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Cell Jul 2023Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental...
Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.
Topics: Mice; Animals; Circadian Clocks; Circadian Rhythm; Suprachiasmatic Nucleus; Protein Processing, Post-Translational; Mammals
PubMed: 37369203
DOI: 10.1016/j.cell.2023.05.045 -
Biochemical Pharmacology Sep 2021Daylight is ubiquitous and is crucial for mammalian vision as well as for non-visual input to the brain via the intrinsically photosensitive retinal ganglion cells... (Review)
Review
Daylight is ubiquitous and is crucial for mammalian vision as well as for non-visual input to the brain via the intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin. The ipRGCs project to the circadian clock in the suprachiasmatic nuclei and thereby ensure entrainment to the 24-hour day-night cycle, and changes in daylength trigger the appropriate seasonal behaviours. The ipRGCs also project to the perihabenular nucleus and surrounding brain regions that modulate mood, stress and learning in animals and humans. Given that light has strong direct effects on mood, cognition, alertness, performance, and sleep, light can be considered a "drug" to treat many clinical conditions. Light therapy is already well established for winter and other depressions and circadian sleep disorders. Beyond visual and non-visual effects via the retina, daylight contributes to prevent myopia in the young by its impact on eye development, and is important for Vitamin D synthesis and bone health via the skin. The sun is the most powerful light source and, dependent on dose, its ultraviolet radiance is toxic for living organisms and can be used as a disinfectant. Most research involves laboratory-based electric light, without the dynamic and spectral changes that daylight undergoes moment by moment. There is a gap between the importance of daylight for human beings and the amount of research being done on this subject. Daylight is taken for granted as an environmental factor, to be enjoyed or avoided, according to conditions. More daylight awareness in architecture and urban design beyond aesthetic values and visual comfort may lead to higher quality work and living environments. Although we do not yet have a factual basis for the assumption that natural daylight is overall "better" than electric light, the environmental debate mandates serious consideration of sunlight not just for solar power but also as biologically necessary for sustainable and healthy living.
Topics: Circadian Clocks; Circadian Rhythm; Humans; Light; Mood Disorders; Myopia; Photoperiod; Retina; Retinal Ganglion Cells; Rod Opsins; Suprachiasmatic Nucleus; Vitamin D
PubMed: 33129807
DOI: 10.1016/j.bcp.2020.114304 -
Science (New York, N.Y.) Jun 2023The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that...
The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.
Topics: Animals; Mice; Cilia; Circadian Clocks; Circadian Rhythm; Hedgehog Proteins; Suprachiasmatic Nucleus Neurons; Signal Transduction; Gene Expression Regulation; Mice, Transgenic
PubMed: 37262147
DOI: 10.1126/science.abm1962 -
Trends in Neurosciences Jun 2022The circadian clock provides cue-independent anticipatory signals for diurnal rhythms of baseline glucose levels and glucose tolerance. The central circadian clock is... (Review)
Review
The circadian clock provides cue-independent anticipatory signals for diurnal rhythms of baseline glucose levels and glucose tolerance. The central circadian clock is located in the hypothalamic suprachiasmatic nucleus (SCN), which comprises primarily GABAergic neurons. The SCN clock regulates physiological diurnal rhythms of endogenous glucose production (EGP) and hepatic insulin sensitivity through neurohumoral mechanisms. Disruption of the molecular circadian clock is associated with the extended dawn phenomenon (DP) in type 2 diabetes (T2D), referring to hyperglycemia in the early morning without nocturnal hypoglycemia. The DP affects nearly half of patients with diabetes, with poorly defined etiology and a lack of targeted therapy. Here we review neural and secreted factors in physiological diurnal rhythms of glucose metabolism and their pathological implications for the DP.
Topics: Circadian Clocks; Circadian Rhythm; Diabetes Mellitus, Type 2; Glucose; Humans; Hyperglycemia; Suprachiasmatic Nucleus
PubMed: 35466006
DOI: 10.1016/j.tins.2022.03.010 -
Annual Review of Neuroscience Jul 2023This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity... (Review)
Review
This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior. In Alzheimer's disease, sleep impairments accompany cognitive decline. In mouse models of the disease, circadian disturbances accelerate astroglial activation and other brain pathologies, suggesting that daily functions in astrocytes protect neuronal homeostasis. In brain cancer, treatment in the morning has been associated with prolonged survival, and gliomas have daily rhythms in gene expression and drug sensitivity. Thus, circadian time is fast becoming critical to elucidating reciprocal astrocytic-neuronal interactions in health and disease.
Topics: Mice; Animals; Astrocytes; Circadian Rhythm; Circadian Clocks; Sleep; Suprachiasmatic Nucleus
PubMed: 36854316
DOI: 10.1146/annurev-neuro-100322-112249 -
Progress in Brain Research 2022In this chapter, we will discuss mathematical models of the master circadian rhythm in the suprachiasmatic nucleus of the hypothalamus with a particular emphasis on...
In this chapter, we will discuss mathematical models of the master circadian rhythm in the suprachiasmatic nucleus of the hypothalamus with a particular emphasis on models that incorporate the effect of light on circadian phase resetting and melatonin suppression. We will show that limit cycle oscillators provide a better representation of the salient properties of the human circadian system than a sinusoid. We will then discuss how the phototransduction of light to the SCN has been incorporated in various models. Finally, we will introduce different theoretical and practical applications of these models and highlight areas for future model development.
Topics: Circadian Rhythm; Humans; Melatonin; Models, Theoretical; Suprachiasmatic Nucleus
PubMed: 35940716
DOI: 10.1016/bs.pbr.2022.04.007 -
Cholecystokinin neurons in mouse suprachiasmatic nucleus regulate the robustness of circadian clock.Neuron Jul 2023The suprachiasmatic nucleus (SCN) can generate robust circadian behaviors in mammals under different environments, but the underlying neural mechanisms remained unclear....
The suprachiasmatic nucleus (SCN) can generate robust circadian behaviors in mammals under different environments, but the underlying neural mechanisms remained unclear. Here, we showed that the activities of cholecystokinin (CCK) neurons in the mouse SCN preceded the onset of behavioral activities under different photoperiods. CCK-neuron-deficient mice displayed shortened free-running periods, failed to compress their activities under a long photoperiod, and developed rapid splitting or became arrhythmic under constant light. Furthermore, unlike vasoactive intestinal polypeptide (VIP) neurons, CCK neurons are not directly light sensitive, but their activation can elicit phase advance and counter light-induced phase delay mediated by VIP neurons. Under long photoperiods, the impact of CCK neurons on SCN dominates over that of VIP neurons. Finally, we found that the slow-responding CCK neurons control the rate of recovery during jet lag. Together, our results demonstrated that SCN CCK neurons are crucial for the robustness and plasticity of the mammalian circadian clock.
Topics: Animals; Mice; Cholecystokinin; Circadian Clocks; Circadian Rhythm; Mammals; Neurons; Photoperiod; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide
PubMed: 37172583
DOI: 10.1016/j.neuron.2023.04.016 -
Advances in Experimental Medicine and... 2021Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of...
Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of biological clocks, the suprachiasmatic nucleus (SCN). Substantial oscillatory activity in the brain's reward system is regulated by dopamine. While light serves as a primary time-giver (zeitgeber) of physiological clocks and synchronizes biological rhythms in 24-h cycles, nonphotic stimuli have a profound influence over circadian biology. Indeed, reward-related activities (e.g., feeding, exercise, sex, substance use, and social interactions), which lead to an elevated level of dopamine, alters rhythms in the SCN and the brain's reward system. In this chapter, we will discuss the influence of the dopaminergic reward pathways on circadian system and the implication of this interplay on human health.
Topics: Biological Clocks; Circadian Rhythm; Dopamine; Humans; Reward; Suprachiasmatic Nucleus
PubMed: 34773226
DOI: 10.1007/978-3-030-81147-1_4 -
Nature Neuroscience Mar 2020Mammalian circadian behaviors are orchestrated by the suprachiasmatic nucleus (SCN) in the ventral hypothalamus, but the number of SCN cell types and their functional...
Mammalian circadian behaviors are orchestrated by the suprachiasmatic nucleus (SCN) in the ventral hypothalamus, but the number of SCN cell types and their functional roles remain unclear. We have used single-cell RNA-sequencing to identify the basic cell types in the mouse SCN and to characterize their circadian and light-induced gene expression patterns. We identified eight major cell types, with each type displaying a specific pattern of circadian gene expression. Five SCN neuronal subtypes, each with specific combinations of markers, differ in their spatial distribution, circadian rhythmicity and light responsiveness. Through a complete three-dimensional reconstruction of the mouse SCN at single-cell resolution, we obtained a standardized SCN atlas containing the spatial distribution of these subtypes and gene expression. Furthermore, we observed heterogeneous circadian gene expression between SCN neuron subtypes. Such a spatiotemporal pattern of gene regulation within the SCN may have an important function in the circadian pacemaker.
Topics: Animals; Atlases as Topic; Circadian Rhythm; Circadian Rhythm Signaling Peptides and Proteins; Gene Expression; Gene Expression Regulation; Genomics; Light; Male; Mice; Mice, Inbred C57BL; Neurons; Photic Stimulation; Single-Cell Analysis; Suprachiasmatic Nucleus
PubMed: 32066983
DOI: 10.1038/s41593-020-0586-x -
Nature Apr 2021Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that...
Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-α and REV-ERB-β (referred to here as 'REV-ERB') in the GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCN neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light-dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCN neurons. Chemogenetic stimulation of SCN neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCN neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.
Topics: Animals; Blood Glucose; Circadian Clocks; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; GABAergic Neurons; Glucose; Humans; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nuclear Receptor Subfamily 1, Group D, Member 1; Photoperiod; Suprachiasmatic Nucleus; Synaptic Transmission
PubMed: 33762728
DOI: 10.1038/s41586-021-03358-w