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1.
Nature ; 574(7776): 108-111, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534223

RESUMO

Light discrimination according to colour can confer survival advantages by guiding animals towards food and shelter and away from potentially harmful situations1,2. Such colour-dependent behaviour can be learned or innate. Data on innate colour preference in mammals remain controversial3 and there are limited data for simpler organisms4-7. Here we show that, when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes according to the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based visual photoreceptors and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the transient receptor potential (TRP) channels dTRPA1 and Pyrexia, and is also timed by the clock. By contrast, avoidance of blue light is primarily mediated by multidendritic neurons, requires rhodopsin 7 and the TRP channel Painless, and is independent of the clock. Our findings show that several TRP channels are involved in colour-driven behaviour in Drosophila, and reveal distinct pathways of innate colour preference that coordinate the behavioural dynamics of flies in ambient light.


Assuntos
Relógios Circadianos/fisiologia , Relógios Circadianos/efeitos da radiação , Cor , Drosophila melanogaster/fisiologia , Drosophila melanogaster/efeitos da radiação , Luz , Canais de Receptores Transientes de Potencial/metabolismo , Animais , Antenas de Artrópodes/fisiologia , Antenas de Artrópodes/efeitos da radiação , Dendritos/fisiologia , Dendritos/efeitos da radiação , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Larva/fisiologia , Larva/efeitos da radiação , Luz/efeitos adversos , Masculino , Neurônios/fisiologia , Neurônios/efeitos da radiação , Rodopsinas Sensoriais/metabolismo , Fatores de Tempo , Visão Ocular/efeitos da radiação
2.
Genes Dev ; 33(17-18): 1136-1158, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481537

RESUMO

Circadian rhythms are driven by a transcription-translation feedback loop that separates anabolic and catabolic processes across the Earth's 24-h light-dark cycle. Central pacemaker neurons that perceive light entrain a distributed clock network and are closely juxtaposed with hypothalamic neurons involved in regulation of sleep/wake and fast/feeding states. Gaps remain in identifying how pacemaker and extrapacemaker neurons communicate with energy-sensing neurons and the distinct role of circuit interactions versus transcriptionally driven cell-autonomous clocks in the timing of organismal bioenergetics. In this review, we discuss the reciprocal relationship through which the central clock drives appetitive behavior and metabolic homeostasis and the pathways through which nutrient state and sleep/wake behavior affect central clock function.


Assuntos
Relógios Circadianos/fisiologia , Metabolismo Energético/genética , Hipotálamo/metabolismo , Neurônios/fisiologia , Animais , Ritmo Circadiano/fisiologia , AMP Cíclico/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Transdução de Sinais
3.
Nat Commun ; 10(1): 3750, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434902

RESUMO

ZEITLUPE (ZTL), a photoreceptor with E3 ubiquitin ligase activity, communicates end-of-day light conditions to the plant circadian clock. It still remains unclear how ZTL protein accumulates in the light but does not destabilize target proteins before dusk. Two deubiquitylating enzymes, UBIQUITIN-SPECIFIC PROTEASE 12 and 13 (UBP12 and UBP13), which regulate clock period and protein ubiquitylation in a manner opposite to ZTL, associate with the ZTL protein complex. Here we demonstrate that the ZTL interacting partner, GIGANTEA (GI), recruits UBP12 and UBP13 to the ZTL photoreceptor complex. We show that loss of UBP12 and UBP13 reduces ZTL and GI protein levels through a post-transcriptional mechanism. Furthermore, a ZTL target protein is unable to accumulate to normal levels in ubp mutants. This demonstrates that the ZTL photoreceptor complex contains both ubiquitin-conjugating and -deconjugating enzymes, and that these two opposing enzyme types are necessary for circadian clock pacing. This shows that deubiquitylating enzymes are a core element of circadian clocks, conserved from plants to animals.


Assuntos
Proteínas de Arabidopsis/metabolismo , Relógios Circadianos/fisiologia , Endopeptidases/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Endopeptidases/genética , Regulação da Expressão Gênica de Plantas , Mutação , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases , Ubiquitinação
4.
Nat Commun ; 10(1): 3518, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388006

RESUMO

Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals. As the largest metabolic organ, the liver sensitively responds to the food signals and secretes hepatokines, leading to the robust regulation of metabolic and clock processes. However, it remains unknown which hepatokine mediates the food-driven resetting of the liver clock independent of the master clock. Here, we identify Angptl8 as a hepatokine that resets diurnal rhythms of hepatic clock and metabolic genes in mice. Mechanistically, the resetting function of Angptl8 is dependent on the signal relay of the membrane receptor PirB, phosphorylation of kinases and transcriptional factors, and consequently transient activation of the central clock gene Per1. Importantly, inhibition of Angptl8 signaling partially blocks food-entrained resetting of liver clock in mice. We have thus identified Angptl8 as a key regulator of the liver clock in response to food.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Comportamento Alimentar/fisiologia , Fígado/fisiologia , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Proteínas Semelhantes a Angiopoietina/genética , Animais , Relógios Circadianos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Fígado/metabolismo , Masculino , Camundongos , Modelos Animais , Proteínas Circadianas Period/metabolismo , Fosforilação , Fotoperíodo , Receptores Imunológicos/metabolismo
5.
Environ Pollut ; 252(Pt B): 1455-1463, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265956

RESUMO

Circadian rhythm is believed to play important roles in atherosclerosis. The gut microbiota is found to be closely related to atherogenesis, and shows compositional and functional circadian oscillation. However, it's still unclarified whether circadian clock and intestinal microbiota are involved in the progression of atherosclerosis induced by environmental pollutant acrolein. Herein, patients with atherosclerosis showed higher MMP9, a promising biomarker for atherosclerosis, and lower Bmal1 and Clock expression in the plasma. Interestingly, acrolein exposure contributed to the increased MMP9, decreased Clock and Bmal1, and activated MAPK pathways in human umbilical vein endothelial cells (HUVECs). We found that knockdown of Clock or Bmal1 lead to upregulation of MMP9 in HUVECs, and that Clock and Bmal1 expression was elevated while MAPK pathways were blocked. Atherosclerotic apolipoproteinE-deficient mice consumed a high-fat diet were used and treated with acrolein (3 mg/kg/day) in the drinking water for 12 weeks. Upregulation of MMP9, and downregulation of Clock and Bmal1 were also observed in plasma of the mice. Besides, acrolein feeding altered gut microbiota composition at a phylum level especially for an increased Firmicutes and a decreased Bacteroidetes. Additionally, gut microbiota showed correlation with atherosclerotic plaque, MMP9 and Bmal1 levels. Therefore, our findings indicated that acrolein increased the expression of MMP9 through MAPK regulating circadian clock, which was associated with gut microbiota regulation in atherosclerosis. Circadian rhythms and gut microbiota might be promising targets in the prevention of cardiovascular disease caused by environmental pollutants.


Assuntos
Fatores de Transcrição ARNTL/sangue , Aterosclerose/patologia , Proteínas CLOCK/sangue , Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Fatores de Transcrição ARNTL/genética , Acroleína , Adulto , Animais , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Proteínas CLOCK/genética , Linhagem Celular , Relógios Circadianos/fisiologia , Dieta Hiperlipídica , Regulação para Baixo , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Knockout
6.
PLoS Biol ; 17(7): e3000360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306430

RESUMO

The evidence that diel patterns of physiology and behaviour in mammals are governed by circadian 'clocks' is based almost entirely on studies of nocturnal rodents. The emergent circadian paradigm, however, neglects the roles of energy metabolism and alimentary function (feeding and digestion) as determinants of activity pattern. The temporal control of activity varies widely across taxa, and ungulates, microtine rodents, and insectivores provide examples in which circadian timekeeping is vestigial. The nocturnal rodent/human paradigm of circadian organisation is unhelpful when considering the broader manifestation of activity patterns in mammals.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Mamíferos/fisiologia , Animais , Evolução Biológica , Humanos , Mamíferos/classificação , Mamíferos/metabolismo , Roedores/classificação , Roedores/metabolismo , Roedores/fisiologia , Especificidade da Espécie , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiologia
7.
Int J Mol Sci ; 20(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195684

RESUMO

The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.


Assuntos
Relógios Circadianos/fisiologia , Rim/fisiologia , Adenina , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Núcleo Supraquiasmático/fisiopatologia
8.
Genes (Basel) ; 10(7)2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252693

RESUMO

The sea slug Onchidium reevesii inhabits the intertidal zone, which is characterized by a changeable environment. Although the circadian modulation of long-term memory (LTM) is well documented, the interaction of the circadian clock with light-dark masking in LTM of intertidal animals is not well understood. We characterized the LTM of Onchidium and tested the expression levels of related genes under a light-dark (LD) cycle and constant darkness (i.e., dark-dark, or DD) cycle. Results indicated that both learning behavior and LTM show differences between circadian time (CT) 10 and zeitgeber time (ZT) 10. In LD, the cry1 gene expressed irregularly, and per2 expression displayed a daily pattern and a peak expression level at ZT 18. OnCREB1 (only in LD conditions) and per2 transcripts cycled in phase with each other. In DD, the cry1 gene had its peak expression at CT 10, and per2 expressed its peak level at CT 18. OnCREB1 had two peak expression levels at ZT 10 or ZT 18 which correspond to the time node of peaks in cry1 and per2, respectively. The obtained results provide an LTM pattern that is different from other model species of the intertidal zone. We conclude that the daily transcriptional oscillations of Onchidium for LTM were affected by circadian rhythms and LD cycle masking.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Gastrópodes/metabolismo , Memória de Longo Prazo/fisiologia , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Criptocromos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Escuridão , Gastrópodes/genética , Proteínas Circadianas Period/metabolismo , Fotoperíodo
9.
Nat Commun ; 10(1): 2543, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186426

RESUMO

The circadian clock is known to regulate plant innate immunity but the underlying mechanism of this regulation remains largely unclear. We show here that mutations in the core clock component LUX ARRHYTHMO (LUX) disrupt circadian regulation of stomata under free running and Pseudomonas syringae challenge conditions as well as defense signaling mediated by SA and JA, leading to compromised disease resistance. RNA-seq analysis reveals that both clock- and defense-related genes are regulated by LUX. LUX binds to clock gene promoters that have not been shown before, expanding the clock gene networks that require LUX function. LUX also binds to the promoters of EDS1 and JAZ5, likely acting through these genes to affect SA- and JA-signaling. We further show that JA signaling reciprocally affects clock activity. Thus, our data support crosstalk between the circadian clock and plant innate immunity and imply an important role of LUX in this process.


Assuntos
Arabidopsis/genética , Relógios Circadianos/genética , Imunidade Vegetal/genética , Arabidopsis/microbiologia , Relógios Circadianos/fisiologia , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas , Mutação , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Estômatos de Plantas/fisiologia , Pseudomonas syringae/fisiologia , Análise de Sequência de RNA
10.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248072

RESUMO

Autonomous endogenous time-keeping is ubiquitous across many living organisms, known as the circadian clock when it has a period of about 24 h. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungus Neurospora crassa is a well-established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock of Neurospora is composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex, which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics, we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedback among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 h. Our model reveals a switch between WC1-induced transcription and FFC-assisted inactivation of WC1. Using the new model, we also study the possible mechanisms of glucose compensation. A fairly simple model with just three nonlinearities helps to elucidate clock dynamics, revealing a mechanism of rhythms' production. The model can further be utilized to study entrainment and temperature compensation.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Modelos Biológicos , Neurospora/fisiologia
11.
Yale J Biol Med ; 92(2): 169-178, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249477

RESUMO

Four inter-related measures of phase are described to study the phase synchronization of cellular oscillators, and computation of these measures is described and illustrated on single cell fluorescence data from the model filamentous fungus, Neurospora crassa. One of these four measures is the phase shift ϕ in a sinusoid of the form x(t) = A(cos(ωt + ϕ), where t is time. The other measures arise by creating a replica of the periodic process x(t) called the Hilbert transform x̃(t), which is 90 degrees out of phase with the original process x(t). The second phase measure is the phase angle FH (t) between the replica x̃(t) and x(t), taking values between -π and π. At extreme values the Hilbert Phase is discontinuous, and a continuous form FC (t) of the Hilbert Phase is used, measuring time on the nonnegative real axis (t). The continuous Hilbert Phase FC (t) is used to define the phase MC (t 1 ,t 0 ) for an experiment beginning at time t 0 and ending at time t 1. In that phase differences at time t 0 are often of ancillary interest, the Hilbert Phase FC (t 0 ) is subtracted from FC (t 1 ). This difference is divided by 2π to obtain the phase MC (t 1 ,t 0 ) in cycles. Both the Hilbert Phase FC (t) and the phase MC (t 1 ,t 0 ) are functions of time and useful in studying when oscillators phase-synchronize in time in signal processing and circadian rhythms in particular. The phase of cellular clocks is fundamentally different from circadian clocks at the macroscopic scale because there is an hourly cycle superimposed on the circadian cycle.


Assuntos
Relógios Biológicos/fisiologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Neurospora crassa/fisiologia , Análise de Célula Única/métodos , Algoritmos , Relógios Biológicos/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Medições Luminescentes/métodos , Modelos Biológicos , Neurospora crassa/citologia , Neurospora crassa/metabolismo , Processos Estocásticos , Fatores de Tempo
12.
Yale J Biol Med ; 92(2): 187-199, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249479

RESUMO

The activity/rest rhythm of mammals reflects the output of an endogenous circadian oscillator entrained to the solar day by light. Despite detailed understanding of the neural and molecular bases of mammalian rhythms, we still lack practical tools for achieving rapid and flexible adjustment of clocks to accommodate shift-work, trans-meridian jet travel, or space exploration. Efforts to adapt clocks have focused on resetting the phase of an otherwise unaltered circadian clock. Departing from this tradition, recent work has demonstrated that bifurcation of circadian waveform in mice facilitates entrainment to extremely long and short zeitgeber periods. Here we evaluate the formal nature of entrainment to extreme non-24 h days in male Syrian hamsters. Wheel-running rhythms were first bifurcated into a 24 h rest/activity/rest/activity cycle according to established methods. Thereafter the 24 h lighting cycle was incrementally adjusted over several weeks to 30 h or to 18 h. Almost without exception, wheel-running rhythms of hamsters in gradually lengthened or shortened zeitgebers remained synchronized with the lighting cycle, with greater temporal precision observed in the former condition. Data from animals transferred abruptly from 24 h days to long or short cycles suggested that gradual adaptation facilitates but is not necessary for successful behavioral entrainment. The unprecedented behavioral adaptation following waveform bifurcation reveals a latent plasticity in mammalian circadian systems that can be realized in the absence of pharmacological or genetic manipulations. Oscillator interactions underlying circadian waveform manipulation, thus, represent a tractable target for understanding and enhancing circadian rhythm resetting.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Mesocricetus/fisiologia , Atividade Motora/efeitos da radiação , Adaptação Fisiológica/fisiologia , Adaptação Fisiológica/efeitos da radiação , Animais , Cricetinae , Luz , Masculino , Camundongos , Atividade Motora/fisiologia , Fotoperíodo , Fatores de Tempo
13.
Yale J Biol Med ; 92(2): 225-231, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249483

RESUMO

From bacteria to mammals, nearly all organisms have adapted their physiology and behavior to a daily rhythm. These circadian (daily) rhythms influence virtually all aspects of physiological architecture (i.e., from gene expression to organismal behavior). Therefore, it is not surprising that several features of the immune response are regulated in a time-of-day dependent manner. The field of chrono-immunology has expanded tremendously over the past decade. In this abridged review, we present studies from the past five years that have revealed new parameters of the immune system that demonstrate daily variations in the control of pathogens and response to microbial components. These studies analyzed how the disruption of circadian rhythms impairs immune function, how microbial components alter the circadian clock, and how immune responses demonstrate daily variations in human subjects. Further elucidating the intricate connections between the circadian clock and the immune system will hopefully provide opportunities for chrono-immunotherapy in disease treatment and prevention.


Assuntos
Relógios Circadianos/imunologia , Ritmo Circadiano/imunologia , Sistema Imunitário/imunologia , Mamíferos/imunologia , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/imunologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Sistema Imunitário/microbiologia , Sistema Imunitário/parasitologia , /parasitologia , Mamíferos/microbiologia , Mamíferos/parasitologia
14.
Yale J Biol Med ; 92(2): 233-240, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249484

RESUMO

Circadian rhythms control many biochemical and physiological functions within the body of an organism. These circadian rhythms are generated by a molecular clock that is located in almost every cell of the body. Accumulating data indicate that dysfunction of the circadian clock negatively affects the health status of the tissue in which the circadian clock has been disabled. The eye also contains a complex circadian system that regulates many important functions such as the processing of light information, the release of neurotransmitters, and phagocytic activity by the retinal pigment epithelium, to name just a few. Emerging experimental evidence indicates that dysfunction of the circadian clock within the retina has severe consequence for retinal function and photoreceptor viability. The aim of this review is to provide the reader with a summary of current knowledge about the eye circadian system and what effects emerge with a disruption of this system.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/fisiologia , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Biológicos
15.
Yale J Biol Med ; 92(2): 241-250, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249485

RESUMO

Circadian clocks drive biological rhythms in physiology and behavior, providing a selective advantage by enabling organisms to synchronize to the 24 h environmental day. This process depends on light-dark transitions as the main signal that shifts the phase of the clock. In mammals, the light input reaches the master circadian clock in the hypothalamic suprachiasmatic nucleus through glutamatergic afferents from the retina, resulting in phase-shifts of the overt rhythms which depend on the time of the day at which light is applied, leading to changes in the activity of circadian core clock genes (i.e., Per1). This circadian gating of the synchronizing effect of light is dependent on the specific activation of signal transduction pathways involving several kinases acting on protein effectors. Protein phosphorylation is also an important regulatory mechanism essential for the generation and maintenance of circadian rhythms and plays a crucial role in the degradation and the appropriate turnover of PER proteins. In this work, we review the role of the main kinases implicated in the function of the master clock, with emphasis in those involved in circadian photic entrainment.


Assuntos
Relógios Circadianos/fisiologia , Transdução de Sinal Luminoso/fisiologia , Mamíferos/fisiologia , Proteínas Quinases/metabolismo , Animais , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Luz , Mamíferos/genética , Mamíferos/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fosforilação/efeitos da radiação
16.
Yale J Biol Med ; 92(2): 251-258, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249486

RESUMO

Bmal1 is the only single circadian clock gene that is essential for rhythmic gene expression in the mammalian circadian timing system. Genetic approaches targeting Bmal1 expression have been used to further assess its role in the circadian clock and to test for behavioral effects of clock disruption. In particular, disruptions in circadian clock function have been implicated in human mood disorders, and clock gene manipulation in mice may provide valuable models for studying depression-like behavior. In this review, we explore various approaches to manipulating Bmal1 in mouse models and review their effects on the brain's master circadian pacemaker, on circadian rhythmicity in other brain regions, and on circadian and mood-related behavior.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Encéfalo/fisiologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Fatores de Transcrição ARNTL/genética , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos Knockout , Modelos Biológicos , Fatores de Tempo
17.
Yale J Biol Med ; 92(2): 259-270, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249487

RESUMO

Circadian disruption has been linked to markers for poor health outcomes in humans and animal models. What is it about circadian disruption that is problematic? One hypothesis is that phase resetting of the circadian system, which occurs in response to changes in environmental timing cues, leads to internal desynchrony within the organism. Internal desynchrony is understood as acute changes in phase relationships between biological rhythms from different cell groups, tissues, or organs within the body. Do we have strong evidence for internal desynchrony associated with or caused by circadian clock resetting? Here we review the literature, highlighting several key studies from measures of gene expression in laboratory rodents. We conclude that current evidence offers strong support for the premise that some protocols for light-induced resetting are associated with internal desynchrony. It is important to continue research to test whether internal desynchrony is necessary and/or sufficient for negative health impact of circadian disruption.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Periodicidade , Fotoperíodo , Animais , Relógios Circadianos/genética , Relógios Circadianos/efeitos da radiação , Ritmo Circadiano/genética , Ritmo Circadiano/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Luz , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiopatologia , Núcleo Supraquiasmático/efeitos da radiação
18.
Yale J Biol Med ; 92(2): 271-281, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249488

RESUMO

Circadian rhythms, or biological oscillations of approximately 24 hours, impact almost all aspects of our lives by regulating the sleep-wake cycle, hormone release, body temperature fluctuation, and timing of food consumption. The molecular machinery governing these rhythms is similar across organisms ranging from unicellular fungi to insects, rodents, and humans. Circadian entrainment, or temporal synchrony with one's environment, is essential for survival. In mammals, the central circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and mediates entrainment to environmental conditions. While the light:dark cycle is the primary environmental cue, arousal-inducing, non-photic signals such as food consumption, exercise, and social interaction are also potent synchronizers. Many of these stimuli enhance dopaminergic signaling suggesting that a cohesive circadian physiology depends on the relationship between circadian clocks and the neuronal circuits responsible for detecting salient events. Here, we review the inner workings of mammalian circadian entrainment, and describe the health consequences of circadian rhythm disruptions with an emphasis on dopamine signaling.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Transdução de Sinais/fisiologia , Núcleo Supraquiasmático/fisiopatologia , Animais , Dopamina/metabolismo , Humanos , Fotoperíodo , Núcleo Supraquiasmático/metabolismo
19.
Yale J Biol Med ; 92(2): 283-290, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249489

RESUMO

The cardiovascular (CV) system has been established to be significantly influenced by the molecular components of circadian rhythm. Oscillations of circadian rhythm occur within the circulation to affect thrombosis and blood pressure and within CV tissues including arteries, heart, and kidney to control function. Physiologic and molecular oscillations of circadian rhythm have been well connected via global, tissue-specific, and transgenic reporter mouse models of key core clock signals such as Bmal1, Period, and Clock, which can produce both pathology and protection with their mutation. With different nuances of CV clock action continuing to emerge in studies of the cardiovascular system, new questions are raised in both new and old mouse model system observations that underscore the importance, complexity, and continued study of the circadian clock mechanism in cardiovascular disease.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Relógios Circadianos/fisiologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/fisiologia , Ritmo Circadiano/fisiologia , Animais , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiologia , Relógios Circadianos/genética , Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação da Expressão Gênica , Humanos
20.
Yale J Biol Med ; 92(2): 291-303, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249490

RESUMO

Huntington's disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Doença de Huntington/fisiopatologia , Disautonomias Primárias/fisiopatologia , Animais , Humanos , Hipotálamo Anterior/fisiopatologia , Modelos Biológicos , Doenças Neurodegenerativas/fisiopatologia , Fatores de Tempo
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