation of the interplay between CS and SS in order to interfere in the pathophysiology of trauma-related disorders are of theoretical interest and deserve thorough further investigation through preclinical research and clinical confirmation.

For example, exogenous application of GCs and GC-analogs in a time-of-day dependent fashion i. On the other hand, pharmacological GR-antagonism has been found associated with insomnia symptoms improvement and could also represent a potential approach.

As sleep promotes memory consolidation, particularly for emotionally salient information, sleep deprivation in the beginning of the resting phase directly after traumatic stress exposure may also decrease the risk of PTSD development , possibly through reduction of mPFC-amygdala connectivity , , Furthermore, first findings suggest that casein kinase 1ϵ, a closely related clock components implicated in period determination, could represent a novel target of pharmacological inhibition, thus stabilizing the circadian clock against phase shift Finally, it is important to mention, that selective serotonine reuptake inhibitors SSRI , as first-line treatment option for PTSD, have been shown to exert additional, CS-related effects.

In particular, fluoxetine treatment was shown to modulate the CS via phase advances of SCN neuronal firing and also normalize disrupted circadian locomotor activity and hippocampal clock gene expression in a genetic mouse model of high trait anxiety and depression This periodic movement of our planet has contributed to the evolution of the internal time-keeping system, that creates and maintains cellular and systemic rhythmicity, through temporal organization of physiologic processes throughout several structural levels in the organism, the CS.

The award of the Nobel Prize in Physiology or Medicine to J. Hall, M. Rosbash and M. However, over the past seven decades, modern society has cultivated a new, round-the-clock lifestyle, which enhances temporal misalignment between internal i.

Given the close interconnection between the CS and the SS at various levels, internal desynchrony could synergistically contribute to the development of a higher stress sensitivity and vulnerability for stress-related disorders.

Understanding the mechanisms susceptible to chronodisruption following toxic stress exposure and their role in a chronically dysregulated circadian network in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and enabling preventive strategies in stress-exposed populations 74 , , AA managed all literature searches.

AA and NN wrote the first draft of the paper. VB, GC, and PP contributed with significant text passages and revised the draft for important intellectual content. All authors have contributed to, read and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Synthetic glucocorticoids have been widely used in the treatment of several inflammatory disorders and hematologic malignancies Since target tissue glucocorticoid sensitivity is lower in the morning and higher in the evening, glucocorticoid analogs should be administered in a time-of-day dependent fashion to achieve a beneficial therapeutic outcome and to avoid their detrimental side effects, such as osteoporosis, weight gain, glucose intolerance, and psychiatric symptoms.

Therefore, patients with autoimmune disorders are treated with prednisolone or other synthetic glucocorticoids in the evening, given that the hGRα is less acetylated during that time In addition to inflammatory disorders, chronic administration of glucocorticoids is frequently used as substitution treatment of hypocortisolemic disorders, such as adrenal insufficiency, regardless of its etiology.

Approximately two-thirds of hydrocortisone dose is usually given in the morning, while the remainder one-third is administered in two doses in the mid-day and in the early evening Recent advances in the therapeutic manipulation of adrenal insufficiency have shown that a dual-release hydrocortisone formulation, which resembles circadian cortisol secretion, results in improved quality of life, decreased body weight and blood pressure, and improved glucose tolerance , Although we have gained important insight in the molecular communication between the stress system and the circadian clock system, there are many physiologic and pathophysiologic aspects of their interrelation that still elude us.

The molecular mechanisms underlying resetting of peripheral clocks by glucocorticoids are under intense investigation both in normal and pathologic conditions. Moreover, the tight synchronization of peripheral clocks with the central clock remains poorly understood.

Furthermore, our understanding on the function and significance of local adrenal clocks is still increasing. Future in vitro and in vivo studies will shed light on the functional significance of the cross talk between the stress system and the circadian clock system of living organisms to increase survival chance.

Importantly, in parallel with the tremendous progress of molecular, cellular, and structural biology, significant advances in the field of mathematical and computer biosciences will undoubtedly help us have a deeper understanding of system interrelations.

Such efforts will be useful for accurate predictions of a system response to acute or chronic stress, as well as to pharmacotherapy with novel medications. All authors contributed equally to the conception of the work, drafted the manuscript or revisited it critically for important intellectual content, finally approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Chrousos GP, Gold PW.

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Hydration for staying hydrated during sports events dramatic Circadian rhythm stress in energy demands by the rhythmic Repeatable meal cadence Circadiaj night and Cigcadian on our planet has rhyfhm a geophysical evolutionary need for biological etress organization across phylogeny. The human CS atress Repeatable meal cadence and bidirectionally interconnected to the Hydration for staying hydrated during sports events system SS. Thereby, the understanding of the Optimizing nutrient delivery channels Hydration for staying hydrated during sports events between stressors and Circxdian responses is critical for the comprehension of the molecular basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune, and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations. Circadian rhythm stress Circadian rhythm stress article is included in the How Recommended fat ratio Circadian rhythm stress resilience rhgthm biological strexs collection. Addiction, Circadian, Clock, Circaian, HPA, Reward, Stress, Vulnerability. Two systems, the circadian and stress response systems, have evolved to afford adaptability to both recurring and spontaneous environmental changes. To fully understand this phenomenon, current research seeks to understand the effects of stress in the brain reviewed in McEwen et al. Many neuropsychiatric disorders have long been associated with altered circadian rhythm Mills et al.

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