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1.
Curr Biol ; 31(22): R1456-R1458, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34813745

RESUMO

Foster provides an overview of the hormone melatonin, discussing its role in seasonal biology and its more controversial function in human sleep.

2.
Transl Psychiatry ; 11(1): 588, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782594

RESUMO

Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest-activity profiles of GluA1-knockout mice (Gria1-/-). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest-activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1-2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides-vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)-differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts' short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.

3.
Mil Med Res ; 8(1): 55, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645526

RESUMO

The military population face a unique set of risk factors that may increase the risk of being diagnosed with dementia. Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) have a higher prevalence in this group in comparison to the civilian population. By delving into the individual relationships between TBI and dementia, and PTSD and dementia, we are able to better explore dementia in the military and veteran populations. While there are some inconsistencies in results, the TBI-dementia association has become more widely accepted. Moderate-to-severe TBI has been found to increase the risk of being diagnosed with Alzheimer's disease. A correlation between PTSD and dementia has been established, however, whether or not it is a causal relationship remains unclear. Factors such as blast, combat and chemical exposure may occur during a deployment, along with TBI and/or PTSD diagnosis, and can impact the risk of dementia. However, there is a lack of literature exploring the direct effects of deployment on dementia risk. Sleep problems have been observed to occur in those following TBI, PTSD and deployment. Poor sleep has been associated with possible dementia risk. Although limited studies have focused on the link between sleep and dementia in military and veteran populations, sleep is a valuable factor to study due to its association and interconnection with other military/veteran factors. This review aims to inform of various risk factors to the cognitive health of military members and veterans: TBI, PTSD, deployment, and sleep.

4.
Front Neurosci ; 15: 744543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650401

RESUMO

Light plays a critical role in regulating physiology and behavior, including both visual and non-visual responses. In mammals, loss of both eyes abolishes all of these responses, demonstrating that the photoreceptors involved are exclusively ocular. By contrast, many non-mammalian species possess extra-ocular photoreceptors located in the pineal complex and deep brain. Whilst there have been suggestions of extra-ocular photoreception in mammals, including man, evidence for these photoreceptors is limited. One approach to objectively determine the presence of such receptors is to measure brain responses to light using functional magnetic resonance imaging (fMRI). Moreover, by using participants who are clinically anophthalmic (congenital and acquired), it is possible to investigate potential light detection in the absence of the retina. Here we scanned participants with anophthalmia and sighted participants in 4 different conditions; the first 3 conditions had a bright light source applied to the following locations: behind the right ear ("ear"), just below the nasal bridge and between the eyes ("head"), and at the right popliteal fossa ("knee"). In the fourth and final scan, the light source was switched off so that there was no light stimulus. All participants were scanned in a completely dark room. No consistent brain activity was detected during any of the light conditions in either sighted controls or anophthalmic participants. Thus, we do not provide any evidence for the presence of extraocular photoreceptors modulating human brain activity, despite recent evidence for gene transcription that may occur as a result of these photoreceptors.

5.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34556572

RESUMO

Light provides the primary signal for entraining circadian rhythms to the day/night cycle. In addition to rods and cones, the retina contains a small population of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). Concerns have been raised that exposure to dim artificial lighting in the evening (DLE) may perturb circadian rhythms and sleep patterns, and OPN4 is presumed to mediate these effects. Here, we examine the effects of 4-h, 20-lux DLE on circadian physiology and behavior in mice and the role of OPN4 in these responses. We show that 2 wk of DLE induces a phase delay of ∼2 to 3 h in mice, comparable to that reported in humans. DLE-induced phase shifts are unaffected in Opn4 -/- mice, indicating that rods and cones are capable of driving these responses in the absence of melanopsin. DLE delays molecular clock rhythms in the heart, liver, adrenal gland, and dorsal hippocampus. It also reverses short-term recognition memory performance, which is associated with changes in preceding sleep history. In addition, DLE modifies patterns of hypothalamic and cortical cFos signals, a molecular correlate of recent neuronal activity. Together, our data show that DLE causes coordinated realignment of circadian rhythms, sleep patterns, and short-term memory process in mice. These effects are particularly relevant as DLE conditions-due to artificial light exposure-are experienced by the majority of the populace on a daily basis.


Assuntos
Ritmo Circadiano , Luz , Memória de Curto Prazo/fisiologia , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/fisiologia , Sono/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Ganglionares da Retina/citologia
6.
Life Sci Alliance ; 4(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34389686

RESUMO

Absence of dystrophin, an essential sarcolemmal protein required for muscle contraction, leads to the devastating muscle-wasting disease Duchenne muscular dystrophy. Dystrophin has an actin-binding domain, which binds and stabilises filamentous-(F)-actin, an integral component of the RhoA-actin-serum-response-factor-(SRF) pathway. This pathway plays a crucial role in circadian signalling, whereby the suprachiasmatic nucleus (SCN) transmits cues to peripheral tissues, activating SRF and transcription of clock-target genes. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised dystrophin loss causes circadian deficits. We show for the first time alterations in the RhoA-actin-SRF-signalling pathway, in dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios, altered MRTF levels, dysregulated core-clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from Duchenne patients harbouring an array of mutations. Furthermore, we show dystrophin is absent in the SCN of dystrophic mice which display disrupted circadian locomotor behaviour, indicative of disrupted SCN signalling. Therefore, dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

7.
Neuroophthalmology ; 45(2): 75-86, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108778

RESUMO

The aim of this study was to compare the pattern of changes in brain structure resulting from congenital and acquired bilateral anophthalmia. Brain structure was investigated using 3T magnetic resonance imaging (MRI) in Oxford (congenital) or Manchester (acquired). T1-weighted structural and diffusion-weighted scans were acquired from people with anophthalmia and sighted control participants. Differences in grey matter between the groups were quantified using voxel-based morphometry and differences in white matter microstructure using tract-based spatial statistics. Quantification of optic nerve volume and cortical thickness in visual regions was also performed in all groups. The optic nerve was reduced in volume in both anophthalmic populations, but to a greater extent in the congenital group and anophthalmia acquired at an early age. A similar pattern was found for the white matter microstructure throughout the occipitotemporal regions of the brain, suggesting a greater reduction of integrity with increasing duration of anophthalmia. In contrast, grey matter volume changes differed between the two groups, with the acquired anophthalmia group showing a decrease in the calcarine sulcus, corresponding to the area that would have been peripheral primary visual cortex. In contrast, the acquired anophthalmia group showed a decrease in grey matter volume in the calcarine sulcus corresponding to the area that would have been peripheral primary visual cortex. There are both qualitative and quantitative differences in structural brain changes in congenital and acquired anophthalmia, indicating differential effects of development and degeneration.

8.
Sleep Health ; 7(3): 293-302, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33795195

RESUMO

Polyphasic sleep is the practice of distributing multiple short sleep episodes across the 24-hour day rather than having one major and possibly a minor ("nap") sleep episode each day. While the prevalence of polyphasic sleep is unknown, anecdotal reports suggest attempts to follow this practice are common, particularly among young adults. Polyphasic-sleep advocates claim to thrive on as little as 2 hours of total sleep per day. However, significant concerns have been raised that polyphasic sleep schedules can result in health and safety consequences. We reviewed the literature to identify the impact of polyphasic sleep schedules (excluding nap or siesta schedules) on health, safety, and performance outcomes. Of 40,672 potentially relevant publications, with 2,023 selected for full-text review, 22 relevant papers were retained. We found no evidence supporting benefits from following polyphasic sleep schedules. Based on the current evidence, the consensus opinion is that polyphasic sleep schedules, and the sleep deficiency inherent in those schedules, are associated with a variety of adverse physical health, mental health, and performance outcomes. Striving to adopt a schedule that significantly reduces the amount of sleep per 24 hours and/or fragments sleep into multiple episodes throughout the 24-hour day is not recommended.

9.
Nat Commun ; 12(1): 2113, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837202

RESUMO

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.


Assuntos
Adenosina/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Relógios Circadianos/efeitos dos fármacos , Sono/fisiologia , Animais , Encéfalo/patologia , Cafeína/farmacologia , Linhagem Celular Tumoral , Transtornos Cronobiológicos/tratamento farmacológico , Transtornos Cronobiológicos/etiologia , Transtornos Cronobiológicos/patologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Humanos , Luz , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fotoperíodo , Quinazolinas/administração & dosagem , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos da radiação , Sono/efeitos dos fármacos , Privação do Sono/complicações , Triazóis/administração & dosagem
10.
Transl Psychiatry ; 11(1): 226, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875641

RESUMO

Psychotic experiences (PE) are associated with poorer functioning, higher distress and the onset of serious mental illness. Environmental exposures (e.g. childhood abuse) are associated with the development of PE. However, which specific exposures convey risk for each type or dimension of PE has rarely been explored. The Oxford Wellbeing Life and Sleep (OWLS) survey includes 22 environmental risk factors for psychosis and was designed to examine how environmental risks are associated with specific dimensions of PE. Multivariate logistic regression models were fit using these risk factors to predict six dimensions of PE (perceptual abnormalities, persecutory ideation, bizarre ideas, cognitive disorganisation, delusional mood and negative symptoms). Models were built using only 70% of the data, and then fit to the remaining data to assess their generalisability and quality. 1789 (27.2% men; mean age = 27.6; SD = 10.9) survey responses were analysed. The risk factors predictive of the most PE were anxiety, social withdrawal during childhood and trauma. Cannabis and depression predicted three dimensions with both predicting bizarre ideas and persecutory ideation. Psychological abuse and sleep quality each predicted two dimensions (persecutory ideation and delusional mood). Risk factors predicting one PE dimension were age (predicting cognitive disorganisation), physical abuse (bizarre ideas), bullying and gender (persecutory ideation); and circadian phase (delusional mood). These results lend support for a continuum of psychosis, suggesting environmental risks for psychotic disorders also increase the risk of assorted dimensions of PE. Furthermore, it advocates the use of dimensional approaches when examining environmental exposures for PE given that environmental risks distribute differently across dimensions.


Assuntos
Transtornos Psicóticos , Ansiedade , Transtornos de Ansiedade , Criança , Humanos , Relações Interpessoais , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/etiologia , Fatores de Risco
11.
Sleep ; 44(9)2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-33838033

RESUMO

STUDY OBJECTIVES: Torpor is a regulated and reversible state of metabolic suppression used by many mammalian species to conserve energy. Whereas the relationship between torpor and sleep has been well-studied in seasonal hibernators, less is known about the effects of fasting-induced torpor on states of vigilance and brain activity in laboratory mice. METHODS: Continuous monitoring of electroencephalogram (EEG), electromyogram (EMG), and surface body temperature was undertaken in adult, male C57BL/6 mice over consecutive days of scheduled restricted feeding. RESULTS: All animals showed bouts of hypothermia that became progressively deeper and longer as fasting progressed. EEG and EMG were markedly affected by hypothermia, although the typical electrophysiological signatures of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, and wakefulness enabled us to perform vigilance-state classification in all cases. Consistent with previous studies, hypothermic bouts were initiated from a state indistinguishable from NREM sleep, with EEG power decreasing gradually in parallel with decreasing surface body temperature. During deep hypothermia, REM sleep was largely abolished, and we observed shivering-associated intense bursts of muscle activity. CONCLUSIONS: Our study highlights important similarities between EEG signatures of fasting-induced torpor in mice, daily torpor in Djungarian hamsters and hibernation in seasonally hibernating species. Future studies are necessary to clarify the effects on fasting-induced torpor on subsequent sleep.


Assuntos
Torpor , Vigília , Animais , Cricetinae , Jejum , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sono
12.
J Sleep Res ; 30(4): e13278, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33622029

RESUMO

Primary insomnia is often considered a disorder of 24-hr hyperarousal. Numerous attempts have been made to investigate nocturnal heart rate (HR) and its variability (HRV) as potential pathophysiological hallmarks of altered arousal levels in insomnia, with mixed results. We have aimed to overcome some of the pitfalls of previous studies by using a young, medication-free, age- and gender-matched population consisting of 43 students aged 18-30 years half with a subthreshold insomnia complaint. We employed at-home ambulatory polysomnography and compared this attenuated insomnia group to a good sleeping group. The poor sleepers had significantly higher wake after sleep onset, arousal count, mean HR in all sleep stages (with the exception of Stage 1) and lower sleep efficiency. Consistent with previous research, we also found a significant group-by-sleep stage interaction in the prediction of nocturnal HR, highlighting the insomnia group to have a lower wake-sleep HR reduction compared to good sleepers. When restricting our analyses to insomnia with objectively determined short sleep duration, we found significantly lower standard deviation of RR intervals (SDNN; a measure of HRV) compared to good sleepers. Taken together, this lends credence to the hyperarousal model of insomnia and may at least partially explain the increased prevalence of cardiovascular morbidity and mortality observed in patients with insomnia.


Assuntos
Frequência Cardíaca , Polissonografia , Autorrelato , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Sono/fisiologia , Adolescente , Adulto , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Adulto Jovem
13.
Biochem Pharmacol ; 191: 114404, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33412102

RESUMO

Acute exposure to light exerts widespread effects on physiology, in addition to its key role in photoentrainment. Although the modulatory effect of light on physiological arousal is well demonstrated in mice, its effect on memory performance is inconclusive, as the direction of the effect depends on the nature of the behavioural task employed and/or the type of stimulus utilised. Moreover, in all rodent studies that reported significant effects of light on performance, brain activity was not assessed during the task and thus it is unclear how brain activity was modulated by light or the exact relationship between light-modulated brain activity and performance. Here we examine the modulatory effects of light of varying intensities on recognition memory performance and frontoparietal waking electroencephalography (EEG) in mice using the spontaneous recognition memory task. We report a light-intensity-dependent disruptive effect on recognition memory performance at the group level, but inspection of individual-level data indicates that light-intensity-dependent facilitation is observed in some cases. Using linear mixed-effects models, we then demonstrate that EEG fast theta (θ) activity at the time of encoding negatively predicts recognition memory performance, whereas slow gamma (γ) activity at the time of retrieval positively predicts performance. These relationships between θ/γ activity and performance are strengthened by increasing light intensity. Thus, light modulates θ and γ band activities involved in attentional and mnemonic processes, thereby affecting recognition memory performance. However, extraneous factors including the phase of the internal clock at which light is presented and homeostatic sleep pressure may determine how photic input is translated into behavioural performance.


Assuntos
Encéfalo/fisiologia , Ritmo Gama/fisiologia , Memória/fisiologia , Estimulação Luminosa/métodos , Reconhecimento Psicológico/fisiologia , Ritmo Teta/fisiologia , Animais , Eletroencefalografia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Olfato/fisiologia
14.
Methods Mol Biol ; 2130: 233-247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33284449

RESUMO

Circadian rhythms are 24-h cycles in physiology and behavior that occur in virtually all organisms. These processes are not simply driven by changes in the external environment as they persist under constant conditions, providing evidence for an internal biological clock. In mammals, this clock is located in the hypothalamic suprachiasmatic nuclei (SCN) and is based upon an intracellular mechanism composed of a transcriptional-translational feedback loop composed of a number of core clock genes. However, a clock is of no use unless it can be set to the correct time. The primary time cue for the molecular clock in the SCN is light detected by the eye. The photoreceptors involved in this process include the rods and cones that mediate vision, as well as the recently identified melanopsin-expressing photosensitive retinal ganglion cells (pRGCs). Light information is conveyed to the SCN via the retinohypothalamic tract, resulting in an intracellular signaling cascade which converges on cAMP-response elements in the promoters of several key clock genes. Over the last two decades a number of studies have investigated the transcriptional response of the SCN to light stimuli with the aim of further understanding these molecular signaling pathways. Here we provide an overview of these studies and provide protocols for studying the molecular responses to light in the SCN clock.


Assuntos
Relógios Circadianos , Microdissecção e Captura a Laser/métodos , Visão Ocular , Animais , Camundongos , Proteoma/genética , Proteoma/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiologia , Transcriptoma , Vias Visuais/metabolismo , Vias Visuais/fisiologia
15.
Biology (Basel) ; 9(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708259

RESUMO

Light around twilight provides the primary entrainment signal for circadian rhythms. Here we review the mechanisms and responses of the mouse and human circadian systems to light. Both utilize a network of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). In both species action spectra and functional expression of OPN4 in vitro show that melanopsin has a λmax close to 480 nm. Anatomical findings demonstrate that there are multiple pRGC sub-types, with some evidence in mice, but little in humans, regarding their roles in regulating physiology and behavior. Studies in mice, non-human primates and humans, show that rods and cones project to and can modulate the light responses of pRGCs. Such an integration of signals enables the rods to detect dim light, the cones to detect higher light intensities and the integration of intermittent light exposure, whilst melanopsin measures bright light over extended periods of time. Although photoreceptor mechanisms are similar, sensitivity thresholds differ markedly between mice and humans. Mice can entrain to light at approximately 1 lux for a few minutes, whilst humans require light at high irradiance (>100's lux) and of a long duration (>30 min). The basis for this difference remains unclear. As our retinal light exposure is highly dynamic, and because photoreceptor interactions are complex and difficult to model, attempts to develop evidence-based lighting to enhance human circadian entrainment are very challenging. A way forward will be to define human circadian responses to artificial and natural light in the "real world" where light intensity, duration, spectral quality, time of day, light history and age can each be assessed.

16.
Interface Focus ; 10(3): 20190098, 2020 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-32382406

RESUMO

At the core of human thought, for the majority of individuals in the developed nations at least, there is the tacit assumption that as a species we are unfettered by the demands imposed by our biology and that we can do what we want, at whatever time we choose, whereas in reality every aspect of our physiology and behaviour is constrained by a 24 h beat arising from deep within our evolution. Our daily circadian rhythms and sleep/wake cycle allow us to function optimally in a dynamic world, adjusting our biology to the demands imposed by the day/night cycle. The themes developed in this review focus upon the growing realization that we ignore the circadian and sleep systems at our peril, and this paper considers the mechanisms that generate and regulate circadian and sleep systems; what happens mechanistically when these systems collapse as a result of societal pressures and disease; how sleep disruption and stress are linked; why sleep disruption and mental illness invariably occur together; and how individuals and employers can attempt to mitigate some of the problems associated with working against our internal temporal biology. While some of the health costs of sleep disruption can be reduced, in the short-term at least, there will always be significant negative consequences associated with shift work and sleep loss. With this in mind, society needs to address this issue and decide when the consequences of sleep disruption are justified in the workplace.

17.
Mol Psychiatry ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404948

RESUMO

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

18.
Chronobiol Int ; 37(7): 1034-1047, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32233647

RESUMO

Experimental evidence suggests that perinatal light imprinting of circadian clocks and systems may affect downstream physiology and cancer risk in later life. For humans, the predominant circadian stimulus is the daily light-dark cycle. Herein, we explore associations between perinatal photoperiod characteristics (photoperiod: duration of daylight as determined by time-of-year and location) and childhood cancer risk. We use pooled data on 182,856 mothers and babies from prospective birth cohorts in six countries (Australia, Denmark, Israel, Norway, UK, USA) within the International Childhood Cancer Cohort Consortium (I4C). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In line with predicted differential dose-responses, restricted cubic splines indicate a potential non-linear, non-monotonic relationship between perinatal mean daily photoperiod (0-24 h) and childhood cancer risk. In a restricted analysis of 154,121 individuals who experienced third trimester photoperiods exclusively within the 8-16-h range, the relative risk of developing childhood cancer decreased by 9% with every hour increase in third trimester mean daily photoperiod [HR: 0.91 (95%CIs: 0.84-0.99)]. In conclusion, in this first study of perinatal photoperiod and childhood cancer, we detected an inverse ["protective"] linear association between third trimester mean daily photoperiod and childhood cancer risk in the 8-16-h set of the total study population. Limited statistical power impeded the investigation of risks with individuals exposed to more extreme photoperiods. Future studies are needed to confirm differential photoperiod-associated risks and further investigations into the hypothesized circadian imprinting mechanism are warranted.


Assuntos
Neoplasias , Fotoperíodo , Austrália , Criança , Ritmo Circadiano , Feminino , Humanos , Israel , Luz , Neoplasias/epidemiologia , Neoplasias/etiologia , Noruega , Gravidez , Estudos Prospectivos
19.
Nat Rev Endocrinol ; 16(4): 213-223, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32055029

RESUMO

Meal timing and composition are frequently reported in the literature as zeitgebers (that is, time cues) for the circadian system of humans and animal models, albeit secondary to light. Although widely assumed to be true, evidence for food zeitgeber effects specific to humans is notably scarce. Fostering zeitgeber hygiene in the general population as the development and practice of healthy use of zeitgebers could potentially reduce chronobiological strain, which is defined as disruption or misalignment within the circadian system. Such chronobiological strain is associated with modern 24/7 lifestyles (for example, shift work) and several negative health outcomes. Adjustments to meal timing and composition are an attractive strategy to synchronize circadian rhythms and develop zeitgeber hygiene. Thus, clarifying the actual effect of meal timing and composition on the human circadian system is a crucial piece of the human chronobiology puzzle. This Review weighs the evidence from human studies pertaining to the hypothesis that food is a circadian zeitgeber by comparing findings against formal zeitgeber criteria put forward by Jürgen Aschoff in the 1950s.


Assuntos
Comportamento Alimentar/fisiologia , Ritmo Circadiano/fisiologia , Dieta , Feminino , Humanos , Masculino , Fatores de Tempo
20.
Sleep Med X ; 2: 100011, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33458648

RESUMO

Objective: To evaluate the impact of a school-based sleep education programme on adolescent sleep and sleep knowledge. Methods: This is the first outcome report on 'Teensleep': a novel, teacher-led programme, comprising ten lessons that can be delivered flexibly. Students in Year 10 (n = 1504; mean age = 14.14 ± 0.35 years) from ten UK state (non-fee-paying) secondary schools received the lessons and parents received a leaflet. Effectiveness was assessed using measures across two time points (pre- and post-intervention). Students completed questionnaires on sleep knowledge, sleep quality, sleep behaviour, sleep hygiene, daytime sleepiness and health-related quality of life. A sub-sample provided objective (actigraphy, n = 84) and subjective (sleep diary, n = 74) sleep measures. Results: Large improvements in sleep knowledge (d = 0.78), and smaller improvements in sleep quality (d = 0.15) and sleep hygiene (d = 0.11) were observed, but not in daytime sleepiness or health-related quality of life. Small and limited changes in subjective and objective sleep patterns were found. Baseline sleep quality was differentially associated with key outcomes, with those initially self-reporting poor sleep demonstrating an improvement in sleep quality, sleep hygiene and sleepiness. Conclusion: Teensleep was effective at improving sleep knowledge but sleep changes were small. Such interventions have traditionally focused on gains for all students, but this study suggests that poor sleepers may be the most likely to experience immediate direct sleep benefits. Follow-up studies are required to investigate whether or not sleep education provides long-term benefits as a step towards preventative sleep medicine.

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