Astrocytes Sustain Circadian Oscillation and Bidirectionally Determine Circadian Period, But Do Not Regulate Circadian Phase in the Suprachiasmatic Nucleus

Journal of Neuroscience, Journal Year: 2022, Volume and Issue: 42(28), P. 5522 - 5537

Published: May 24, 2022

The suprachiasmatic nucleus (SCN) is the master circadian clock of mammals, generating and transmitting an internal representation environmental time that produced by cell-autonomous transcriptional/post-translational feedback loops (TTFLs) 10,000 neurons 3500 glial cells. Recently, we showed TTFL function in SCN astrocytes alone sufficient to drive timekeeping behavior, raising questions about respective contributions within circuit. We compared their relative roles mouse explants, either sex. Treatment with glial-specific toxin fluorocitrate revealed a requirement for metabolically competent circuit-level timekeeping. Recombinase-mediated genetically complemented Cryptochrome (Cry) proteins Cry1-deficient and/or Cry2-deficient SCNs were used compare influence TTFLs or initiation de novo oscillation pacemaking. While both initiated lengthened period equally, kinetics different, taking twice as long. Furthermore, could shorten period, but not potently neurons. Chemogenetic manipulation Gi- Gq-coupled signaling pathways acutely advanced delayed ensemble phase, respectively. In contrast, comparable manipulations without effect. Thus, can initiate rhythms bidirectionally control albeit lower potency than Nevertheless, activation does phase. emergent properties high-amplitude oscillation, rhythmicity, pacemaking, phase are differentially regulated: sustain ongoing its determined SIGNIFICANCE STATEMENT hypothalamic encodes disseminates time-of-day information allow mammals adapt physiology daily cycles. Recent investigations have role astrocytes, addition neurons, regulation this rhythm. Using pharmacology, genetic complementation, chemogenetics, abilities determining determination These findings parameterize astrocyte population reveal types contribute heterogeneous cellular network.

Language: Английский

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The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: April 27, 2022

Circadian rhythms convergently evolved to allow for optimal synchronization of individuals’ physiological and behavioral processes with the Earth’s 24-h periodic cycling environmental light temperature. Whereas suprachiasmatic nucleus (SCN) is considered primary pacemaker mammalian circadian system, many extra-SCN oscillatory brain regions have been identified not only exhibit sustainable in molecular clock function, but also overall region activity/function mediated behaviors. In this review, we present most recent evidence ventral tegmental area (VTA) accumbens (NAc) serve as oscillators highlight studies that illustrate functional significance VTA’s NAc’s inherent properties they relate reward-processing, drug abuse, vulnerability develop substance use disorders (SUDs).

Language: Английский

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Circadian Oscillations in Skin and Their Interconnection with the Cycle of Life

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5635 - 5635

Published: March 15, 2023

Periodically oscillating biological processes, such as circadian rhythms, are carefully concerted events that only beginning to be understood in the context of tissue pathology and organismal health, well molecular mechanisms underlying these interactions. Recent reports indicate light can independently entrain peripheral clocks, challenging currently prevalent hierarchical model. Despite recent progress has been made, a comprehensive overview periodic processes skin is lacking literature. In this review, clock machinery factors govern it have highlighted. Circadian rhythm closely linked immunological homeostasis, its desynchrony perturbation skin. The interplay between annual, seasonal oscillations, impact on skin, described. Finally, changes occur over lifespan presented. This work encourages further research into occurring lays foundation for future strategies combat adverse effects desynchrony, which would likely implications other tissues influenced by oscillatory processes.

Language: Английский

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The clock gene BHLHE40 and atypical CCNG2 control androgen-induced cellular senescence as a novel tumor suppressive pathway in prostate cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: June 20, 2024

Abstract Background The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological level (SAL), in bipolar therapy, inhibits growth of PCa suggesting tumor-suppressive activity by SAL. SAL was shown induce cellular senescence PCa. Methods RNA-seq transcriptome analysis, ChIP-seq, human 3D spheroids, mouse xenografted castration-resistant PCa, knockdown overexpression, Co-immunoprecipitation (Co-IP), translocation immune detection, qRT-PCR, protein–protein interaction modelling. Results Here, mice xenografts tumors show that vivo activates mechanism. ChIP-seq revealed the clock gene BHLHE40 novel direct target. Compared adjacent tissues, expression reduced associated survival. Knockdown suggests mediates SAL-induced including tumor spheroids. Interestingly, large overlap differentially expressed sets identified between leading identification four classes SAL-BHLHE40 landscapes. Co-IP modelling suggest binding their co-translocation into nucleus treatment. Further, analysis indicate atypical suppressive cyclin G2 emerged as downstream mediator senescence. Conclusions data provide evidence signaling AR-BHLHE40-CCNG2 axis for androgen-induced senescence, linking circadian rhythm factor pathway.

Language: Английский

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Chronobiotic and cytoprotective activity of melatonin in the cardiovascular system. Doses matter

Deleted Journal, Journal Year: 2024, Volume and Issue: 1(1)

Published: Sept. 9, 2024

Language: Английский

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Melatonin as a Chronobiotic and Cytoprotector in Non-communicable Diseases: More than an Antioxidant

Sub-cellular biochemistry/Subcellular biochemistry, Journal Year: 2024, Volume and Issue: unknown, P. 217 - 244

Published: Jan. 1, 2024

Language: Английский

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Melatonin as a Chronobiotic/Cytoprotective Agent in REM Sleep Behavior Disorder

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(5), P. 797 - 797

Published: May 13, 2023

Dream-enactment behavior that emerges during episodes of rapid eye movement (REM) sleep without muscle atonia is a parasomnia known as REM disorder (RBD). RBD constitutes prodromal marker α-synucleinopathies and serves one the best biomarkers available to predict diseases such Parkinson disease, multiple system atrophy dementia with Lewy bodies. Most patients showing will convert an α-synucleinopathy about 10 years after diagnosis. The diagnostic advantage relies on prolonged time, its predictive power absence disease-related treatments could act confounders. Therefore, are candidates for neuroprotection trials delay or prevent conversion pathology abnormal α-synuclein metabolism. administration melatonin in doses exhibiting chronobiotic/hypnotic effect (less than mg daily) commonly used first line treatment (together clonazepam) RBD. At higher dose, may also be effective cytoprotector halt progression. However, allometric derived from animal studies (in 100 mg/day range) rarely employed clinically regardless demonstrated toxicity phase 1 pharmacological up normal volunteers. This review discusses application RBD: (a) symptomatic RBD; (b) possible disease-modifying α-synucleinopathies. To what degree has therapeutic efficacy prevention awaits further investigation, particular multicenter double-blind trials.

Language: Английский

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The nuclear transportation of CHRONO regulates the circadian rhythm

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 107917 - 107917

Published: Oct. 1, 2024

Language: Английский

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Molecular Genetic Mechanisms of Circadian Rhythm Regulation and Their Role in Psychopathology

Российский физиологический журнал им  И  М  Сеченова, Journal Year: 2023, Volume and Issue: 109(11), P. 1522 - 1546

Published: Nov. 1, 2023

Circadian rhythms are cyclic fluctuations in the intensity of biological processes associated with change day and night, to which many organisms have adapted during evolution. Disturbances circadian triggered by both environmental factors (e.g., altering time zone or length day/night) disrupted internal regulation cycles mutations key clock genes). These changes can lead pathogenesis various diseases, including psychopathologies. Since mechanisms underlying rather evolutionarily conservative, experimental animal models actively used probe these their relationship Here, we discuss rhythms, as well cross-taxon similarities differences between mammals teleost fish (zebrafish, Danio rerio). We also recent findings on molecular genetic link mental disorders humans model organisms.

Language: Английский

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Circadian Clocks in Mammals: General Aspects of Oscillating Systems and Roles in Medicine

Royal Society of Chemistry eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 13 - 40

Published: Feb. 23, 2024

The circadian system generates about 24-hour rhythms in body functions to adjust their performances cyclic environments, thereby ensuring survival. Misalignment of internal periodicities and environmental cycles eventually leads both mental physical malfunctions. To gain insight into misalignment, it is absolutely necessary understand the principle entrainment, especially relation light–dark (LD) cycle. Non-parametric parametric entrainments are basic concepts two coupled oscillators likely involved stable entrainment its seasonal changes. It critical molecular mechanism comprehend regulation system. discovery clock genes has greatly increased our knowledge but we now grappling with complexity suprachiasmatic nucleus hypothalamus serves as central clock, which entrains LD cycle regulates peripheral clocks located almost all tissues organs. Modern society chaotic terms time structure, where easily disrupted. Understanding underlying disorders important for prevention treatment. concept chronomedicine, was proposed several decades ago, ready be materialized advent chronobiology.

Language: Английский

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