RESUMO
Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms. Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations in epithelial STAT3 expression and activation that produced rhythmic antimicrobial protein expression and caused resistance to Salmonella Typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal , Imunidade Inata , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Aderência Bacteriana , Adesão Celular , Células Epiteliais/microbiologia , Comportamento Alimentar , Intestino Delgado/microbiologia , Intestino Delgado/ultraestrutura , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Muramidase/metabolismo , Proteínas Associadas a Pancreatite/metabolismo , Fator de Transcrição STAT3/metabolismo , Salmonelose Animal/microbiologia , Transdução de SinaisRESUMO
Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
Assuntos
Doença de Crohn/microbiologia , Células Epiteliais/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidade Classe II/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Transcriptoma/genética , Animais , Antibacterianos/farmacologia , Relógios Circadianos/fisiologia , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Dieta , Células Epiteliais/citologia , Células Epiteliais/imunologia , Citometria de Fluxo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Homeostase , Hibridização in Situ Fluorescente , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Intestino Delgado/fisiologia , Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Periodicidade , Linfócitos T/imunologia , Transcriptoma/fisiologiaRESUMO
Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.
Assuntos
Fatores de Transcrição ARNTL/fisiologia , Relógios Circadianos/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Comportamento Alimentar/fisiologia , Feminino , Homeostase , Luz , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Especificidade de Órgãos/fisiologia , Fotoperíodo , Núcleo Supraquiasmático/metabolismoRESUMO
Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to â¼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.
Assuntos
Fatores de Transcrição ARNTL/fisiologia , Relógios Circadianos/genética , Fígado/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Feminino , Regulação da Expressão Gênica , Homeostase , Luz , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Especificidade de Órgãos/fisiologia , Fotoperíodo , Núcleo Supraquiasmático/metabolismoRESUMO
In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal â¼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.
Assuntos
Relógios Circadianos/fisiologia , Comportamento Alimentar/fisiologia , Proteínas Circadianas Period/metabolismo , Animais , Ritmo Circadiano/fisiologia , Feminino , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Mamíferos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor IGF Tipo 1/metabolismo , Transdução de SinaisRESUMO
Diverse factors including metabolism, chromatin remodeling, and mitotic kinetics influence development at the cellular level. These factors are well known to interact with the circadian transcriptional-translational feedback loop (TTFL) after its emergence. What is only recently becoming clear, however, is how metabolism, mitosis, and epigenetics may become organized in a coordinated cyclical precursor signaling module in pluripotent cells prior to the onset of TTFL cycling. We propose that both the precursor module and the TTFL module constrain cellular identity when they are active during development, and that the emergence of these modules themselves is a key lineage marker. Here we review the component pathways underlying these ideas; how proliferation, specification, and differentiation decisions in both developmental and adult stem cell populations are or are not regulated by the classical TTFL; and emerging evidence that we propose implies a primordial clock that precedes the classical TTFL and influences early developmental decisions.
Assuntos
Relógios Circadianos/fisiologia , Desenvolvimento Embrionário , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Linhagem da Célula/genética , Relógios Circadianos/genética , Desenvolvimento Embrionário/genética , Epigênese Genética , Humanos , Fatores de TempoRESUMO
Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.
Assuntos
Relógios Circadianos/fisiologia , Metaboloma , Animais , Dieta Hiperlipídica , Metabolismo Energético , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Córtex Pré-Frontal/metabolismo , Núcleo Supraquiasmático/metabolismo , Proteína Desacopladora 1/metabolismoRESUMO
Neurons use two main schemes to encode information: rate coding (frequency of firing) and temporal coding (timing or pattern of firing). While the importance of rate coding is well established, it remains controversial whether temporal codes alone are sufficient for controlling behavior. Moreover, the molecular mechanisms underlying the generation of specific temporal codes are enigmatic. Here, we show in Drosophila clock neurons that distinct temporal spike patterns, dissociated from changes in firing rate, encode time-dependent arousal and regulate sleep. From a large-scale genetic screen, we identify the molecular pathways mediating the circadian-dependent changes in ionic flux and spike morphology that rhythmically modulate spike timing. Remarkably, the daytime spiking pattern alone is sufficient to drive plasticity in downstream arousal neurons, leading to increased firing of these cells. These findings demonstrate a causal role for temporal coding in behavior and define a form of synaptic plasticity triggered solely by temporal spike patterns.
Assuntos
Plasticidade Neuronal , Sono/fisiologia , Potenciais de Ação , Animais , Relógios Circadianos/fisiologia , Drosophila , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Modelos Neurológicos , Neurônios/metabolismo , Optogenética , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Transmissão SinápticaRESUMO
To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep-wake cycles but also a host of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.
Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Animais , Relógios Circadianos/fisiologia , Drosophila melanogaster/fisiologia , Humanos , Mamíferos/fisiologiaRESUMO
Humans, like all mammals, partition their daily behaviour into activity (wakefulness) and rest (sleep) phases that differ largely in their metabolic requirements. The circadian clock evolved as an autonomous timekeeping system that aligns behavioural patterns with the solar day and supports the body functions by anticipating and coordinating the required metabolic programmes. The key component of this synchronization is a master clock in the brain, which responds to light-darkness cues from the environment. However, to achieve circadian control of the entire organism, each cell of the body is equipped with its own circadian oscillator that is controlled by the master clock and confers rhythmicity to individual cells and organs through the control of rate-limiting steps of metabolic programmes. Importantly, metabolic regulation is not a mere output function of the circadian system, but nutrient, energy and redox levels signal back to cellular clocks in order to reinforce circadian rhythmicity and to adapt physiology to temporal tissue-specific needs. Thus, multiple systemic and molecular mechanisms exist that connect the circadian clock with metabolism at all levels, from cellular organelles to the whole organism, and deregulation of this circadian-metabolic crosstalk can lead to various pathologies.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Animais , Encéfalo/fisiologia , Humanos , Mamíferos/fisiologiaRESUMO
Research into the molecular mechanisms of eukaryotic circadian clocks has proceeded at an electrifying pace. In this review, we discuss advances in our understanding of the structures of central molecular players in the timing oscillators of fungi, insects, and mammals. A series of clock protein structures demonstrate that the PAS (Per/Arnt/Sim) domain has been used with great variation to formulate the transcriptional activators and repressors of the clock. We discuss how posttranslational modifications and external cues, such as light, affect the conformation and function of core clock components. Recent breakthroughs have also revealed novel interactions among clock proteins and new partners that couple the clock to metabolic and developmental pathways. Overall, a picture of clock function has emerged wherein conserved motifs and structural platforms have been elaborated into a highly dynamic collection of interacting molecules that undergo orchestrated changes in chemical structure, conformational state, and partners.
Assuntos
Proteínas CLOCK/fisiologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Animais , Bovinos , Drosophila , Fungos/fisiologia , Glicosilação , Humanos , Insetos/fisiologia , Luz , Fosforilação , Fotoquímica/métodos , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Rodopsina/fisiologia , Opsinas de Bastonetes/fisiologia , Transdução de Sinais , Transcrição GênicaRESUMO
An intrinsic cellular circadian clock is located in nearly every cell of the body. The peripheral circadian clocks within the cells of the kidney contribute to the regulation of a variety of renal processes. In this review, we summarize what is currently known regarding the function, mechanism, and regulation of kidney clocks. Additionally, the effect of extrarenal physiological processes, such as endocrine and neuronal signals, on kidney function is also reviewed. Circadian rhythms in renal function are an integral part of kidney physiology, underscoring the importance of considering time of day as a key biological variable. The field of circadian renal physiology is of tremendous relevance, but with limited physiological and mechanistic information on the kidney clocks this is an area in need of extensive investigation.
Assuntos
Relógios Circadianos , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Sistema Endócrino , Humanos , Rim/fisiologiaRESUMO
Circadian rhythms influence many behaviours and diseases1,2. They arise from oscillations in gene expression caused by repressor proteins that directly inhibit transcription of their own genes. The fly circadian clock offers a valuable model for studying these processes, wherein Timeless (Tim) plays a critical role in mediating nuclear entry of the transcriptional repressor Period (Per) and the photoreceptor Cryptochrome (Cry) entrains the clock by triggering Tim degradation in light2,3. Here, through cryogenic electron microscopy of the Cry-Tim complex, we show how a light-sensing cryptochrome recognizes its target. Cry engages a continuous core of amino-terminal Tim armadillo repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal Tim helix, reminiscent of the interactions between light-insensitive cryptochromes and their partners in mammals. The structure highlights how the Cry flavin cofactor undergoes conformational changes that couple to large-scale rearrangements at the molecular interface, and how a phosphorylated segment in Tim may impact clock period by regulating the binding of Importin-α and the nuclear import of Tim-Per4,5. Moreover, the structure reveals that the N terminus of Tim inserts into the restructured Cry pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the long-short Tim polymorphism adapts flies to different climates6,7.
Assuntos
Relógios Circadianos , Ritmo Circadiano , Criptocromos , Proteínas de Drosophila , Drosophila melanogaster , Animais , Relógios Circadianos/fisiologia , Relógios Circadianos/efeitos da radiação , Ritmo Circadiano/fisiologia , Ritmo Circadiano/efeitos da radiação , Criptocromos/química , Criptocromos/metabolismo , Criptocromos/ultraestrutura , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/efeitos da radiação , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/ultraestrutura , Luz , Mamíferos/metabolismo , Microscopia Crioeletrônica , Transporte Ativo do Núcleo Celular/efeitos da radiação , alfa Carioferinas/metabolismoRESUMO
In our 24/7 well-lit world, it's easy to skip or delay sleep to work, study, and play. However, our circadian rhythms are not easily fooled; the consequences of jet lag and shift work are many and severe, including metabolic, mood, and malignant disorders. The internal clock that keeps track of time has at its heart the reversible phosphorylation of the PERIOD proteins, regulated by isoforms of casein kinase 1 (CK1). In-depth biochemical, genetic, and structural studies of these kinases, their mutants, and their splice variants have combined over the past several years to provide a robust understanding of how the core clock is regulated by a phosphoswitch whereby phosphorylation of a stabilizing site on PER blocks phosphorylation of a distant phosphodegron. The recent structure of a circadian mutant form of CK1 implicates an internal activation loop switch that regulates this phosphoswitch and points to new approaches to regulation of the clock.
Assuntos
Caseína Quinase I/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Proteínas Circadianas Period/metabolismo , Animais , Caseína Quinase I/genética , Humanos , Proteínas Circadianas Period/genética , Fosforilação/fisiologiaRESUMO
It has been assumed that the suprachiasmatic nucleus (SCN) synchronizes peripheral circadian oscillators. However, this has never been convincingly shown, since biochemical time series experiments are not feasible in behaviorally arrhythmic animals. By using long-term bioluminescence recording in freely moving mice, we show that the SCN is indeed required for maintaining synchrony between organs. Surprisingly, however, circadian oscillations persist in the livers of mice devoid of an SCN or oscillators in cells other than hepatocytes. Hence, similar to SCN neurons, hepatocytes can maintain phase coherence in the absence of Zeitgeber signals produced by other organs or environmental cycles.
Assuntos
Relógios Circadianos/fisiologia , Hepatócitos/fisiologia , Núcleo Supraquiasmático/fisiologia , Animais , Relógios Circadianos/genética , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Supraquiasmático/cirurgiaRESUMO
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Proteínas Circadianas Period/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores Etários , Envelhecimento/genética , Animais , Proteínas CLOCK/genética , Ritmo Circadiano/fisiologia , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD/metabolismo , Proteínas Circadianas Period/genética , Sirtuína 1/metabolismo , Sirtuínas/metabolismoRESUMO
The amplitude of circadian rhythms dampens with age, but Levine et al. (2020) now show that nicotinamide adenine dinucleotide (NAD+) can restore robust circadian gene expression and behavior in aged mice through SIRT1-dependent deacetylation of the core clock protein PER2.
Assuntos
Ritmo Circadiano/genética , Proteínas Circadianas Period/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores Etários , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Citocinas/metabolismo , Humanos , Camundongos , NAD/metabolismo , Proteínas Circadianas Period/genética , Sirtuína 1/metabolismo , Sirtuínas/metabolismoRESUMO
The circadian clock throughout the day organizes the activity of neural stem cells (NSCs) in the dentate gyrus (DG) of adult hippocampus temporally. However, it is still unclear whether and how circadian signals from the niches contribute to daily rhythmic variation of NSC activation. Here, we show that norepinephrinergic (NEergic) projections from the locus coeruleus (LC), a brain arousal system, innervate into adult DG, where daily rhythmic release of norepinephrine (NE) from the LC NEergic neurons controlled circadian variation of NSC activation through ß3-adrenoceptors. Disrupted circadian rhythmicity by acute sleep deprivation leads to transient NSC overactivation and NSC pool exhaustion over time, which is effectively ameliorated by the inhibition of the LC NEergic neuronal activity or ß3-adrenoceptors-mediated signaling. Finally, we demonstrate that NE/ß3-adrenoceptors-mediated signaling regulates NSC activation through molecular clock BMAL1. Therefore, our study unravels that adult NSCs precisely coordinate circadian neural circuit and intrinsic molecular circadian clock to adapt their cellular behavior across the day.
Assuntos
Relógios Circadianos , Células-Tronco Neurais , Humanos , Adulto , Ritmo Circadiano/fisiologia , Hipocampo , Relógios Circadianos/fisiologia , Receptores AdrenérgicosRESUMO
Time-restricted feeding (RF) is known to shift the phasing of gene expression in most primary metabolic tissues, whereas a time misalignment between the suprachiasmatic nucleus circadian clock (SCNCC) and its peripheral CCs (PCC's) is known to induce various pathophysiological conditions, including a metabolic syndrome. We now report that a unique "light therapy," involving different light intensities (TZT0-ZT12150-TZT0-ZT12700 lx, TZT0-ZT1275-TZT0-ZT12150 lx, and TZT0-ZT12350-TZT0-ZT12700 lx), realigns the RF-generated misalignment between the SCNCC and the PCC's. Using such high-light regime, we show that through shifting the SCNCC and its activity, it is possible in a RF and "night-shifted mouse model" to prevent/correct pathophysiologies (e.g., a metabolic syndrome, a loss of memory, cardiovascular abnormalities). Our data indicate that such a "high-light regime" could be used as a unique chronotherapy, for those working on night shifts or suffering from jet-lag, in order to realign their SCNCC and PCC's, thereby preventing the generation of pathophysiological conditions.