Sleep-wake Cycle Research Articles

The effects of baicalin in depression: preclinical evidence construction based on meta-analysis.

Depression manifests as a mental disorder characterized by a low mood, suicidal tendencies, disturbances in sleep-wake cycles, psychomotor agitation, and pronounced feelings of hopelessness and anhedonia. Baicalin, a natural flavonoid compound, shows significant promise in alleviating depressive symptoms in animals. This study aims to assess the impact of baicalin on experimental models of depression. A systematic search of electronic databases was conducted using the search terms "baicalin" AND "depression" OR "depressed" OR "anti-depression". Preclinical animal models representing experimental depression were included in the analysis. The risk of bias in the included studies was evaluated using the CAMARADES tools. Baicalin significantly increased sucrose preference test (SPT) [SMD= 21.31, 95%CI (16.32, 26.31), P < 0.00001]. mThe tail suspension test (TST) duration significantly decreased in the baicalin group compared to the model group [SMD = -39.3, 95%CI (-49.71, -28.89), P < 0.0001]. Furthermore, baicalin reduced immobility time in rats subjected to the forced swim test (FST) [SMD = -39.73, 95%CI (-48.77, -30.69) P < 0.0001]. Compared to the model group, baicalin treatment also significantly increased the frequency of crossings in the open field test (OFT) [SMD = 32.44, 95%CI (17.74, 47.13), P < 0.00001]. Baicalin significantly improves the manifestations of depressive symptoms. The effect of baicalin against depression is exerted through its anti-inflammatory actions, inhibition of oxidative stress, regulation of the HPA axis, and restoration of neuroplasticity. Future studies will be needed to further explore how these promising preclinical findings can be translated into clinical treatment for depression. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023472181.

Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice.

Narcolepsy type-1 (NT1) is a lifelong sleep disease, characterised by impairment of the orexinergic system, with a typical onset during adolescence and young adulthood. Since the wake-sleep cycle physiologically changes with ageing, this study aims to compare sleep patterns between orexin-knockout (KO) and wild type (WT) control mice at different ages. Four groups of age-matched female KO and WT mice (16 weeks of age: 8 KO-YO and 9 WT-YO mice; 87 weeks of age: 13 KO-OLD and 12 WT-OLD mice) were implanted with electrodes for discriminating wakefulness, rapid-eye-movement sleep (REMS), and non-REMS (NREMS). Mice were recorded for 48 h in their home cages and for 7 more hours into a plethysmographic chamber to characterise their sleep-breathing pattern. Regardless of orexin deficiency, OLD mice spent less time awake and had fragmentation of this behavioural state showing more bouts of shorter length than YO mice. OLD mice also had more NREMS bouts and less frequent NREMS apneas than YO mice. Regardless of age, KO mice showed cataplexy-like episodes and shorter REMS latency than WT controls and had a faster breathing rate and an increased minute ventilation during REMS. KO mice also had more wakefulness, NREMS and REMS bouts, and a shorter mean length of wakefulness bouts than WT controls. Our experiment indicated that the lack of orexins as well as ageing importantly modulate the sleep and breathing phenotype in mice. The narcoleptic phenotype caused by orexin deficiency in female mice was substantially preserved with ageing.

Effect of Centella asiatica ethanol extract on zebrafish larvae (Danio rerio) insomnia model through inhibition of Orexin, ERK, Akt and p38

Background: Insomnia is difficulty initiating or maintaining sleep for at least three nights a week or more and lasting for at least 3 months. One of the molecules that play a role in the circadian rhythm of arousal system is hypocretin/orexin. Orexin activates the p38-MAPK signaling pathway and increases phosphorylated ERK1/2 levels. Centella asiatica (CA) has a role in the signal work of the MAPK/ERK, Akt, and p38 path in many various diseases. Methods: The research method used is true laboratory experimental. The research approach used was randomized control group post-test only. Zebrafish embryos aged 0-7 dpf were used in this study. The treatment group consisted of 5 groups: normal, insomnia, insomnia + 2.5 μg/mL CA, insomnia + 5 μg/mL CA, and insomnia + 10 μg/mL CA. The locomotor motion of zebrafish larvae was observed using Basler cameras on days five-, six- and seven-day post fertilization (dpf), then analyzed by using Western Blot method. Results: The results proved that exposure to CA extract was able to reduce the expression of orexin (91963 ± 9129) and p38 (117425 ± 6398) as an arousal trigger in the sleep-wake cycle, with the most optimal concentration of CA 5 μg/mL. Exposure to CA extract was also able to reduce the expression of ERK (94795 ± 30830) and Akt (60113.5 ± 27833.5) with an optimum concentration of CA 2.5 μg/mL. Conclusion: Exposure to CA extract was able to improve the sleep activity of zebrafish larvae insomnia model by extending the total inactivity time (cumulative duration) and shortening the duration of first sleep (latency to first) in light and dark phases through inhibition of orexin, ERK, p38, and Akt.

Narcolepsy and pediatric acute-onset neuropsychiatric syndrome: A case report that suggests a putative link between the two disorders

Narcolepsy with cataplexy (NT1) is a rare hypothalamic disorder that presents with a dysregulation of the sleep–wake cycle (i.e., excessive daytime sleepiness and sleep and cataplectic attacks) and other motor, cognitive, psychiatric, metabolic, and autonomic disturbances, with putative autoimmune pathogenesis. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder that presents with acute-onset obsessive–compulsive symptoms and/or a severe eating restriction, with concomitant cognitive, behavioral, or affective symptoms caused by infections and other environmental triggers provoking an inflammatory brain response, which evolves into a chronic or progressive neuroimmune disorder. In this study, we present the case of a 13-year-old boy with vocal tics and syncopal-like episodes, eventually diagnosed as NT1 and PANS, and from this we discuss the hypothesis that both NT1 and PANS might belong to the same immunological spectrum, resulting in comparable imbalances in key neurotransmitter axes (i.e., orexinergic and dopaminergic), with conceptual and operational implications, especially with regards to the pharmacological tretament

Management of post-extubation anxiety in the intensive care unit

Post-extubation anxiety causes significant distress in intensive care unit patients. This review provides treatment recommendations for managing anxiety during weaning and extubation from mechanical ventilation. Factors predisposing to anxiety include cerebral vascular disease, endocrine disorders, cardiopulmonary decompensation, disrupted sleep-wake cycles, and the stressful ICU environment. This review analyzed 21 articles sourced from Google Scholar and PubMed, focusing on case reports, case series, systematic reviews, and meta-analyses. These studies reported that dexmedetomidine effectively reduces extubation time and ICU length of stay through its anxiolytic properties. Antipsychotics, like quetiapine, showed potential in managing anxiety during ventilator weaning, but high-dose haloperidol posed risks. Benzodiazepines were linked to paradoxical agitation and respiratory suppression. Non-pharmacological treatments, such as aromatherapy, music therapy, and massage therapy, appeared to reduce anxiety and improve sleep quality. Caregiver approaches, including parental presence and psychological training, also reduced anxiety. In conclusion, non-pharmacological approaches should be prioritized, and pharmacological treatments considered when necessary. More research is essential to identify optimal treatments for post-extubation anxiety with minimal patient risk and effective symptom control. Keywords: Anxiety, ICU patients, critically ill patients, post-extubation

Greenness assessment and comparison of the developed and validated green HPLC-PDA, HPLC-FLD, and HPLC-ELSD methods for the determination of melatonin in various products using analytical eco-scale, NEMI, GAPI, and AGREE greenness metric tools

Melatonin, recognized as the hormone governing sleep, is an endogenous hormone synthesized by the pineal gland situated in the brain. It orchestrates the sleep-wake cycle and fosters optimal circadian rhythm. Owing to its manifold metabolic advantages, particularly in the realm of circadian rhythm regulation, melatonin finds extensive application in various supplementary formulations. The elimination of hazardous chemical waste in common chromatographic separations has become an essential issue. We present a green, eco-friendly, novel, sensitive, rapid, robust, and three simple methods including the HPLC-PDA, HPLC-FLD, and HPLC-ELSD approach for the simultaneous determination of MEL in various products. The mobile phase of all the HPLC methods consists of only water and an ethanol mixture and is free from any toxic solvents. All the separations were made on a C18 column (5 μm particle size, 250 mm x 4.6 mm id.). LODs were found to be as 1.20 ng mL−1, 0.02 ng mL−1, 1.26 µg mL−1, and LOQs 4.00 ng mL−1, 0.07 ng mL−1, 4.21 µg mL−1 for PDA, FLD and ELSD, respectively. The recovery results were found to be within 98.58–102.35 %. Moreover, the greenness assessment of all the HPLC methods was assessed using the Analytical Eco-scale, NEMI, AGREE, and GAPI. The developed methods have been demonstrated to be applicable in routine analyses for the determination of melatonin in various preparations.

Effects of Age and MPTP-Induced Parkinson's Disease on the Expression of Genes Associated with the Regulation of the Sleep-Wake Cycle in Mice.

Parkinson's disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep-wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep-wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep-wake cycle regulation in the development of PD.

Postoperative EEG abnormalities in relation to neurodevelopmental outcomes after pediatric cardiac surgery.

We had reported that postoperative EEG background including sleep-wake cycle (SWC) and discharge (seizures, spikes/sharp waves) abnormalities were significantly correlated with adverse early outcomes in children after cardiac surgery. We aimed to analyze the relations between these EEG abnormalities and neurodevelopmental outcomes at about2 years after cardiac surgery. We enrolled 121 patients undergoing cardiac surgery at 3.3 months (0.03 ~ 28 months). EEG abnormalities described above during the first postoperative 48 h were evaluated. Griffiths Mental Development Scales-Chinese was used to evaluate the quotients of overall development and 5 subscales of the child's locomotor, language, personal-social, eye-hand coordination and performance skills at 16 ~ 31 months of age. EEG background abnormalities occurred in 59/121 (48.8%) patients and 33 (55.9%) unrecovered to normal by 48 h. Abnormal SWC occurred in 15 (12.4%) patients and 7 (5.8%) unrecovered to normal by 48 h. EEG seizures occurred in 11 (9.1%) patients with frontal lobe seizures in 4. Spikes/sharp waves occurred in 100 (82.6%). EEG background abnormalities, number of spikes/sharp waves and frontal lobe seizures were significantly associated with neurodevelopmental impairment at about 1 ~ 2 year after surgery (Ps ≤ 0.05). Most parameters of EEG abnormalities were significantly associated with neurodevelopmental impairment after cardiac surgery. Neurodevelopmental impairment in children with congenital heart disease remain poorly understood. Previous studies had reported that either EEG seizures or background abnormalities were associated with worse neurodevelopmental outcomes. Our present study showed that all the EEG background and discharge abnormalities including EEG background, seizures and spikes/sharp waves in the early postoperative period were significantly associated with neurodevelopmental impairment at about 1 ~ 2 years after cardiac surgery. Comprehensive evaluation of early postoperative EEG may provide further insights about postoperative brain injury, its relation with neurodevelopmental impairment, and guide to improve clinical management.

Insight into thecardioprotective effects of melatonin: shining a spotlight on intercellular Sirt signaling communication.

Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.

Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

Restoration of locus coeruleus noradrenergic transmission during sleep.

Sleep is indispensable for health and wellbeing, but its basic function remains elusive. The locus coeruleus (LC) powerfully promotes arousal by releasing noradrenaline. We found that noradrenaline transmission is reduced by prolonged wakefulness and restored during sleep. Fiber-photometry imaging of noradrenaline using its biosensor showed that its release evoked by optogenetic LC neuron activation was strongly attenuated by three hours of sleep deprivation and restored during subsequent sleep. This is accompanied by the reduction and recovery of the wake-promoting effect of the LC neurons. The reduction of both LC evoked noradrenaline release and wake-inducing potency is activity dependent, and the rate of noradrenaline transmission recovery depends on mammalian target of rapamycin (mTOR) signaling. The decline and recovery of noradrenaline transmission also occur in spontaneous sleep-wake cycles on a timescale of minutes. Together, these results reveal an essential role of sleep in restoring transmission of a key arousal-promoting neuromodulator.

Efficient Sleep–Wake Cycle Staging via Phase–Amplitude Coupling Pattern Classification

The objective and automatic detection of the sleep–wake cycle (SWC) stages is essential for the investigation of its physiology and dysfunction. Here, we propose a machine learning model for the classification of SWC stages based on the measurement of synchronization between neural oscillations of different frequencies. Publicly available electrophysiological recordings of mice were analyzed for the computation of phase–amplitude couplings, which were then supplied to a multilayer perceptron (MLP). Firstly, we assessed the performance of several architectures, varying among different input choices and numbers of neurons in the hidden layer. The top performing architecture was then tested using distinct extrapolation strategies that would simulate applications in a real lab setting. Although all the different choices of input data displayed high AUC values (&gt;0.85) for all the stages, the ones using larger input datasets performed significantly better. The top performing architecture displayed high AUC values (&gt;0.95) for all the extrapolation strategies, even in the worst-case scenario in which the training with a single day and single animal was used to classify the rest of the data. Overall, the results using multiple performance metrics indicate that the usage of a basic MLP fed with highly descriptive features such as neural synchronization is enough to efficiently classify SWC stages.

Hypothesis on the potential of repetitive transcranial magnetic stimulation to modulate neurochemical pathways and circadian rhythm in ADHD

Disturbances in the circadian rhythms are generally present in adults subjects with Attention Deficit Hyperactivity Disorder. However, may present in children with the same clinical condition. Poor sleep quality interferes with neural inputs and outputs in areas that are fundamental in neurobiological aspects, such as the dorsolateral prefrontal cortex, which can affect circadian rhythm, cognition, emotional and social control. The dorsolateral prefrontal cortex is an area involved in executive functions and sleep–wake regulation and is underactivated in subjects Attention Deficit Hyperactivity Disorder, which may be one of the main causes of alterations in the circadian cycle. Currently, studies with non-invasive therapeutic methods for adult populations and children with these disorders remain scarce, revealing a significant gap in understanding and treatment. In this context, the aim is investigate the potential effectiveness of repetitive transcranial magnetic stimulation as alternative non-invasive treatment of these disorders. In the present study, it is suggested that use excitatory currents from 10 Hz to 20 Hz in the right dorsolateral prefrontal cortex leads to an improvement in the circadian rhythm mechanism. This is because the excitatory current will promote an increase in dopamine (a neurotransmitter that regulates the circadian cycle) and an increase in glutamate and glutamine concentrations to restore homeostasis in brain regions linked to the sleep–wake cycle.

Role of the Locus Coeruleus Arousal Promoting Neurons in Maintaining Brain Criticality across the Sleep-Wake Cycle.

Sleep control depends on a delicate interplay among brain regions. This generates a complex temporal architecture with numerous sleep-stage transitions and intermittent fluctuations to micro-states and brief arousals. These temporal dynamics exhibit hallmarks of criticality, suggesting that tuning to criticality is essential for spontaneous sleep-stage and arousal transitions. However, how the brain maintains criticality remains not understood. Here, we investigate θ- and δ-burst dynamics during the sleep-wake cycle of rats (Sprague-Dawley, adult male) with lesion in the wake-promoting locus coeruleus (LC). We show that, in control rats, θ- and δ-bursts exhibit power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, as well as power-law long-range temporal correlations (LRTCs)-typical of non-equilibrium systems self-organizing at criticality. Furthermore, consecutive θ- and δ-bursts durations are characterized by anti-correlated coupling, indicating a new class of self-organized criticality that emerges from underlying feedback between neuronal populations and brain areas involved in generating arousals and sleep states. In contrast, we uncover that LC lesion leads to alteration of θ- and δ-burst critical features, with change in duration distributions and correlation properties, and increase in θ-δ coupling. Notably, these LC-lesion effects are opposite to those observed for lesions in the sleep-promoting ventrolateral preoptic (VLPO) nucleus. Our findings indicate that critical dynamics of θ- and δ-bursts arise from a balanced interplay of LC and VLPO, which maintains brain tuning to criticality across the sleep-wake cycle-a non-equilibrium behavior in sleep micro-architecture at short timescales that coexists with large-scale sleep-wake homeostasis.

What’s driving rhythmic gene expression: Sleep or the clock?

Rhythmic gene expression can originate not only from the autonomous rhythm of clock genes but likely also from sleep-wake cycles. Jan and colleagues used a novel model-based approach to dissect these individual effects and found that both factors contribute to gene expression rhythms, varying in degree within and across tissues.

The circadian system: A neglected player in neurodevelopmental disorders.

Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep-wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre-clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention-deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship.

Polymer-based laminar probes with an ultra-long flexible spiral-shaped cable for in vivo neural recordings

Compared to conventional rigid silicon probes, flexible penetrating neural implants exhibit improved mechanical compliance with brain tissue, enabling high-quality neural recordings over extended periods of time. However, the length of the implantable shank and extension cable of most flexible devices falls short of clinical electrodes used in diagnostics and treatment of neurological disorders. In this study, we demonstrate the design, fabrication, and in vivo validation of polyimide-based neural probes with a thin spiral-shaped cable that reaches a length of 27 centimeters, comparable to that of clinical electrodes. The spiral probe comprises a 3.9-mm-long, 75–280-µm-wide and 10-µm-thick implantable shank with 24 linearly placed gold microelectrodes (diameter: 20 µm; electrode pitch: 150 µm) placed either close to the shank edge or centered on the shank. The electrical impedance of the microelectrodes was ∼266 kΩ at 1 kHz measured in vitro. In acute rodent experiments, we recorded high-quality local field potentials (e.g., cortical slow waves and hippocampal gamma activity), single and multiunit activities. In addition, the probes could simultaneously detect the activity of about 10 well-isolated single units, with an average spike amplitude of 65 µV. Furthermore, devices chronically implanted in rats successfully recorded spiking activity over several consecutive days. As demonstrated here, the developed spiral probes can be applied to various tasks, such as the laminar analysis of brain oscillations or the study of the sleep-wake cycle in naturally sleeping animals. In conclusion, our flexible probe design may stimulate the development of novel implantable devices for application in large animal models or clinical settings.

Recent advances in sleep cycle regulation and hormonal imbalance: a comprehensive review

A vital physiological function, sleep is necessary for general health and wellbeing. It is essential for several body processes, including as metabolism, immunological response, emotional control, and cognitive function. A complicated mechanism involving intricate connections between brain circuits, neurotransmitters, and hormone cues governs the sleep-wake cycle. Scientific research has recently made significant progress in understanding the mechanisms behind the control of the sleep cycle and how it relates to hormone imbalance. The goal of this thorough review is to examine the most recent research in this area, with a particular emphasis on the interaction between hormone variations and sleep regulation.

Readjustment of circadian clocks by exercise intervention is a potential therapeutic target for sleep disorders: a narrative review.

Circadian clocks are evolved endogenous biological systems that communicate with environmental cues to optimize physiological processes, such as the sleep-wake cycle, which is nearly related to quality of life. Sleep disorders can be treated using pharmacological strategies targeting melatonin, orexin, or core clock genes. Exercise has been widely explored as a behavioral treatment because it challenges homeostasis in the human body and affects the regulation of core clock genes. Exercise intervention at the appropriate time of the day can induce a phase shift in internal clocks. Although exercise is a strong external time cue for resetting the circadian clock, exercise therapy for sleep disorders remains poorly understood. This review focused on exercise as a potential treatment for sleep disorders by tuning the internal circadian clock. We used scientific paper depositories, including Google Scholar, PubMed, and the Cochrane Library, to identify previous studies that investigated the effects of exercise on circadian clocks and sleep disorders. The exercise-induced adjustment of the circadian clock phase depended on exercise timing and individual chronotypes. Adjustment of circadian clocks through scheduled morning exercises can be appropriately prescribed for individuals with delayed sleep phase disorders. Individuals with advanced sleep phase disorders can synchronize their internal clocks with their living environment by performing evening exercises. Exercise-induced physiological responses are affected by age, sex, and current fitness conditions. Personalized approaches are necessary when implementing exercise interventions for sleep disorders.

Multifaceted Roles of Melatonin in Sleep Disorders

Hormone protein melatonin helps regulate the sleep–wake cycle or circadian rhythm, making it a critical substance in sleep regulation. Melatonin synthesis mainly occurs in the epiphysis of the pineal gland, although extra-pineal melatonin has been observed in other sites of the body, such as salivary glands, the gastrointestinal tract, the placenta and breast milk. Over the years, research into melatonin has shown that it has multiple roles in sleep disorders, revealing its mechanisms of action, clinical implications and therapeutic performance. In this paper, we review recent findings on the role of melatonin in sleep disorders which include insomnia, delayed sleep phase disorder (DSPD), jet lag, and shift work sleep disorder (SWSD). In addition, we report results where melatonin agonists and novel therapeutic targets have been designed and utilized to manipulate the melatonin receptors. This paper helps delineate melatonin’s role in sleep disorders from the literature, and clarify new perspectives for prevention and treatment of human health.