Rhythm Of Melatonin Secretion Research Articles

Melatonin receptor agonists in neurodegenerative diseases and psychiatric disorders

Neurodegenerative and psychiatric diseases remain a therapeutic challenge. Mental illnesses such as depression and bipolar affective disorder lead to disruption of the diurnal rhythm of melatonin secretion and disruption of the sleep-wake axis. The use of new melatonergic drugs has received special attention in recent years. Selective melatoninergic M1 and M2 receptor agonists (tasimelteon, ramelteon) show a more favorable metabolic profile, better regulation of circadian rhythms, and effects on total sleep time and sleep quality compared to the already well-studied melatonin. In addition, these drugs show no addictive potential. Agomelatine, through its action on M1 and M2 receptors, as well as serotonergic 5-HT2C and 5-HT2B receptors, exhibits antidepressant, normothymic, and neuroprotective effects, providing primary therapy or adjunctive treatment.

Are circadian rhythms in disarray in patients with chronic critical illness?

The aim of our study is to assess circadian rhythms in patients with chronic critical illness due to severe brain injury in intensive care unit by establishing the relation between melatonin and cortisol secretion, considering astronomical time and the sleep-wake cycle in chronic critical illness. The study included 54 adult patients with chronic critical illness who resided in the intensive care unit for at least 30 days. The level of consciousness was determined using the CRS-R scale. We did the continuous electroencephalographic (EEG) monitoring with polygraphic leads for 24h. Also, we determined the serum levels of cortisol and melatonin using the tandem mass spectrometry method with ultra-performance liquid chromatography. 90.74% of patients had one acrophase in melatonin secretion curve, which suggests the preservation of the rhythmic secretion of melatonin. These acrophases of the melatonin rhythm occurred during the night time in 91.8% of patients. Most of the patients (69.3%) slept during the period from 2:00 to 4:00 a.m. The evening levels of cortisol and melatonin had an inverse relation (rs=0.61, p<0.05), i.e., a decrease in the level of cortisol secretion accompanies an increase in melatonin. We concluded from our study that the rhythmic secretion of melatonin and cortisol is preserved in patients with chronic critical illness that resulted from severe brain injury. No statistically significant discrepancy between melatonin and cortisol secretion, day-and-night time and the sleep-wake cycle are found. We may focus our future work on finding more reliable methods to stabilize the preservation of circadian rhythms to protect vital organ functions.

Maternal melatonin levels and temporal dietary intake: results from MY-CARE cohort study

Chrononutrition emerges as a novel approach to promote circadian alignment and metabolic health by means of time-of-the-day dietary intake. However, the relationship between maternal circadian rhythm and temporal dietary intake during pregnancy remains understudied. This study aimed to determine the change in melatonin levels in pregnant women across gestation and its association with temporal energy and macronutrient intake. This was a prospective cohort involving 70 healthy primigravidas. During the second and third trimesters, pregnant women provided salivary samples collected at 9:00, 15:00, 21:00, and 3:00 h over a 24 h day for melatonin assay. Data on chrononutrition characteristics were collected using a 3-day food record. Parameters derived from melatonin measurements including mean, amplitude, maximal level, area under the curve with respect to increase (AUCI), and area under the curve with respect to ground (AUCG) were computed. A rhythmic melatonin secretion over the day that remained stable across trimesters was observed among the pregnant women. There was no significant elevation in salivary melatonin levels as pregnancy advanced. In the second trimester, higher energy intake during 12:00–15:59 h and 19:00–06:59 h predicted a steeper melatonin AUCI (β=-0.32, p = 0.034) and higher AUCG (β = 0.26, p = 0.042), respectively. Macronutrient intake within 12:00–15:59 h was negatively associated with mean melatonin (Fat: β=-0.28, p = 0.041) and AUCG (Carbohydrate: β=-0.37, p = 0.003; Protein: β=-0.27, p = 0.036; Fat: β=-0.32, p = 0.014). As pregnant women progressed from the second to the third trimester, a flatter AUCI was associated with a reduced carbohydrate intake during 12:00–15:59 h (β=-0.40, p = 0.026). No significant association was detected during the third trimester. Our findings show that higher energy and macronutrient intakes particularly during 12:00–15:59 h and 19:00–06:59 h are associated with the disparities in maternal melatonin levels. Findings suggest the potential of time-based dietary approaches to entrain circadian rhythm in pregnant women.

Circadian rhythm disturbance and delirium in ICU patients: a prospective cohort study

BackgroundPatients treated in the intensive care unit (ICU) may experience a reversal of day and night. The circadian rhythm in ICU patients can be disturbed.MethodsTo explore the relationship between ICU delirium and the circadian rhythms of melatonin, cortisol and sleep. A prospective cohort study was carried out in a surgical ICU of a tertiary teaching hospital. Patients who were conscious during the ICU stay after surgery and were scheduled to stay in the ICU for more than 24 h were enrolled. Serum melatonin and plasma cortisol levels were measured three times a day by drawing arterial blood on the first three days after ICU admission. Daily sleep quality was assessed by the Richard-Campbell Sleep Questionnaire (RCSQ). The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was performed twice a day to screen for ICU delirium.ResultsA total of 76 patients were included in this study, and 17 patients developed delirium during their ICU stay. Melatonin levels were different at 8:00 (p = 0.048) on day 1, at 3:00 (p = 0.002) and at 8:00 (p = 0.009) on day 2, and at all three time points on day 3 (p = 0.032, 0.014, 0.047) between delirium and non-delirium patients. The plasma cortisol level in the delirium patients was significantly lower than that in the non-delirium patients at 16:00 on day 1 (p = 0.025). The changes in melatonin and cortisol secretion levels exhibited obvious biological rhythmicity in non-delirium patients (p < 0.001 for melatonin, p = 0.026 for cortisol), while no rhythmicity was found in melatonin and cortisol secretion levels in the delirium group (p = 0.064 for melatonin, p = 0.454 for cortisol). There was no significant difference in RCSQ scores in the first three days between the two groups.ConclusionsThe disturbance of the circadian rhythm of melatonin and cortisol secretion was associated with the development of delirium in ICU patients. Clinical staff should pay more attention to the importance of maintaining patients’ normal circadian rhythms in the ICU.Trial registrationThe study was registered with the US National Institutes of Health ClinicalTrials.gov(NCT05342987) (25/04/2022).

Structural properties and binding mechanism of DNA aptamers sensing saliva melatonin for diagnosis and monitoring of circadian clock and sleep disorders

Circadian desynchrony with the external light-dark cycle influences the rhythmic secretion of melatonin which is among the first signs of circadian rhythm sleep disorders. An accurate dim light melatonin onset (established indicator of circadian rhythm sleep disorders) measurement requires lengthy assays, and antibody affinities alterations, especially in patients with circadian rhythm disorders whose melatonin salivary levels vary significantly, making antibodies detection mostly inadequate. In contrast, aptamers with their numerous advantages (e.g., target selectivity, structural flexibility in tuning binding affinities, small size, etc.) can become preferable biorecognition molecules for salivary melatonin detection with high sensitivity and specificity. This study thoroughly characterizes the structural property and binding mechanism of a single-stranded DNA aptamer full sequence (MLT-C-1) and its truncated versions (MLT-A-2, MLT-A-4) to decipher its optimal characteristics for saliva melatonin detection. We use circular dichroism spectroscopy to determine aptamers’ conformational changes under different ionic strengths and showed that aptamers display a hairpin loop structure where few base pairs in the stem play a significant role in melatonin binding and formation of aptamer stabilized structure. Through microscale thermophoresis, aptamers demonstrated a high binding affinity in saliva samples (MLT-C-1F Kd = 12.5 ± 1.7 nM; MLT-A-4F Kd = 11.2 ± 1.6 nM; MLT-A-2F Kd = 2.4 ± 2.8 nM; limit-of-detection achieved in pM, highest sensitivity attained for MLT-A-2F aptamer with the lowest detection limit of 1.35 pM). Our data suggest that aptamers are promising as biorecognition molecules and provide the baseline parameters for the development of an aptamer-based point-of-care diagnostic system for melatonin detection and accurate profiling of its fluctuations in saliva.

Age-related and individual features of the HPA axis stress responsiveness under constant light in nonhuman primates.

The hypothalamic-pituitary-adrenal (HPA) axis is a key adaptive neuroendocrine system, dysfunction of which plays an important role in the increasing incidence of stress-dependent age-related pathology. Among the environmental factors effecting increase age-related diseases, great importance is given to disturbances of the light-dark schedule, particularly with increased illumination at night. While disruption of the light-dark schedule has long been recognized as a powerful behavioral stressor, little is known regarding stress reactivity of the HPA under constant light (CL) conditions, especially with aging and depending on the features of stress behavior. The purpose of this investigation was to study the age-related and individual features of the HPA axis response to acute stress exposure (ASE) under chronic CL in nonhuman primates that are known to differ in behavioral responsiveness to stress. Young and old female rhesus monkeys (with control standard behavior or anxiety and depression-like behavior) were exposed to CL (24h light/day, 330-400 lux for 4 to 8 weeks). Control young and old monkeys were exposed to standard lighting (SL) with natural light during the day and darkness at night. All animals were subjected to ASE (restriction of mobility for 2 hours), functional tests with corticotrophin-releasing hormone and arginine-vasopressin, and study of circadian rhythms of cortisol and pineal melatonin secretion. For the first time an inhibitory effect of CL on the reaction of the adrenal cortex to ASE was revealed in all individuals, regardless of age and preexisting behavior stress reactivity, the mechanisms of which were age-dependent: due to inhibition of the pituitary ACTH secretion in young animals and mainly not affecting the ACTH secretion in old individuals. There were no significant changes in melatonin secretion both in young and old animals. The observed CL inhibition of adrenal cortical reactivity to ASE may be useful to correct increased vulnerability to ASE observed in individuals with preexisting anxiety and depression-like stress behaviors. On the other hand, the CL induced decrease in adrenal stress reactivity of behaviorally normal animals suggests a potential risk of reducing the adaptive capacity of the organism under conditions of continuous light exposure.

Circ-ERC2 Is Involved in Melatonin Synthesis by Regulating the miR-125a-5p/MAT2A Axis

The circadian rhythm of melatonin secretion in the pineal gland is highly conserved in vertebrates. Melatonin levels are always elevated at night. Acetylserotonin O-methyltransferase (ASMT) is the last enzyme in the regulation of melatonin biosynthesis (N-acetyl-5-hydroxytryptamine-melatonin). S-adenosylmethionine (SAM) is an important methyl donor in mammals and can be used as a substrate for the synthesis of melatonin. Methionine adenosyltransferase (MAT) catalyzes the synthesis of SAM from methionine and ATP and has a circadian rhythm. CircRNA is an emerging type of endogenous noncoding RNA with a closed loop. Whether circRNAs in the pineal gland can participate in the regulation of melatonin synthesis by binding miRNAs to target mat2a as part of the circadian rhythm is still unclear. In this study, we predicted the targeting relationship of differentially expressed circRNAs, miRNAs and mRNAs based on the results of rat pineal RNA sequencing. Mat2a siRNA transfection confirmed that mat2a is involved in the synthesis of melatonin. Circ-ERC2 and miR-125a-5p were screened out by software prediction, dual-luciferase reporter experiments, cell transfection, etc. Finally, we constructed a rat superior cervical ganglionectomy model (SCGx), and the results showed that circ-ERC2 could participate in the synthesis of melatonin through the miR-125a-5p/MAT2A axis. The results of the study revealed that circ-ERC2 can act as a molecular sponge of miR-125a-5p to regulate the synthesis of melatonin in the pineal gland by targeting mat2a. This experiment provides a basis for research on the circadian rhythm of noncoding RNA on pineal melatonin secretion.

Melatonin pretreatment prevents propofol-induced sleep disturbance by modulating circadian rhythm in rats

Postoperative sleep disorder frequently occurs in patients after surgery. Sleep disturbance aggravates pain, anxiety, and delirium, which is an important risk factor for poor recovery. Circadian rhythm disorder induced by general anesthesia plays important role in postoperative sleep disorders. A large number of clinical studies have shown that various forms and duration of general anesthesia can lead to postoperative sleep disorders. In this study, the effect of prolonged propofol anesthesia on biological rhythm was comprehensively evaluated by wireless physiological telemetry system, and the therapeutic effect of exogenous melatonin pretreatment was further investigated. The results showed that prolonged propofol anesthesia had significant impacts on the circadian rhythm of sleep, body temperature, locomotor activity and endogenous melatonin secretion within 24 h following anesthesia, resulting in diminished oscillation amplitude. In hypothalamus, the expression of circadian factor PER and CRY were inhibited by propofol, possibly through activation of CAMK-CREB signaling pathway. Post-translational factors GSK-3β, SIRT1, AMPK were also involved in the regulation of circadian factors after propofol anesthesia. Melatonin pretreatment could restore circadian rhythm process by regulating circadian factor expression through post-translational modulation and prohibit the over-synthesis of melatonin in pineal gland. This study verified the effects of anesthetics on circadian rhythm and further evaluated the potential therapeutic effect of melatonin on postoperative circadian rhythm and sleep disorders.

Preliminary Study on Changes of Sleep EEG Power and Plasma Melatonin in Male Patients With Major Depressive Disorder After 8 Weeks Treatment.

Objective: To clarify the effects of escitalopram on sleep EEG power in patients with Major depressive disorder (MDD).Method: Polysomnography (PSG) was detected overnight, and blood samples were collected at 4 h intervals over 24 h from 13 male healthy controls and 13 male MDD patients before and after treatment with escitalopram for 8 weeks. The outcome measures included plasma melatonin levels, sleep architecture, and the sleep EEG power ratio.Results: Compared with healthy controls, MDD patients presented abnormalities in the diurnal rhythm of melatonin secretion, including peak phase delayed 3 h and a decrease in plasma melatonin levels at night and an increase at daytime, accompanied by sleep disturbances, a decrease in low-frequency bands and an increase in high-frequency bands, and the dominant right-side brain activity. Several of these abnormalities (abnormalities in the diurnal rhythm of melatonin secretion, partial sleep architecture parameters) persisted for at least the 8-week testing period.Conclusions: Eight weeks of treatment with escitalopram significantly improved subjective sleep perception and depressive symptoms of patients with MDD, and partially improved objective sleep parameters, while the improvement of circadian rhythm of melatonin was limited.

Modeling the Heterodimer Interfaces of Melatonin Receptors.

Melatonin receptors are Class A G protein-coupled receptors (GPCRs) that regulate a plethora of physiological activities in response to the rhythmic secretion of melatonin from the pineal gland. Melatonin is a key regulator in the control of circadian rhythm and has multiple functional roles in retinal physiology, memory, immunomodulation and tumorigenesis. The two subtypes of human melatonin receptors, termed MT1 and MT2, utilize overlapping signaling pathways although biased signaling properties have been reported in some cellular systems. With the emerging concept of GPCR dimerization, melatonin receptor heterodimers have been proposed to participate in system-biased signaling. Here, we used computational approaches to map the dimerization interfaces of known heterodimers of melatonin receptors, including MT1/MT2, MT1/GPR50, MT2/GPR50, and MT2/5-HT2C. By homology modeling and membrane protein docking analyses, we have identified putative preferred interface interactions within the different pairs of melatonin receptor dimers and provided plausible structural explanations for some of the unique pharmacological features of specific heterodimers previously reported. A thorough understanding of the molecular basis of melatonin receptor heterodimers may enable the development of new therapeutic approaches against aliments involving these heterodimeric receptors.

Circadian Rhythm and Concentration of Melatonin in Breast Cancer Patients.

Melatonin is a biomarker of the central circadian clock and its chronobiotic actions entraining circadian rhythms to the light-dark cycle are well known. Reduction in melatonin levels and altered circadian rhythms have been associated with a high risk of breast cancer. Melatonin has also been shown to display anti-proliferative effects on breast cancer growth and proliferation. Evaluation of melatonin circadian rhythm alterations in patients bearing breast cancer may have interesting prognostic and therapeutic applications. To review studies evaluating the circadian rhythm of melatonin in breast cancer patients. The effects of surgery and chemotherapy on melatonin secretion were also reviewed. Electronic databases, including PubMed/MEDLINE and Scopus, were searched from their inception to May 2020, using the keywords "Melatonin", "Circadian rhythm" and "Breast cancer". Patients with breast cancer maintain a circadian rhythm of melatonin secretion with relatively high levels during the night and low levels during the day, however, a reduction in nocturnal melatonin peak and decreased amplitude of melatonin circadian rhythms in these patients have also been reported. Melatonin levels can influence estrogen receptor concentrations in hormone-dependent estrogen- positive breast cancer. Chemotherapy alters melatonin levels and breast surgery tends to alter melatonin secretion at first-day post-operation. Melatonin levels correlate with clinical and psychological symptoms of breast cancer, such as sleep quality and depression severity. Circadian rhythm and the concentration of melatonin in the blood are altered in patients with breast cancers, and it can modify not only the sleep-wake cycle and, thus, patients' quality of life but due to melatonin's antioxidant effects, the effect of therapies can be modulated. Due to the heterogonous protocols used to assess melatonin and variable environmental factors during sampling, further studies need to control, such variables in order to tailor clinical trials based on melatonin rhythm adjustment and/or supplementation in breast cancer patients.

Melatonin and Melatonin-Rich Foods

Vegetables and fruits are found in the most popular diets. And they are considered as rich sources of vitamins and minerals. Vitamin and mineral deficiency are one of the major causes of various diseases that are common nowadays. Especially vitamins which are known to affect directly on various hormones in our body. Melatonin (N-acetyl-5-methoxytryptamine), one of these hormones, is synthesized in various peripheral organs and tissues, especially the pineal gland and retina. Endogenous melatonin secretion rhythm is regulated by the suprachiasmatic nucleus and maintained with a bright dark cycle. Melatonin hormone is responsible for many activities in the human body. In addition to, especially is found in various foods (milk and milk product, nuts, olive oil, and various fruits). In this review, the recent studies that focused on the biosynthesis and metabolism of melatonin in addition to those investigated food content of melatonin and their effects on physiological and biological human health.

Norepinephrine Is a Major Regulator of Pineal Gland Secretory Activity in the Domestic Goose (Anser anser).

This study determined the effect of norepinephrine and light exposure on melatonin secretion in goose pineal explants. Additionally, it investigated changes in the content of norepinephrine, dopamine, and their metabolites [3,4-dihydroxyphenylacetic acid; vanillylmandelic acid (VMA); homovanillic acid] in goose pineal glands in vivo under 12 h of light and 12 h of darkness (LD), a reversed cycle (DL), constant light (LL), and constant darkness (DD). In vitro content of melatonin was measured by radioimmunoassay; contents of catecholamines and their metabolites were measured by high-performance liquid chromatography. Exposure of pineal explants to LD or DL established rhythmic melatonin secretion; this rhythm was much better entrained with norepinephrine exposure during photophase than without it. When the explants were kept in LL or DD, the rhythm was abolished, unless NE was administered during natural scotophase of a daily cycle. In vivo, norepinephrine and dopamine levels did not display rhythmic changes, but their respective metabolites, HMV and VMA, displayed well-entrained diurnal rhythms. These results indicate that norepinephrine and sympathetic innervation play key roles in regulation of pineal secretory activity in geese, and that pineal levels of VMA and HMV provide precise information about the activity of sympathetic nerve fibers in goose pineal glands.

Clock Gene, Melatonin, and the Sleep–Wake Cycle

The review examines the role of the Clock gene and melatonin as participants in human circadian rhythms. The results of studies on the association of the Clock gene polymorphisms and the sleep–wake cycle, as well as circadian rhythms of melatonin secretion in different chronotypes and insomnia, are presented. A hypothesis about the role of the Clock 3111T/C gene polymorphism in the formation of insomnia in Caucasian women living in Eastern Siberia is considered.

Effects of general versus regional anaesthesia on circadian melatonin rhythm and its association with postoperative delirium in elderly patients undergoing hip fracture surgery: study protocol for a prospective cohort clinical trial

IntroductionPostoperative delirium (POD) is a common neurological complication after hip fracture surgery and is associated with high morbidity and mortality in elderly patients. Although the specific mechanism of POD remains...

Primary role for melatonin MT2 receptors in the regulation of anhedonia and circadian temperature rhythm

Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm.Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors.MT1-/- , MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice.MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia.Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function.

Promising directions of medical technologies for the correction of sleep disorders in menopausal women of various ethnic groups

ethnic groups.&#x0D; Materials and methods.The objects of the study were menopausal women of Russian and Buryat ethnic groups (n=466), who were divided into a control group (without sleep disturbances) and main subgroups (with insomnia and comorbidity of insomnia with obstructive sleep apnea syndrome). All women underwent clinical and anamnestic examination, genotyping for3111T/C Clock gene polymorphism, determination of the circadian profile of melatonin secretion, parameters of lipid metabolism and the system lipid peroxidation antioxidant protection.&#x0D; Results.In Caucasians with sleep disorders, a higher prevalence of the3111T/T genotype and theClockgene3111Tallele was revealed as compared to the control (p0.05). Perimenopausal Caucasians showed a shift in the peak of melatonin secretion to the morning hours; in Mongoloids, both peri- and postmenopausal women, a decrease in melatonin total levels was revealed. Dyslipoproteinemia is characteristic of both races patients who have comorbidity of insomnia and obstructive sleep apnea syndrome, and it is more pronounced in postmenopausal Caucasians. Oxidative stress in sleep disorders is more pronounced in Mongoloids. The medical technologies directions for correction of sleep disorders are proposed: the use of melatonin drugs in the evening and light therapy in the early morning hours in Caucasians who are carriers of the3111T Clockgene allele; melatonin drugs to increase its total level in Mongoloids; personalized prescription of antioxidant therapy in all patients; specific therapy to eliminate breathing disorders during sleep in those who have obstructive sleep apnea syndrome.&#x0D; Conclusions.Presence of insomnia, chronobiological rhythms of melatonin secretion, lipid peroxidation processes in sleep disorders are ethnospecific.

73‐3: Invited Paper: Influences of Circadian Illuminances from Lighting and TV on the Human Locomotor Activity, Sleep Disorder, EEG, HRV, and Melatonin Secretion

To address the need for an accurate evaluation of circadian illuminance (CIL) that precisely characterizes the intensity of blue light emanated by displays and/or lighting and to investigate how the blue light affects the human body biology, we developed the circadian illuminometer and applied it to two comparative clinical studies. In terms of the CIL from lighting, all of the circadian rhythm of locomotor activity, sleep quality, and melatonin secretion were improved for 12 subjects under circadian lighting in comparison to normal lighting. In a comparative study of the effects of evening watching TVs in high dynamic range mode, i. e., using two different types of 65‐inch TVs (A and B) in the market, on an electroencephalography (EEG), heart rate variability (HRV), and melatonin secretion, B is found for 32 subjects to have a better health effect on the human body than A in perspective of visual fatigue, arousal, concentration, comfort, and sleep disorder. A also showed significant circadian disturbance, which are mainly caused by a higher CIL in A (54.28 blx) than in B (25.18 blx). Finally, our results show evidence that the effects of CIL on locomotor activity, sleep disorder, EEG, HRV, melatonin, and circadian rhythm can potentially play the role of a new performance metric for human‐centric displays/lighting.

RETRACTED: Diurnal rhythm disruptions induced by chronic unpredictable stress relate to depression-like behaviors in rats

The relationship between circadian rhythms and mood disorders has been established, circadian dysregulations are believed to exacerbate the severity of mood disorders and vice versa. Although many studies on diurnal changes of clock genes in animal model of depression have been performed from the RNA level, only a few studies have been carried out from the protein level. In this study, we investigated the diurnal changes induced by chronic unpredictable stress (CUS) using various methods, including free-running wheel test, enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB). Besides, we examined the depression-like behaviors of rats by sucrose preference test (SPT) and forced swim test (FST). We found that CUS induced significant reductions in the quantity of free-running wheel activity and the amplitude of melatonin secretion rhythm. We also found that CUS induced rhythmic disruptions of clock proteins in hippocampus. Furthermore, we found that the amplitude of PER1 in CA1 was positively related to the severity of depression-like behaviors. These results suggest that stress results in both changes in circadian rhythms and in depression-like behaviors and that it is suggested that these changes are related.

Factors Disrupting Melatonin Secretion Rhythms During Critical Illness.

The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile. Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission. Multiple specialized ICUs within an academic medical center. Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit. None. Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2. Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.