Endocrine Rhythms Research Articles

Stress Hormones Cortisol and Aldosterone, and Selected Markers of Oxidative Stress in Response to Long-Term Supplementation with Omega-3 Fatty Acids in Adolescent Children with Depression.

Late childhood and adolescence are crucial periods of brain development with high vulnerability to environmental insults. The aim of this study was to test the hypotheses that in adolescents with depression (a) 12 weeks-supplementation with omega-3 fatty acids results in the attenuation of salivary stress hormone concentrations; (b) the mentioned supplementation improves potentially disrupted daily rhythm of stress hormones; (c) stress hormone concentrations correlate with values of selected markers of oxidative stress. The sample consisted of 60 patients suffering from depression aged 11–18 years. Hormone concentrations in saliva were measured in the morning and midday before (baseline) and after (6, 12 weeks) food supplementation with omega-3 or omega-6 (as comparator) fatty acids. Morning cortisol decreased in response to omega-3 but not omega-6 fatty acids at 12 weeks compared to baseline. No changes were observed in aldosterone concentrations. The obtained results show that adolescent children with depression preserved the daily rhythm of both stress hormones. Baseline morning cortisol concentrations correlated positively with depression severity and lipoperoxides, and negatively with docosahexaenoic acid. Aldosterone concentrations correlated positively with 8-isoprostane. Thus, both hormones showed positive correlation with the selected markers of oxidative stress suggesting that enhanced stress hormone secretion may be associated with increased oxidative tissue damage in adolescent children with depression. This study was registered with the ISRCTN registry (DEPOXIN study, ISRCTN81655012).

Breast Milk and the Importance of Chrononutrition.

During pregnancy the human fetus receives timed cues from the circadian rhythms of temperature, metabolites, and hormones from the mother. This influence is interrupted after parturition, the infant does not secrete melatonin and their circadian rhythms are still immature. However, evolution provided the solution to this problem. The newborn can continue receiving the mother's timed cues through breastmilk. Colostrum, transitional, and mature human milk are extraordinary complex biofluids that besides nutrients, contain an array of other non-nutritive components. Upon birth the first milk, colostrum, is rich in bioactive, immunological factors, and in complex oligosaccharides which help the proper establishment of the microbiome in the gut, which is crucial for the infants' health. Hormones, such as glucocorticoids and melatonin, transfer from the mother's plasma to milk, and then the infant is exposed to circadian cues from their mother. Also, milk components of fat, proteins, amino acids, and endogenous cannabinoids, among others, have a markedly different concentration between day and night. In the present review, we give an overview of nutritive and non-nutritive components and their daily rhythms in human milk and explore their physiological importance for the infant. Finally, we highlight some interventions with a circadian approach that emphasize the importance of circadian rhythms in the newborn for their survival, proper growth, and development. It is estimated that ~600,000 deaths/year are due to suboptimal breastfeeding. It is advisable to increase the rate of exclusive breastfeeding, during the day and night, as was established by the evolution of our species.

Misaligned hormonal rhythmicity: Mechanisms of origin and their clinical significance.

Rhythmic hormonal secretion is key for sustaining health. While a central pacemaker in the hypothalamus is the main driver of circadian periodicity, many hormones oscillate with different frequencies and amplitudes. These rhythms carry information about healthy physiological functions, while at the same time they must be able to respond to external cues and maintain their robustness against severe perturbations. Since endocrine disruptions can lead to hormonal misalignment and disease, understanding the clinical significance of these rhythms can help support diagnosis and disease management. While the misalignment of dynamic hormone profiles can be quantitatively analysed though statistical and computational techniques, mathematical modelling can provide fundamental understanding about the mechanisms underpinning endocrine rhythms, particularly around the question of what makes them robust to some perturbations but fragile to others. In this study, I will review the key challenges of understanding hormonal rhythm misalignment from a mathematical perspective, including their causes and clinical significance. By reviewing modelling examples of coupled endocrine axes, I will address the question of how perturbations in one endocrine axis propagate to another, leading to the more complex issue of disentangling the contribution of each endocrine system to a robust dynamic environment.

Relationship between Sleep Disorders and Diabetes Mellitus in Adults: Results of the First Phase of Shahedieh Cohort Study 2015-2017

Introduction: Disruption of the sleep cycle can disrupt the activity of the hormonal rhythms. Given that diabetes mellitus (DM) is the most common endocrine disease, and few studies have been conducted to investigate its relationship with sleep quality, the present study aimed to investigate the relationship between sleep disorders and diabetes mellitus.
 Methods: The present study was a descriptive, cross-sectional study. In this study, all adults aged 35-70 years from Shahedieh, Ashkezar, and Zarch Cities were investigated. The data used in this study included demographics, sleep variables, and fasting blood sugar level. Data were analyzed using SPSS V. 16 and Chi-square, T-test, ANOVA and regression.
 Results: The results showed that the prevalence of sleep less than 6 hours was significantly higher in people with diabetes type2, and also, the sleep latency increased with increasing blood sugar level (R=0.06, P=0.001). The results of regression analysis indicated that the chance of diabetes in people with a sleep duration of less than 6 hours was 12%, in people with a sleep latency of more than 15 minutes was 11%, in people who used sleep medications continuously was 15% and in people who nap during the day was 27% higher than other people.
 Conclusion: According to the findings of this study, the prevalence of sleep disorders was higher in people with diabetes and sleep was a strong predictor for diabetes type2.

Optimized office lighting advances melatonin phase and peripheral heat loss prior bedtime

Improving indoor lighting conditions at the workplace has the potential to support proper circadian entrainment of hormonal rhythms, sleep, and well-being. We tested the effects of optimized dynamic daylight and electric lighting on circadian phase of melatonin, cortisol and skin temperatures in office workers. We equipped one office room with an automated controller for blinds and electric lighting, optimized for dynamic lighting (= Test room), and a second room without any automated control (= Reference room). Young healthy participants (n = 34) spent five consecutive workdays in each room, where individual light exposure data, skin temperatures and saliva samples for melatonin and cortisol assessments were collected. Vertical illuminance in the Test room was 1177 ± 562 photopic lux (mean ± SD) , which was 320 lux higher than in the Reference room (p < 0.01). Melanopic equivalent daylight (D65) illuminance was 931 ± 484 melanopic lux in the Test room and 730 ± 390 melanopic lux in the Reference room (p < 0.01). Individual light exposures resulted in a 50 min earlier time of half-maximum accumulated illuminance in the Test than the Reference room (p < 0.05). The melatonin secretion onset and peripheral heat loss in the evening occurred significantly earlier with respect to habitual sleeptime in the Test compared to the Reference room (p < 0.05). Our findings suggest that optimized dynamic workplace lighting has the potential to promote earlier melatonin onset and peripheral heat loss prior bedtime, which may be beneficial for persons with a delayed circadian timing system.

Effect of circadian system disruption on the concentration and daily oscillations of cortisol, progesterone, melatonin, serotonin, growth hormone, and core body temperature in periparturient dairy cattle

Metabolic, circadian, sleep, and reproductive systems are integrated and reciprocally regulated, but the understanding of the mechanism is limited. To study this integrated regulation, the circadian timing system was disrupted by exposing late pregnant nonlactating (dry) cows to chronic shifts in the light-dark phase, and rhythms of body temperature and circulating cortisol (CORT), progesterone (P4), serotonin (5HT), melatonin (MEL), and growth hormone (GH) concentrations were measured. Specifically, across 2 identical studies (1 and 2), at 35 d before expected calving (BEC) multiparous cows were assigned to control (CON; n = 24) and exposed to 16 h light and 8 h dark or phase shift (PS; n = 24) treatments and exposed to 6-h light-dark phase shifts every 3 d until parturition. All cows were exposed to control lighting after calving. Blood samples were collected in the first study at 0600 h on d 35 BEC, d 21 BEC, and 2 d before calving, and d 0, 2, 9, 15, and 22 postpartum (PP). A subset of cows (n = 6/group) in study 1 was blood sampled every 4 h over 48 h beginning on d 23 BEC, 9 BEC, and 5 PP. Body temperature was measured every 30 min (n = 8-16/treatment) for 48 h at 23 BEC and 9 BEC in both studies; and at 14 PP and 60 PP only in study 2. Treatment did not affect levels of CORT, GH, or P4 at 0600 h, but overall level of 5HT was lower and MEL higher in PS cows across days sampled. A 2-component versus single-component cosinor model better described [>coefficient of determination (R2); <Akaike information criterion and <Bayesian information criterion] daily oscillations of all hormones and temperature for both treatments. Circadian rhythm fit (R2) of body temperature and MEL increased from 23 BEC to 9 BEC in CON and was marked by loss of feeding time influence on oscillations in both treatments. Both treatments exhibited circadian rhythms of CORT at 9 BEC, CON cows also exhibited circadian rhythms in P4 at 23 BEC, and 5HT at 9 BEC. Daily oscillations in temperature and hormones, except CORT, were affected by PS treatment in the prepartum and were associated with longer gestation. In the PP, circadian rhythmicity was lost or diminished for all hormones and body temperature in both treatments. Stronger rhythms of body temperature and multiple hormones at 1 wk prepartum may indicate a synchronizing cue to time parturition. Therefore, dairy systems may need to consider management factors that affect circadian clocks in late-gestation cows.

Benefits, mechanisms, and risks of intermittent fasting in metabolic syndrome and type 2 diabetes.

One of the emergent nutritional strategies for improving multiple features of cardiometabolic diseases is the practice of intermittent fasting (IF), which consists of alternating periods of eating and fasting. IF can reduce circulating glucose and insulin levels, fat mass, and the risk of developing age-related pathologies. IF appears to upregulate evolution-conserved adaptive cellular responses, such as stress-response pathways, autophagy, and mitochondrial function. IF was also observed to modulate the circadian rhythms of hormones like insulin or leptin, among others, which levels change in conditions of food abundance and deficit. However, some contradictory results regarding the duration of the interventions and the anterior metabolic status of the participants suggest that more and longer studies are needed in order to draw conclusions. This review summarizes the current knowledge regarding the role of IF in the modulation of mechanisms involved in type 2 diabetes, as well as the risks.

Diurnal rhythms in testicular blood flow, testicular morphometry and reproductive hormones in Shiba goats.

Testicular blood flow (TBF) is crucial for testicular function. The pattern of TBF in Shiba goats indicates seasonal variations. This study aimed to investigate the effect of diurnal variations on TBF, testis volume (TV), testicular echogenicity, and reproductive hormones in goats over a 24-h period. In three trials that went for three consecutive days each, 12 bucks were scanned using Triplex ultrasonography to assess the TV, pixel intensity of testicular echotexture (PIX), and Doppler indices of TBF (resistive index: RI and pulsatility index: PI) in four-time points a day (at 6.00, 12.00, 18.00, and 00.00h). Concomitantly, the changes in circulating FSH, LH, inhibin, testosterone (T), estradiol (E2), cortisol, and melatonin were assessed. Results revealed diurnal alterations in the calculated RI of TBF and the PIX of testicular parenchyma (P <0.05). Lower RI values of the TBF were observed at 6.00h compared to other time points. There were significant diurnal alterations in the levels of FSH (P <0.05), LH (P <0.05), T (P <0.0001), E2 (P <0.0001), cortisol (P <0.0001), and melatonin (P <0.0001). FSH attained a higher concentration at 18.00h compared to 12.00h. Concentrations of LH were significantly higher at 06.00h compared to those at 18.00h. Concentrations of T were significantly higher at 6.00 compared to other time points. E2 showed higher concentrations at 6.00h and 00.00h compared to 12.00h and 18.00h. On the contrary, concentrations of cortisol were significantly higher at 12.00h and 18.00h compared to 06.00h and 00.00h. The highest concentrations of melatonin were observed at 00.00h compared to other time points, while the lowest concentrations were at 12.00h. Diurnal rhythm induces significant changes in TBF, testicular PIX, and circulating FSH, LH, T, E2, cortisol, and melatonin over the 24-hday. The outcomes of the study are reflected in the advisability of monitoring the TBF at a fixed time a day to avoid the circadian rhythm effect.

Disrupted Circadian Control of Hormonal Rhythms and Anticipatory Thirst by Dim Light at Night.

Our study addresses underlying mechanisms of disruption of the circadian timing system by low-intensity artificial light at night (ALAN), which is a growing global problem, associated with serious health consequences. Rats were exposed to low-intensity (∼2 lx) ALAN for 2 weeks. Using in situ hybridization, we assessed 24-h profiles of clock and clock-controlled genes in the suprachiasmatic nuclei (SCN) and other hypothalamic regions, which receive input from the master clock. Moreover, we measured the daily rhythms of hormones within the main neuroendocrine axes as well as the detailed daily pattern of feeding and drinking behavior in metabolic cages. ALAN strongly suppressed the molecular clockwork in the SCN, as indicated by the suppressed rhythmicity in the clock (Per1, Per2, and Nr1d1) and clock output (arginine vasopressin) genes. ALAN disturbed rhythmic Per1 expression in the paraventricular and dorsomedial hypothalamic nuclei, which convey the circadian signals from the master clock to endocrine and behavioral rhythms. Disruption of hormonal output pathways was manifested by the suppressed and phase-advanced corticosterone rhythm and lost daily variations in plasma melatonin, testosterone, and vasopressin. Importantly, ALAN altered the daily profile in food and water intake and eliminated the clock-controlled surge of drinking 2 h prior to the onset of the rest period, indicating disturbed circadian control of anticipatory thirst and fluid balance during sleep. Our findings highlight compromised time-keeping function of the central clock and multiple circadian outputs, through which ALAN disturbs the temporal organization of physiology and behavior.

Hibernation with rhythmicity: the circadian clock and hormonal adaptations of the hibernating Asiatic toads (Bufo gargarizans).

Hibernation is one of the fundamental strategies in response to cold environmental temperatures. During hibernation, the endocrine and circadian systems ensure minimal expenditure of energy for survival. The circadian rhythms of key hormones, melatonin (MT), corticosterone (CORT), triiodothyronine (T3 ), and thyroxine (T4 ), and the underlying molecular regulatory mechanisms of hibernation have been well determined in mammals but not in ectotherms. Here, a terrestrial hibernating species, Asiatic toad (Bufo gargarizans), was employed to investigate the plasma CORT, MT, T3 , and T4 ; and the retina, brain, and liver mRNA expression of the core clock genes, including circadian locomotor output cycles kaput (Clock), brain and muscle ARNT-like 1 (Bmal1), cryptochrome (Cry) 1 and 2, and period (Per) 1 and 2, at 7-time points over a 24-h period under acute cold (1 day at 4°C), and hibernation (45 days at 4°C). Our results showed that the circadian rhythms of the core clock genes were rather unaffected by acute cold exposure in the retina, unlike the brain and liver. In contrast, during hibernation, the liver clock genes displayed significant circadian oscillations, while those in the retina and brain stopped ticking. Furthermore, plasma CORT expressed circadian oscillations in both groups, and T3 in acute cold exposure group, whereas T4 and MT did not. Our results reveal that the plasma CORT and the liver sustain rhythmicity when the brain was not, indicating that the liver clock along with the adrenal clock synergistically maintains the metabolic requirements to ensure basic survival in hibernating Asiatic toads.

Effects of Intermittent Fasting on the Circulating Levels and Circadian Rhythms of Hormones.

Intermittent fasting has become an increasingly popular strategy in losing weight and associated reduction in obesity-related medical complications. Overwhelming studies support metabolic improvements from intermittent fasting in blood glucose levels, cardiac and brain function, and other health benefits, in addition to weight loss. However, concerns have also been raised on side effects including muscle loss, ketosis, and electrolyte imbalance. Of particular concern, the effect of intermittent fasting on hormonal circadian rhythms has received little attention. Given the known importance of circadian hormonal changes to normal physiology, potential detrimental effects by dysregulation of hormonal changes deserve careful discussions. In this review, we describe the changes in circadian rhythms of hormones caused by intermittent fasting. We covered major hormones commonly pathophysiologically involved in clinical endocrinology, including insulin, thyroid hormones, and glucocorticoids. Given that intermittent fasting could alter both the level and frequency of hormone secretion, decisions on practicing intermittent fasting should take more considerations on potential detrimental consequences versus beneficial effects pertaining to individual health conditions.

Eat, sleep, repeat - endocrine regulation of behavioural circadian rhythms.

The adaptation of organisms to a rhythmic environment is mediated by an internal timing system termed the circadian clock. In mammals, molecular clocks are found in all tissues and organs. This circadian clock network regulates the release of many hormones, which in turn influence some of the most vital behavioural functions. Sleep-wake cycles are under strict circadian control with strong influence of rhythmic hormones such as melatonin, cortisol and others. Food intake, in contrast, receives circadian modulation through hormones such as leptin, ghrelin, insulin and orexin. A third behavioural output covered in this review is mating and bonding behaviours, regulated through circadian rhythms in steroid hormones and oxytocin. Together, these data emphasize the pervasive influence of the circadian clock system on behavioural outputs and its mediation through endocrine networks.

Suprachiasmatic hypothalamic nuclei (SCN) in regulation of homeostasis: a role beyond circadian control?

ABSTRACT The role of suprachiasmatic nuclei (SCN) in the anterior hypothalamus as a master ~24 h oscillator (clock) and synchronizer of the circadian regulatory system is reviewed extensively. In contrast, the ample evidence that SCN also exert a circadian-independent impact on homeostasis and metabolism is underappreciated. Therefore, herein we focus on the evidence for SCN participation in homeostatic (non-circadian) mechanisms in regulation of arterial blood pressure and hydro-mineral balance, plasma glucose level, food intake, renin, ACTH/corticosterone, GH, thyroid hormones and melatonin secretion. We conclude that, in addition to their major role in circadian control, SCN also selectively participate in homeostatic control. The evidence supports a model where the ventrolateral region of SCN and especially its vasointestinal polypeptide (VIP)-containing neurons convey the homeostatic influences of SCN to the metabolic regulatory pathways. The precise mechanisms of the rhythmic wisdom of the body, i.e., how SCN circadian clock and the daily behavioral and endocrine rhythms harmonize with the homeostatic regulatory systems defending the relative constancy of the internal milieu, remain to be elucidated. The non-circadian SCN contributions in responses to homeostatic challenges certainly deserve careful consideration in future studies. Abbreviations 2-DG: 2-deoxy-D-glucose; AV3V: anteroventral third ventricle region; GRF - growth-hormone-releasing factor; MnPO: median preoptic nucleus; NTS: nucleus of the solitary tract; OVLT: organum vasculosum of the lamina terminalis; PRA: plasma renin activity; SCN: suprachiasmatic nuclei; SD: sleep deprivation; VIP: vasoactive intestinal polypeptide.

Вплив штучно подовженого світлового дня на концентрацію деяких гормонів, показники мінерального обміну та імунітету у студентів

In this work, we studied the influence of artificially prolonged daylight on the concentration of some hormones, the state of mineral metabolism, and immunity in students. Material and methods. The study involved 50 second-year students (44 girls and 6 boys) of Kharkiv National Medical University with different chronotypes. All students were on a proper diet, did not play sports, did not have any chronic diseases, and were healthy during the study period. Students were divided into 2 groups: 1) waking period from 5:00 to 23:00 (25 people), 2) waking period from 8:00 to 3:00 (25 people). Saliva was collected after careful oral hygiene at 8 a.m., 12 a.m., 4 p.m., and 12 p.m. Results and discussion. Our study showed that the artificial prolongation of daylight reduces the concentration of melatonin, especially at night (at the peak of secretion). It is established that at the artificial prolongation of the light day there is an inversion of a rhythm of thyroid's hormones secretion, decrease in their maximum concentration which probably is connected with the adaptation of an organism to an active mental activity at night. The obtained results showed that in students with the evening chronotype, the concentration of cortisol reduced both during the day and at 24 hours, which was probably associated with a decrease in melatonin secretion and its regulatory effect on the adrenal glands. Decreased concentrations of melatonin, cortisol, and thyroid hormones led to the impaired functional activity of the immune system, as evidenced by a decrease in secretory immunoglobulin and lysozyme in the saliva of students with evening chronotype, compared with students with morning chronotype of activity. Changing circadian rhythms of thyroid hormone secretion, reducing their concentration and cortisol content led to the development of metabolic disorders. We noted that dysfunction of mineral metabolism in students with evening chronotype caused a decrease in the concentration of calcium, magnesium, zinc in the saliva of students. The identified characteristics indicate that prolonged daylight reduced the ability to maintain the daily balance of the studied nutrients, which may be a manifestation of desynchrony. The concentration of immunoglobulin A in the saliva of students in the second group in the morning and the evening was significantly lower than in students of group 1, which indicated an absolute deficiency of immunoglobulin and, accordingly, a decrease in immunity with prolonged daylight. Students of group 2 also had a decrease in the content of lysozyme in saliva, which indicated a decrease in the degree of antibacterial protection. The peculiarities in the content of immunoglobulin A and lysozyme are most likely associated with a decrease in the concentration of melatonin. Conclusion. The artificial prolongation of daylight decreased the melatonin concentration in saliva and cortisol concentration. It also caused an inversion of secretion rhythm of thyroid hormones. The students with evening chronotype had a decrease in immunoglobulin A concentration, decrease in lysozyme in saliva and disturbance in a mineral metabolism

A mathematical model of circadian rhythms and dopamine

BackgroundThe superchiasmatic nucleus (SCN) serves as the primary circadian (24hr) clock in mammals and is known to control important physiological functions such as the sleep-wake cycle, hormonal rhythms, and neurotransmitter regulation. Experimental results suggest that some of these functions reciprocally influence circadian rhythms, creating a highly complex network. Among the clock’s downstream products, orphan nuclear receptors REV-ERB and ROR are particularly interesting because they coordinately modulate the core clock circuitry. Recent experimental evidence shows that REV-ERB and ROR are not only crucial for lipid metabolism but are also involved in dopamine (DA) synthesis and degradation, which could have meaningful clinical implications for conditions such as Parkinson’s disease and mood disorders.MethodsWe create a mathematical model consisting of differential equations that express how the circadian variables are influenced by light, how REV-ERB and ROR feedback to the clock, and how REV-ERB, ROR, and BMAL1-CLOCK affect the dopaminergic system. The structure of the model is based on the findings of experimentalists.ResultsWe compare our model predictions to experimental data on clock components in different light-dark conditions and in the presence of genetic perturbations. Our model results are consistent with experimental results on REV-ERB and ROR and allow us to predict the circadian variations in tyrosine hydroxylase and monoamine oxidase seen in experiments. By connecting our model to an extant model of dopamine synthesis, release, and reuptake, we are able to predict circadian oscillations in extracellular DA and homovanillic acid that correspond well with experimental observations.ConclusionsThe predictions of the mathematical model are consistent with a wide variety of experimental observations. Our calculations show that the mechanisms proposed by experimentalists by which REV-ERB, ROR, and BMAL1-CLOCK influence the DA system are sufficient to explain the circadian oscillations observed in dopaminergic variables. Our mathematical model can be used for further investigations of the effects of the mammalian circadian clock on the dopaminergic system. The model can also be used to predict how perturbations in the circadian clock disrupt the dopaminergic system and could potentially be used to find drug targets that ameliorate these disruptions.

Cell Autonomous Circadian Systems and Their Relation to Inflammation.

All living beings on earth have an important mechanism of 24-h periodicity, which controls their physiology, metabolism, and behavior. In humans, 24-h periodicity is regulated by the superchiasmatic nucleus (SCN) through external and environmental cues. Peripheral organs demonstrate circadian rhythms and circadian clock functions, and these are also observed in cultured cell lines. Every cell contains a CLOCK: BMAL1 loop for the generation of circadian rhythms. In this review, we focused on cell autonomous circadian rhythms in immune cells, the inflammatory diseases caused by disruption of circadian rhythms in hormones, and the role of clock genes in inflammatory diseases.

Fiat Lux: The Light Became Therapy. An Overview on the Bright Light Therapy in Alzheimer's Disease Sleep Disorders.

A system of photosensitive retinal ganglion cells provides 'non-visual' information on the circadian sequences of light to the suprachiasmatic nucleus (SCN), which, as the 'master clock', synchronizes the chronobiological mechanisms of all the biological clocks. Damage to SCN structure alters circadian behavioral and hormonal rhythms and interferes with a regular sleep-wake pattern. Several studies have shown that, in aging and in Alzheimer's disease (AD), circadian rhythms change their synchronization with the environment and behavior loses sync with light. The current overview aims to examine research studies showing the effect of bright light therapy (BLT) on sleep disorders and sleep-wake patterns in AD. A literature search was conducted, taking into consideration the relevant studies over the last 20 years. Fifteen studies have been thorough: seven followed an environmental-architectural approach and eight followed a treatment devices approach. Studies agree in considering BLT as a promising non-pharmacological intervention to compensate for circadian rhythm alterations and they support the need for standardized protocols that allow a comparison between multicenter studies. Interestingly, in an attempt to contain the spread of the COVID-19 pandemic, health authorities have forced the population to stay home. Therefore, AD people are not currently able to enjoy exposure to sunlight. It is predictable that they may experience an exacerbation of circadian disturbances and that the BLT can be an effective response to prevent such exacerbation.

Disrupted Sleep and Circadian Rhythms in Schizophrenia and Their Interaction With Dopamine Signaling.

Sleep and circadian rhythm disruption (SCRD) is a common feature of schizophrenia, and is associated with symptom severity and patient quality of life. It is commonly manifested as disturbances to the sleep/wake cycle, with sleep abnormalities occurring in up to 80% of patients, making it one of the most common symptoms of this disorder. Severe circadian misalignment has also been reported, including non-24 h periods and phase advances and delays. In parallel, there are alterations to physiological circadian parameters such as body temperature and rhythmic hormone production. At the molecular level, alterations in the rhythmic expression of core clock genes indicate a dysfunctional circadian clock. Furthermore, genetic association studies have demonstrated that mutations in several clock genes are associated with a higher risk of schizophrenia. Collectively, the evidence strongly suggests that sleep and circadian disruption is not only a symptom of schizophrenia but also plays an important causal role in this disorder. The alterations in dopamine signaling that occur in schizophrenia are likely to be central to this role. Dopamine is well-documented to be involved in the regulation of the sleep/wake cycle, in which it acts to promote wakefulness, such that elevated dopamine levels can disturb sleep. There is also evidence for the influence of dopamine on the circadian clock, such as through entrainment of the master clock in the suprachiasmatic nuclei (SCN), and dopamine signaling itself is under circadian control. Therefore dopamine is closely linked with sleep and the circadian system; it appears that they have a complex, bidirectional relationship in the pathogenesis of schizophrenia, such that disturbances to one exacerbate abnormalities in the other. This review will provide an overview of the evidence for a role of SCRD in schizophrenia, and examine the interplay of this with altered dopamine signaling. We will assess the evidence to suggest common underlying mechanisms in the regulation of sleep/circadian rhythms and the pathophysiology of schizophrenia. Improvements in sleep are associated with improvements in symptoms, along with quality of life measures such as cognitive ability and employability. Therefore the circadian system holds valuable potential as a new therapeutic target for this disorder.

Ultradian Secretion of Growth Hormone in Mice: Linking Physiology With Changes in Synapse Parameters Using Super-Resolution Microscopy.

Neuroendocrine circuits are orchestrated by the pituitary gland in response to hypothalamic hormone-releasing and inhibiting factors to generate an ultradian and/or circadian rhythm of hormone secretion. However, mechanisms that govern this rhythmicity are not fully understood. It has been shown that synaptic transmission in the rodent hypothalamus undergoes cyclical changes in parallel with rhythmic hormone secretion and a growing body of evidence suggests that rapid rewiring of hypothalamic neurons may be the source of these changes. For decades, structural synaptic studies have been utilizing electron microscopy, which provides the resolution suitable for visualizing synapses. However, the small field of view, limited specificity and manual analysis susceptible to bias fuel the search for a more quantitative approach. Here, we apply the fluorescence super-resolution microscopy approach direct Stochastic Optical Reconstruction Microscopy (dSTORM) to quantify and structurally characterize excitatory and inhibitory synapses that contact growth hormone-releasing-hormone (GHRH) neurons during peak and trough values of growth hormone (GH) concentration in mice. This approach relies on a three-color immunofluorescence staining of GHRH and pre- and post-synaptic markers, and a quantitative analysis with a Density-Based Spatial Clustering of Applications with Noise (DBSCAN) algorithm. With this method we confirm our previous findings, using electron microscopy, of increased excitatory synaptic input to GHRH neurons during peak levels of GH. Additionally, we find a shift in synapse numbers during low GH levels, where more inhibitory synaptic inputs are detected. Lastly, we utilize dSTORM to study novel aspects of synaptic structure. We show that more excitatory (but not inhibitory) pre-synaptic clusters associate with excitatory post-synaptic clusters during peaks of GH secretion and that the numbers of post-synaptic clusters increase during high hormone levels. The results presented here provide an opportunity to highlight dSTORM as a valuable quantitative approach to study synaptic structure in the neuroendocrine circuit. Importantly, our analysis of GH circuitry sheds light on the potential mechanism that drives ultradian changes in synaptic transmission and possibly aids in GH pulse generation in mice.

Mechanisms of Inhibition of Excessive Microglial Activation by Melatonin.

As the innate immune cells that permanently reside in the central nervous system (CNS), microglia play an increasingly important role in maintaining brain function. Normally, microglia act as resting phenotype, which can be activated by various types of stimuli and release a variety of inflammatory mediators. Melatonin is an endogenous rhythmic hormone secreted principally by the pineal gland. Increasing evidence suggests that melatonin can detoxify reactive oxygen species (ROS) and prevent microglia from over-activation. This review summarizes the mechanisms of melatonin in inhibiting excessive activation of microglia and demonstrates the feasibility of melatonin in the treatment of diseases related to microglial over-activation.