Correction: Slowpoke functions in circadian output cells to regulate rest:activity rhythms.
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ABSTRACT:
SUBMITTER: PLOS ONE Staff
PROVIDER: S-EPMC8115836 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Correction: Slowpoke functions in circadian output cells to regulate rest:activity rhythms.
PloS one 20210512 5
[This corrects the article DOI: 10.1371/journal.pone.0249215.]. ...[more]
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Project description:Though much is known about the cellular and molecular components of the circadian clock, output pathways that couple clock cells to overt behaviors have not been identified. We conducted a screen for circadian-relevant neurons in the Drosophila brain and report here that cells of the pars intercerebralis (PI), a functional homolog of the mammalian hypothalamus, comprise an important component of the circadian output pathway for rest:activity rhythms. GFP reconstitution across synaptic partners (GRASP) analysis demonstrates that PI cells are connected to the clock through a polysynaptic circuit extending from pacemaker cells to PI neurons. Molecular profiling of relevant PI cells identified the corticotropin-releasing factor (CRF) homolog, DH44, as a circadian output molecule that is specifically expressed by PI neurons and is required for normal rest:activity rhythms. Notably, selective activation or ablation of just six DH44+ PI cells causes arrhythmicity. These findings delineate a circuit through which clock cells can modulate locomotor rhythms.
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Project description:Twenty-four hour rhythms in behavior are organized by a network of circadian pacemaker neurons. Rhythmic activity in this network is generated by intrinsic rhythms in clock neuron physiology and communication between clock neurons. However, it is poorly understood how the activity of a small number of pacemaker neurons is translated into rhythmic behavior of the whole animal. To understand this, we screened for signals that could identify circadian output circuits in Drosophila melanogaster. We found that leucokinin neuropeptide (LK) and its receptor (LK-R) were required for normal behavioral rhythms. This LK/LK-R circuit connects pacemaker neurons to brain areas that regulate locomotor activity and sleep. Our experiments revealed that pacemaker neurons impose rhythmic activity and excitability on LK- and LK-R-expressing neurons. We also found pacemaker neuron-dependent activity rhythms in a second circadian output pathway controlled by DH44 neuropeptide-expressing neurons. We conclude that rhythmic clock neuron activity propagates to multiple downstream circuits to orchestrate behavioral rhythms.
| S-EPMC5066395 | biostudies-literature
Project description:Spontaneous action potentials in the suprachiasmatic nucleus (SCN) are necessary for normal circadian timing of behavior in mammals. The SCN exhibits a daily oscillation in spontaneous firing rate (SFR), but the ionic conductances controlling SFR and the relationship of SFR to subsequent circadian behavioral rhythms are not understood. We show that daily expression of the large conductance Ca(2+)-activated K(+) channel (BK) in the SCN is controlled by the intrinsic circadian clock. BK channel-null mice (Kcnma1(-/-)) have increased SFRs in SCN neurons selectively at night and weak circadian amplitudes in multiple behaviors timed by the SCN. Kcnma1(-/-) mice show normal expression of clock genes such as Arntl (Bmal1), indicating a role for BK channels in SCN pacemaker output, rather than in intrinsic time-keeping. Our findings implicate BK channels as important regulators of the SFR and suggest that the SCN pacemaker governs the expression of circadian behavioral rhythms through SFR modulation.
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Project description:ObjectiveDelirium is a complex neurocognitive syndrome suspected to be bidirectionally linked to dementia. Circadian rhythm disturbances likely contribute to dementia pathogenesis, but whether these disturbances are related to delirium risk and progression to all-cause dementia is unknown.MethodsWe analyzed continuous actigraphy data from 53,417 middle-aged or older UK Biobank participants during a median 5 years of follow-up. Four measures were used to characterize the 24-hour daily rest-activity rhythms (RARs): normalized amplitude, acrophase representing the peak activity time, interdaily stability, and intradaily variability (IV) for fragmentation of the rhythm. Cox proportional hazards models examined whether RARs predicted incident delirium (n = 551) and progression to dementia (n = 61).ResultsSuppressed 24-hour amplitude, lowest (Q1) versus highest (Q4) quartile (hazard ratio [HR]Q1 vs Q4 = 1.94, 95% confidence interval [CI] = 1.53-2.46, p < 0.001), and more fragmented (higher IV: HRQ4 vs Q1 = 1.49, 95% CI = 1.18-1.88, p < 0.001) rhythms predicted higher delirium risk, after adjusting for age, sex, education, cognitive performance, sleep duration/disturbances, and comorbidities. In those free from dementia, each hour of delayed acrophase was associated with delirium risk (HR = 1.13, 95% CI = 1.04-1.23, p = 0.003). Suppressed 24-hour amplitude was associated with increased risk of progression from delirium to new onset dementia (HR = 1.31, 95% CI = 1.03-1.67, p = 0.03 for each 1-standard deviation decrease).InterpretationTwenty-four-hour daily RAR suppression, fragmentation, and potentially delayed acrophase were associated with delirium risk. Subsequent progression to dementia was more likely in delirium cases with suppressed rhythms. The presence of RAR disturbances before delirium and prior to progression to dementia suggests that these disturbances may predict higher risk and be involved in early disease pathogenesis. ANN NEUROL 2023;93:1145-1157.
| S-EPMC10247440 | biostudies-literature
Project description:BackgroundDisrupted rest-activity circadian rhythm (RAR) patterns have been associated with poor health outcomes (i.e. diminished cognitive function, increased risk of dementia and falls). Circadian time cues in bone influence the differentiation of osteoblasts and osteoclasts, and bone turnover markers exhibit circadian variation; relationships between bone outcomes and RAR are emerging areas of research. We evaluated associations between RAR and areal bone mineral density (aBMD) at the total hip and femoral neck in older men from the Osteoporotic Fractures in Men (MrOS) cohort. We hypothesized that weaker RAR patterns would be associated with lower aBMD.MethodsMrOS is an ongoing prospective cohort study following ambulatory men ≥ 65 years (n = 5994) at 6 U.S. clinics (baseline enrollment 3/2000-4/2002); participants for this analysis are from an ancillary study, Outcomes of Sleep Disorders in Older Men (MrOS Sleep). We included data from men who had technically adequate measures of RAR and aBMD at Sleep Visit 1 (12/2003-3/2005), with repeat aBMD at core Visit 3 (3/2007-3/2009) (n = 2412; mean age at Sleep Visit 1: 75.7 ± 5.2 years). aBMD was measured by dual energy x-ray absorptiometry (DXA). Actigraphs worn on the non-dominant wrist were used to collect circadian activity data over 4.8 ± 0.8 consecutive 24-hour periods. An extension of the traditional cosine curve was used to fit RAR to the activity data [Ancoli-Israel et al., 2003; Marler et al., 2006]. Six RAR parameters were evaluated: acrophase (time of peak activity), amplitude (rhythm strength), mesor (mean of activity fitted curve), pseudo F-statistic (overall circadian rhythmicity of rest and activity), alpha statistic (daytime to nighttime activity ratio), and beta statistic (daytime activity). Associations between RAR and aBMD (Sleep Visit 1), and RAR and ΔaBMD (Sleep Visit 1-Visit 3) were assessed with generalized linear models. Covariates included age, clinic site, physical activity, race, comorbidity, body mass index (BMI), smoking, alcohol, caffeine, beta blocker use, serum 25(OH) vitamin D and urinary melatonin and calcium.ResultsPseudo F-statistic was significantly associated with total hip aBMD (p-trend = 0.009), femoral neck aBMD (p-trend = 0.007) and total hip ΔaBMD (p-trend = 0.017) in minimally adjusted models but not after multivariate (MV) adjustment. Alpha statistic was significantly associated with femoral neck aBMD (p-trend = 0.029) and femoral neck ΔaBMD (p-trend = 0.019) in minimally adjusted models; significance was retained in the femoral neck ΔaBMD model (p-trend = 0.034) after MV adjustment. There were no consistent, significant associations between the other RAR variables and aBMD or ΔaBMD.ConclusionsThe data demonstrate modest associations between overall circadian rhythmicity of rest and activity (measured by pseudo F-statistic), as well as daytime to nighttime activity ratio (measured by alpha statistic), aBMD and ΔaBMD, but adjustment for covariates related to lifestyle, BMI and comorbidities attenuated most of these associations. These results suggest that RAR patterns are not independently associated with aBMD or four-year ΔaBMD at the total hip or femoral neck in older men, but additional research is needed.
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Project description:Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization.
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Project description:Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward-genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause of deaf-blindness in humans. Whirlin and other Usher proteins are expressed in the mammalian central nervous system, yet their function in the CNS has not been investigated. We show that DYSC is expressed in major neuronal tracts and regulates expression of the calcium-activated potassium channel SLOWPOKE (SLO), an ion channel also required in the circadian output pathway. SLO and DYSC are co-localized in the brain and control each other's expression post-transcriptionally. Co-immunoprecipitation experiments demonstrate they form a complex, suggesting they regulate each other through protein-protein interaction. Furthermore, electrophysiological recordings of neurons in the adult brain show that SLO-dependent currents are greatly reduced in dysc mutants. Our work identifies a Drosophila homolog of a deaf-blindness gene as a new component of the circadian output pathway and an important regulator of ion channel expression, and suggests novel roles for Usher proteins in the mammalian nervous system.
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Project description:Neuronal plasticity helps animals learn from their environment. However, it is challenging to link specific changes in defined neurons to altered behavior. Here, we focus on circadian rhythms in the structure of the principal s-LNv clock neurons in Drosophila. By quantifying neuronal architecture, we observed that s-LNv structural plasticity changes the amount of axonal material in addition to cycles of fasciculation and defasciculation. We found that this is controlled by rhythmic Rho1 activity that retracts s-LNv axonal termini by increasing myosin phosphorylation and simultaneously changes the balance of pre-synaptic and dendritic markers. This plasticity is required to change clock network hierarchy and allow seasonal adaptation. Rhythms in Rho1 activity are controlled by clock-regulated transcription of Puratrophin-1-like (Pura), a Rho1 GEF. Since spinocerebellar ataxia is associated with mutations in human Puratrophin-1, our data support the idea that defective actin-related plasticity underlies this ataxia.
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Project description:The mammalian circadian clock uses interlocked negative feedback loops in which the heterodimeric basic helix-loop-helix transcription factor BMAL1/CLOCK is a master regulator. While there is prominent control of liver functions by the circadian clock, the detailed links between circadian regulators and downstream targets are poorly known. Using chromatin immunoprecipitation combined with deep sequencing we obtained a time-resolved and genome-wide map of BMAL1 binding in mouse liver, which allowed us to identify over 2,000 binding sites, with peak binding narrowly centered around Zeitgeber time 6. Annotation of BMAL1 targets confirms carbohydrate and lipid metabolism as the major output of the circadian clock in mouse liver. Moreover, transcription regulators are largely overrepresented, several of which also exhibit circadian activity. Genes of the core circadian oscillator stand out as strongly bound, often at promoter and distal sites. Genomic sequence analysis of the sites identified E-boxes and tandem E1-E2 consensus elements. Electromobility shift assays showed that E1-E2 sites are bound by a dimer of BMAL1/CLOCK heterodimers with a spacing-dependent cooperative interaction, a finding that was further validated in transactivation assays. BMAL1 target genes showed cyclic mRNA expression profiles with a phase distribution centered at Zeitgeber time 10. Importantly, sites with E1-E2 elements showed tighter phases both in binding and mRNA accumulation. Finally, analyzing the temporal profiles of BMAL1 binding, precursor mRNA and mature mRNA levels showed how transcriptional and post-transcriptional regulation contribute differentially to circadian expression phase. Together, our analysis of a dynamic protein-DNA interactome uncovered how genes of the core circadian oscillator crosstalk and drive phase-specific circadian output programs in a complex tissue.
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