Regulation Of Sleep-wake Cycle Research Articles

Locus coeruleus microstructural integrity is associated with vigilance vulnerability to sleep deprivation.

Insufficient sleep compromises cognitive performance, diminishes vigilance, and disrupts daily functioning in hundreds of millions of people worldwide. Despite extensive research revealing significant variability in vigilance vulnerability to sleep deprivation, the underlying mechanisms of these individual differences remain elusive. Locus coeruleus (LC) plays a crucial role in the regulation of sleep-wake cycles and has emerged as a potential marker for vigilance vulnerability to sleep deprivation. In this study, we investigate whether LC microstructural integrity, assessed by fractional anisotropy (FA) through diffusion tensor imaging (DTI) at baseline before sleep deprivation, can predict impaired psychomotor vigilance test (PVT) performance during sleep deprivation in a cohort of 60 healthy individuals subjected to a rigorously controlled in-laboratory sleep study. The findings indicate that individuals with high LC FA experience less vigilance impairment from sleep deprivation compared with those with low LC FA. LC FA accounts for 10.8% of the variance in sleep-deprived PVT lapses. Importantly, the relationship between LC FA and impaired PVT performance during sleep deprivation is anatomically specific, suggesting that LC microstructural integrity may serve as a biomarker for vigilance vulnerability to sleep loss.

Herbal and Natural Supplements for Improving Sleep: A Literature Review.

Herbal and natural supplements have gained popularity as alternative treatments to insomnia and sleep disorders due to their perceived safety and potential effectiveness. This literature review summarizes the current evidence on the efficacy, safety, and mechanisms of action of commonly used supplements for sleep, including valerian, hops, kava, German chamomile, cherry, tryptophan, theanine, melatonin, magnesium, and zinc. We conducted literature review of clinical research on herbal and supplements for sleep reported to date. We summarized key findings and reviewed outcomes related to clinical efficacy and side effects. Findings suggest that certain supplements, particularly valerian, hops, and melatonin, could be effective in improving sleep quality and reducing insomnia symptoms through modulation of neurotransmitter systems and regulation of sleep-wake cycles. However, the strength of the evidence varies with unestablished optimal dosages, formulations, and treatment durations. Although generally considered safe, these supplements are not without risks, such as rare but serious adverse effects associated with kava and potential interactions with prescription medications. The quality and purity of supplements also vary widely due to a lack of strict regulations. Healthcare providers should remain informed about the latest research and work closely with patients to develop personalized treatment plans. Herbal and natural supplements may offer promising alternatives or adjunct treatments for insomnia and sleep disorders, but their use should be guided by the best available evidence and individual patient requirements. Larger, well-designed clinical trials are needed to establish the efficacy and safety of these supplements for clinical decision-making.

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.

Sleep disturbance associated with the menopause.

Sleep disturbance is one of the most common and debilitating symptoms experienced by women during the menopause transition. However, there are currently no therapies specifically approved for sleep disturbance associated with the menopause. Here, we consider how to characterize sleep disturbance associated with the menopause and discuss its etiology, including the latest advances in our understanding of the neuronal circuits that regulate reproduction, body temperature, sleep, and mood; and reflect on its impact on women's health and well-being. We also examine the current treatment landscape and look to the future of treatment for this condition. We conducted a review of the literature and combined this with discussion with experts in the fields of sleep and menopause as well as experiences from our own clinical practices. Sleep disturbance associated with the menopause is characterized by frequent night-time awakenings and increased awake time after sleep onset. Its impacts are wide-ranging, negatively affecting health as well as personal and social relationships, productivity, and work performance. There is currently an unmet need for effective, safe, and well-tolerated treatments to address this important symptom, and wider recognition of the association between sleep disturbances and the menopause is needed. Sleep disturbances associated with the menopause can result from hormone changes as well as vasomotor and mood symptoms. Growing research has contributed to our knowledge of the role of hypothalamic estrogen-sensitive kisspeptin/neurokinin B/dynorphin neurons. These neurons are thought to integrate the gonadotropin-releasing hormone pathway and the pathways responsible for the homeostatic control of body temperature and the circadian regulation of sleep-wake cycles. Understanding these neurons offers the potential to create treatments that target a key cause of sleep disturbance associated with the menopause. Further research to understand their etiology and characterize the neuronal circuits responsible could benefit the development of these targeted treatment approaches.

Shift and Night Work in Technology Intensive Environment as a Health Hazard

Flexible workday arrangement is a common management practice in the modern technology intensive society. The impact of shift work in night hours on human health has been a subject of a broad range of fundamental and applied studies in occupational medicine and in other fields. Epidemiological data and a body of research findings suggest that shift workers are prone to various pathologies. This paper summarizes current views on the link between shift and night work and the risk of chronic noncommunicable diseases (NCDs), which are a leading cause of morbidity and mortality among working population and are therefore a top priority. Systematic reviews and meta-analyses present strong evidence that shift workers have a higher risk of malignant tumors (breast cancer, prostate cancer, colorectal cancer), coronary heart disease, and type 2 diabetes compared to daytime-only workers. There are, however, individual differences in the risk of NCDs that may depend on the length of employment and other circumstances. Also, factors are discussed that can modify the impact of shift work on the risk of associated pathologies, such as chronotype, changing length of night shifts, proper shift rotation, sufficient rest between shifts, etc. Mechanisms of genetic regulation of individual circadian rhythms and sleep-wake cycle are a crucial element in the conceptual model of influence of night work on body. Insufficient adaptation and plasticity of the circadian system may cause desynchronization between external time and inner biorhythms in shift workers; this is accompanied with changes in circadian genes expression and may lead to pathologies. If disturbed circadian rhythms are the main factor of etiopathogenesis, the term “circadian-related disease” should be used. Deep understanding of the link between circadian desynchronosis and health problems in shift workers is important to implement ‘circadian safety’ measures, i.e. to protect workers from negative consequences of disturbed individual biorhythms that may affect their work capacities and life quality. This will require standard protocols to study circadian disturbances, standard tools and methods to diagnose circadian rhythms in workers, resolving issues of interpretation in respect of occupational capacity, research on proneness and tolerance of workers to circadian-related problems, finding pharmacological and physical approaches to reduce circadian disturbances, considering special aspects of drug therapy of desynchronosis.

Deletion of the Clock Gene Bmal2 Leads to Alterations in Hypothalamic Clocks, Circadian Regulation of Feeding, and Energy Balance.

BMAL2 (ARNTL2) is a paralog of BMAL1 that can form heterodimers with the other circadian factors CLOCK and NPAS2 to activate transcription of clock and clock-controlled genes. To assess a possible role of Bmal2 in the circadian regulation of metabolism, we investigated daily variations of energy metabolism, feeding behavior, and locomotor behavior, as well as ability to anticipate restricted food access in male mice knock-out for Bmal2 (B2KO). While their amount of food intake and locomotor activity were normal compared with wild-type mice, B2KO mice displayed increased adiposity (1.5-fold higher) and fasted hyperinsulinemia (fourfold higher) and tended to have lower energy expenditure at night. Impairment of the master clock in the suprachiasmatic nuclei was evidenced by the shorter free-running period (-14 min/cycle) of B2KO mice compared with wild-type controls and by a loss of daily rhythmicity in expression of intracellular metabolic regulators (e.g., Lipoprotein lipase and Uncoupling protein 2). The circadian window of eating was longer in B2KO mice. The circadian patterns of food intake and meal numbers were bimodal in control mice but not in B2KO mice. In response to restricted feeding, food-anticipatory activity was almost prevented in B2KO mice, suggesting altered food clock that controls anticipation of food availability. In the mediobasal hypothalamus of B2KO mice, expression of genes coding orexigenic neuropeptides (including Neuropeptide y and Agouti-Related Peptide) was downregulated, while Lipoprotein lipase expression lost its rhythmicity. Together, these data highlight that BMAL2 has major impacts on brain regulation of metabolic rhythms, sleep-wake cycle, and food anticipation.

Exploring the Literature on Narcolepsy: Insights into the Sleep Disorder That Strikes during the Day.

Narcolepsy is a chronic sleep disorder that disrupts the regulation of a person's sleep-wake cycle, leading to significant challenges in daily functioning. It is characterized by excessive daytime sleepiness, sudden muscle weakness (cataplexy), sleep paralysis, and vivid hypnagogic hallucinations. A literature search was conducted in different databases to identify relevant studies on various aspects of narcolepsy. The main search terms included "narcolepsy", "excessive daytime sleepiness", "cataplexy", and related terms. The search was limited to studies published until May 2023. This literature review aims to provide an overview of narcolepsy, encompassing its causes, diagnosis, treatment options, impact on individuals' lives, prevalence, and recommendations for future research. The review reveals several important findings regarding narcolepsy: 1. the classification of narcolepsy-type 1 narcolepsy, previously known as narcolepsy with cataplexy, and type 2 narcolepsy, also referred to as narcolepsy without cataplexy; 2. the genetic component of narcolepsy and the complex nature of the disorder, which is characterized by excessive daytime sleepiness, disrupted sleep patterns, and potential impacts on daily life activities and social functioning; and 3. the important implications for clinical practice in the management of narcolepsy. Healthcare professionals should be aware of the different types of narcolepsies and their associated symptoms, as this can aid in accurate diagnosis and treatment planning. The review underscores the need for a multidisciplinary approach to narcolepsy management, involving specialists in sleep medicine, neurology, psychiatry, and psychology. Clinicians should consider the impact of narcolepsy on a person's daily life, including their ability to work, study, and participate in social activities, and provide appropriate support and interventions. There are several gaps in knowledge regarding narcolepsy. Future research should focus on further elucidating the genetic causes and epigenetic mechanisms of narcolepsy and exploring potential biomarkers for early detection and diagnosis. Long-term studies assessing the effectiveness of different treatment approaches, including pharmacological interventions and behavioral therapies, are needed. Additionally, there is a need for research on strategies to improve the overall well-being and quality of life of individuals living with narcolepsy, including the development of tailored support programs and interventions.

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

Role of astrocytes in sleep deprivation: accomplices, resisters, or bystanders?

Sleep plays an essential role in all studied animals with a nervous system. However, sleep deprivation leads to various pathological changes and neurobehavioral problems. Astrocytes are the most abundant cells in the brain and are involved in various important functions, including neurotransmitter and ion homeostasis, synaptic and neuronal modulation, and blood-brain barrier maintenance; furthermore, they are associated with numerous neurodegenerative diseases, pain, and mood disorders. Moreover, astrocytes are increasingly being recognized as vital contributors to the regulation of sleep-wake cycles, both locally and in specific neural circuits. In this review, we begin by describing the role of astrocytes in regulating sleep and circadian rhythms, focusing on: (i) neuronal activity; (ii) metabolism; (iii) the glymphatic system; (iv) neuroinflammation; and (v) astrocyte-microglia cross-talk. Moreover, we review the role of astrocytes in sleep deprivation comorbidities and sleep deprivation-related brain disorders. Finally, we discuss potential interventions targeting astrocytes to prevent or treat sleep deprivation-related brain disorders. Pursuing these questions would pave the way for a deeper understanding of the cellular and neural mechanisms underlying sleep deprivation-comorbid brain disorders.

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders.

Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the severalpathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered.

Photoperiod-driven concurrent changes in hypothalamic and brainstem transcription of sleep and immune genes in migratory redheaded bunting.

The molecular regulation of sleep in avian migrants is still obscure. We thus investigated this in migratory redheaded buntings, where four life-history states (LHS; i.e. non-migratory, pre-migratory, migratory and refractory states) were induced. There was increased night-time activity (i.e. Zugunruhe) during the migratory state with reduced daytime activity. The recordings of the sleep-wake cycle in buntings showed increased night-time active wakefulness coupled with drastically reduced front and back sleep during migratory phase. Interestingly, we found the buntings to feed and drink even after lights-off during migration. Gene expression studies revealed increased hypothalamic expression of glucocorticoid receptor (nr3c1), and pro-inflammatory cytokines (il1b and il6) in pre-migratory and migratory states, respectively, whereas in brainstem Ca2+/calmodulin-dependent protein kinase 2 (camk2) was upregulated during the migratory state. This suggested a heightened pro-inflammatory state during migration which is a feature of chronic sleep loss, and a possible role of Ca2+ signalling in promoting wakefulness. In both the hypothalamus and brainstem, the expression of melatonin receptors (mel1a and mel1b) was increased in the pre-migratory state, and growth hormone-releasing hormone (ghrh, known to induce sleep) was reduced during the migratory state. The current results demonstrate key molecules involved in the regulation of sleep-wake cycle across LHS in migratory songbirds.

Locus Coeruleus Dysfunction and Trigeminal Mesencephalic Nucleus Degeneration: A Cue for Periodontal Infection Mediated Damage in Alzheimer's Disease?

Alzheimer's disease (AD) is a leading neurodegenerative disease with deteriorating cognition as its main clinical sign. In addition to the clinical history, it is characterized by the presence of two neuropathological hallmark lesions; amyloid-beta (Aβ) and neurofibrillary tangles (NFTs), identified in the brain at post-mortem in specific anatomical areas. Recently, it was discovered that NFTs occur initially in the subcortical nuclei, such as the locus coeruleus in the pons, and are said to spread from there to the cerebral cortices and the hippocampus. This contrasts with the prior acceptance of their neuropathology in the enthorinal cortex and the hippocampus. The Braak staging system places the accumulation of phosphorylated tau (p-tau) binding to NFTs in the locus coeruleus and other subcortical nuclei to precede stages I-IV. The locus coeruleus plays diverse psychological and physiological roles within the human body including rapid eye movement sleep disorder, schizophrenia, anxiety, and depression, regulation of sleep-wake cycles, attention, memory, mood, and behavior, which correlates with AD clinical behavior. In addition, the locus coeruleus regulates cardiovascular, respiratory, and gastrointestinal activities, which have only recently been associated with AD by modern day research enabling the wider understanding of AD development via comorbidities and microbial dysbiosis. The focus of this narrative review is to explore the modes of neurodegeneration taking place in the locus coeruleus during the natural aging process of the trigeminal nerve connections from the teeth and microbial dysbiosis, and to postulate a pathogenetic mechanism due to periodontal damage and/or infection focused on Treponema denticola.

Metabotropic glutamate receptor function and regulation of sleep-wake cycles.

Metabotropic glutamate (mGlu) receptors are the most abundant family of G-protein coupled receptors and are widely expressed throughout the central nervous system (CNS). Alterations in glutamate homeostasis, including dysregulations in mGlu receptor function, have been indicated as key contributors to multiple CNS disorders. Fluctuations in mGlu receptor expression and function also occur across diurnal sleep-wake cycles. Sleep disturbances including insomnia are frequently comorbid with neuropsychiatric, neurodevelopmental, and neurodegenerative conditions. These often precede behavioral symptoms and/or correlate with symptom severity and relapse. Chronic sleep disturbances may also be a consequence of primary symptom progression and can exacerbate neurodegeneration in disorders including Alzheimer's disease (AD). Thus, there is a bidirectional relationship between sleep disturbances and CNS disorders; disrupted sleep may serve as both a cause and a consequence of the disorder. Importantly, comorbid sleep disturbances are rarely a direct target of primary pharmacological treatments for neuropsychiatric disorders even though improving sleep can positively impact other symptom clusters. This chapter details known roles of mGlu receptor subtypes in both sleep-wake regulation and CNS disorders focusing on schizophrenia, major depressive disorder, post-traumatic stress disorder, AD, and substance use disorder (cocaine and opioid). In this chapter, preclinical electrophysiological, genetic, and pharmacological studies are described, and, when possible, human genetic, imaging, and post-mortem studies are also discussed. In addition to reviewing the important relationships between sleep, mGlu receptors, and CNS disorders, this chapter highlights the development of selective mGlu receptor ligands that hold promise for improving both primary symptoms and sleep disturbances.

Mathematical insights into the role of dopamine signaling in circadian entrainment

The circadian clock in the mammalian brain comprises interlocked molecular feedback loops that have downstream effects on important physiological functions such as the sleep-wake cycle and hormone regulation. Experiments have shown that the circadian clock also modulates the synthesis and breakdown of the neurotransmitter dopamine. Imbalances in dopamine are linked to a host of neurological conditions including Parkinson’s disease, attention-deficit/hyperactivity disorder, and mood disorders, and these conditions are often accompanied by circadian disruptions. We have previously created a mathematical model using nonlinear ordinary differential equations to describe the influences of the circadian clock on dopamine at the molecular level. Recent experiments suggest that dopamine reciprocally influences the circadian clock. Dopamine receptor D1 (DRD1) signaling has been shown to aid in the entrainment of the clock to the 24-hour light-dark cycle, but the underlying mechanisms are not well understood. In this paper, we use our mathematical model to support the experimental hypothesis that DRD1 signaling promotes circadian entrainment by modulating the clock’s response to light. We model the effects of a phase advance or delay, as well as the therapeutic potential of a REV-ERB agonist. In addition to phase shifts, we study the influences of photoperiod, or day length, in the mathematical model, connect our findings with the experimental and clinical literature, and determine the parameter that affects the critical photoperiod that signals seasonal changes to physiology.

Research Progress on the Pathogenesis of Circadian Rhythm Sleep-Wake Disorders

Circadian rhythm fluctuates within 24 hours, affecting many physiological processes and aspects of daily life, including eating behavior, regulation of sleep wake cycle and metabolic homeostasis. Circadian rhythm sleep-wake disorders(CRSWDs) refer to the inconsistency between the human body's circadian behavioral activities and the needs of social life. Common classifications classify it as Delayed sleep phase type (DSP), Advanced sleep phase type (ASP), Free-running type and Irregular sleep-wake type. The potential pathogenesis of CRSWDs is closely related to human clock genes. Emens et al reported finding that N24H sleep-wake disorder is an important milestone in etiology. Light is the stronges inducement of circadian rhythm. CRSWDs may due to the long-term lack of light and other external timing factors, leading to circadian rhythm disorders and sleep homeostasis imbalance rather than being driven by a disorder of the central circadian clock. Regular exposure to strong light is often used to treat CRSWDs. This paper briefly introduces the historical background of understanding circadian rhythm, and then the common pathogenesis and mechanism of sleep wake disorder with different circadian rhythms and the corresponding treatment were discussed.

Influence of melatonin on the structural and thermal properties of SOPC lipid membranes

Melatonin, a hormone secreted by the pineal gland in the brain, plays a key role in the regulation of sleep-wake cycles. Due to its antioxidant and free radical scavenging properties, it has shown promising protective effects against cancer, and neurodegenerative disorders. Studies pertaining to the use of melatonin and its biophysical effects on cell membranes are important for their biomedical implications. The main goal of our study is to investigate the effect of melatonin on the thermal and structural properties of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) phospholipid membranes using sensitive techniques such as Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). For this purpose, SOPC lipid bilayer membranes were prepared with different melatonin concentrations (10–50 mol%). DSC results have indicated that melatonin strongly interacts with the membrane lipids in a concentration-dependent fashion to form domains and alters the phase behavior by reducing the main phase transition temperature, lipid order, and increasing membrane fluidity. FTIR data have shown that increasing the melatonin concentration caused a reduction in the wavenumber of CO and PO2−antisymmetric stretching vibrations, indicating the possibility of strong hydrogen bonding between melatonin and the SOPC lipid with the nearby water molecules in the environment, suggesting its preferential location near lipid head groups at the interfacial region. Understanding the organization of melatonin in membranes and its influence on membrane properties is important to gain thorough knowledge and to develop safe melatonin-based formulations for therapeutic applications.

Alzheimer's disease and sleep disorders: Insights into the possible disease connections and the potential therapeutic targets.

One of the comorbid conditions in an individual with Alzheimer's disease is a sleep disorder. Clinical features of sleep disorders involve various sleep disturbances such as Obstructive Sleep Apnea (OSAS), Excessive Daytime Sleepiness (EDS), Rapid Eye Movement (REM), Breathing Disorders, Periodic limb movements in sleep (PLMS), etc. The primary tools used for the identification of such disturbances are Polysomnography (PSG) and Wrist actigraphy. This review will highlight and explains the different approaches used in the treatment of sleep disorders. Non-pharmacological treatments include Peter Hauri rules, sleep education program, and light therapy which play a key role in the regulation of sleep-wake cycles. Pharmacological therapy described in this article may be useful in treating sleep destruction in patients with Alzheimer's disease. Along with the Non-pharmacological and pharmacological treatment, here we discuss five commonly recognized plant-based nutraceuticals with hypothesized impact on sleep disorders: caffeine, chamomile, cherries, L-tryptophan, and valerian by the proper emphasis on the known mechanism of their action.

Analyzing potential correlations between light exposure and skin temperature in a climate chamber

Interactions between occupants and buildings are mediated by physiological and psychological stimuli, which may interfere in the perception of environmental variables. Among these variables, recent studies have shown that daylight may play a relevant role both in terms of light and thermal perception of the built environment, as well as in complex physiological mechanisms not directly related to vision. These include secretion of hormones linked to the regulation of sleep-wake cycles and body thermal homeostasis. The study aimed to explore relationships between light-related variables as colour and intensity and changes in skin temperature (Tsk) of male subjects (n = 16) in a thermally controlled environment with varying light exposure conditions (dynamic light versus static electric light). Tsk during the morning hours was found to be significantly related to daylight availability. Results suggest that the suppression of the variability of brightness and correlated colour temperature (CCT) encountered in natural light can affect the rate of Tsk variation and lead to possible circadian dysfunctions.

Orexin A improves the cognitive impairment induced by chronic intermittent hypoxia in mice

The orexin neuron in lateral hypothalamus (LH) was involved in the regulation of sleep-wake cycle. However, the effect of orexin A (OXA) on cognitive impairment resulting from diverse diseases remains controversial. In this study, we investigated the effect of OXA on cognitive impairment induced by chronic intermittent hypoxia (CIH) in mice. Adult (10 weeks old) male C57BL/6 mice were randomly divided into the following four groups: normoxia control (NC)+normal saline (NS), NC + OXA, CIH + NS and CIH + OXA group. Following the CIH mice models establishment, OXA was injected into the right lateral ventricles of mice by a micro-injection system. Water maze test was used to assess spatial memory abilities of the mice. The expression of OXA and c-Fos in LH were analyzed by immunofluorescence staining. Apoptotic cell death and oxidative stress in hippocampus were evaluated using multiple methods including TUNEL, western blot and biochemical analysis. Behavioral tests revealed that CIH significantly increased the escape latency and time of arriving platform, of which were markedly decreased by OXA treatment. Similarly, the CIH + NS group was worse than NC + NS group in terms of the number of platform crossing and time in the target quadrant, of which were also significantly improved by OXA treatment. The number of OXA + neuron in LH was decreased, but the percentage of c-Fos+/OXA + neuron in LH was remarkably increased by CIH. Furthermore, we found that micro-injection of OXA attenuated CIH-induced apoptotic cell death and oxidative stress in the hippocampus. Our results suggested that OXA might improve cognitive impairment induced by CIH through inhibiting hippocampal apoptosis and oxidative stress.

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.