Circadian control of brain glymphatic and lymphatic fluid flow

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Сен. 2, 2020

The glymphatic system is a network of perivascular spaces that promotes movement cerebrospinal fluid (CSF) into the brain and clearance metabolic waste. This transport supported by water channel aquaporin-4 (AQP4) localized to vascular endfeet astrocytes. more effective during sleep, but whether sleep timing function remains unknown. We here show influx exhibit endogenous, circadian rhythms peaking mid-rest phase mice. Drainage CSF from cisterna magna lymph nodes exhibits daily variation opposite influx, suggesting distribution throughout animal depends on time-of-day. polarization AQP4 highest rest loss eliminates day-night difference in both drainage nodes. conclude under control supports this rhythm.

Язык: Английский

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Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling

Neuron, Год журнала: 2017, Номер 93(6), С. 1420 - 1435.e5

Опубликована: Март 1, 2017

The suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms physiology and behavior in mammals. Its circadian (∼24 hr) oscillations gene expression electrical activity are generated intrinsically can persist indefinitely temporal isolation. This robust resilient timekeeping is generally regarded as a product intrinsic connectivity its neurons. Here we show that neurons constitute only one "half" SCN clock, metabolically active during daytime. In contrast, astrocytes nighttime, when they suppress by regulating extracellular glutamate levels. glutamatergic gliotransmission sensed dorsal via specific pre-synaptic NMDA receptor assemblies containing NR2C subunits. Remarkably, somatic genetic re-programming intracellular clocks was capable remodeling behavioral adult mice. Thus, circuit-level arises from interdependent mutually supportive astrocytic-neuronal signaling.

Язык: Английский

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Cell-autonomous clock of astrocytes drives circadian behavior in mammals

Science, Год журнала: 2019, Номер 363(6423), С. 187 - 192

Опубликована: Янв. 11, 2019

Circadian (~24-hour) rhythms depend on intracellular transcription-translation negative feedback loops (TTFLs). How these self-sustained cellular clocks achieve multicellular integration and thereby direct daily of behavior in animals is largely obscure. The suprachiasmatic nucleus (SCN) the fulcrum this pathway from gene to cell circuit mammals. We describe type-specific, functionally distinct TTFLs neurons astrocytes SCN show that, absence other clocks, cell-autonomous astrocytic TTFL alone can drive molecular oscillations circadian mice. Astrocytic by reinstating clock expression function via glutamatergic signals. Our results demonstrate that autonomously initiate sustain complex mammalian behavior.

Язык: Английский

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Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time

Cell, Год журнала: 2019, Номер 177(4), С. 896 - 909.e20

Опубликована: Апрель 25, 2019

In mammals, endogenous circadian clocks sense and respond to daily feeding lighting cues, adjusting internal ∼24 h rhythms resonate with, anticipate, external cycles of day night. The mechanism underlying entrainment time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts physiology, a state that associated with increased incidence chronic diseases such type 2 (T2) diabetes. We show feeding-regulated hormones insulin insulin-like growth factor 1 (IGF-1) reset in vivo vitro by induction PERIOD proteins, signaling organization mouse behavior clock gene expression. Insulin IGF-1 receptor sufficient determine essential parameters, principally via protein synthesis. This requires coincident mechanistic target rapamycin (mTOR) activation, phosphoinositide signaling, microRNA downregulation. Besides its well-known homeostatic functions, we propose are primary signals cellular throughout the body.

Язык: Английский

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A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes

eLife, Год журнала: 2021, Номер 10

Опубликована: Янв. 8, 2021

Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish an attractive model to investigate genetic contributions diseases. However, current CRISPR-Cas9 methods difficult apply large screens studying behavioural phenotypes. To facilitate rapid screening, we developed a simple sequencing-free tool validate gRNAs and highly effective method capable converting >90% injected embryos directly F0 biallelic knockouts. We demonstrate that knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms the circadian clock, escape responses irritants, multi-parameter day-night locomotor behaviours. The technique sufficiently robust knockout multiple in same animal, for example create transparent triple crystal fish imaging. Our cuts experimental time from gene phenotype months one week.

Язык: Английский

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A photoregulatory mechanism of the circadian clock in Arabidopsis

Nature Plants, Год журнала: 2021, Номер 7(10), С. 1397 - 1408

Опубликована: Окт. 14, 2021

Язык: Английский

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Rhythmic cilia changes support SCN neuron coherence in circadian clock

Science, Год журнала: 2023, Номер 380(6648), С. 972 - 979

Опубликована: Июнь 1, 2023

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 coupling among SCN neurons maintain the robustness of internal in mice. Cilia neuromedin S-producing (NMS) exhibit pronounced rhythmicity abundance and length. Genetic ablation ciliogenesis NMS enabled a rapid phase shift under jet-lag conditions. rhythms individual cilia-deficient slices lost their after external Rhythmic changes drive oscillations Sonic Hedgehog (Shh) signaling gene expression. Inactivation Shh phenocopied effects ablation. Thus, cilia-Shh aids coupling.

Язык: Английский

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Evolution of circadian rhythms: from bacteria to human

Sleep Medicine, Год журнала: 2017, Номер 35, С. 49 - 61

Опубликована: Май 8, 2017

Язык: Английский

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Improved Statistical Methods Enable Greater Sensitivity in Rhythm Detection for Genome-Wide Data

PLoS Computational Biology, Год журнала: 2015, Номер 11(3), С. e1004094 - e1004094

Опубликована: Март 20, 2015

Robust methods for identifying patterns of expression in genome-wide data are important generating hypotheses regarding gene function. To this end, several analytic have been developed detecting periodic patterns. We improve one such method, JTK_CYCLE, by explicitly calculating the null distribution that it accounts multiple hypothesis testing and including non-sinusoidal reference waveforms. term method empirical JTK_CYCLE with asymmetry search, we compare its performance to Bonferroni Benjamini-Hochberg correction, as well five other methods: cyclohedron test, address reduction, stable persistence, ANOVA, F24. find F24, consistently outperform three when limited noisy; search gives greatest sensitivity while controlling false discovery rate. Our analysis also provides insight into experimental design that, a fixed number samples, better specificity achieved higher numbers replicates than sampling density. Application circadian rhythms metadataset microarrays quantify time-dependent whole heads Drosophila melanogaster reveals annotations enriched among genes highly asymmetric These include wide range oxidation reduction metabolic genes, transcripts splice forms.

Язык: Английский

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Acute exposure to low-level light at night is sufficient to induce neurological changes and depressive-like behavior

Molecular Psychiatry, Год журнала: 2019, Номер 25(5), С. 1080 - 1093

Опубликована: Май 28, 2019

Язык: Английский

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