Biology subjects

Takahashi, J. S.

Publications and source records attributed to Takahashi, J. S..

18 recordsLinked to original sources

bioRxiv2026

Ascorbate and TET2 couple balanced hematopoiesis to disease tolerance

Infections stimulate myelopoiesis but this comes at the cost of reduced production of other lineages. It is unclear if this imbalance is protective or damaging, and if factors that promote balanced hematopoiesis can impact infection pathology. Here we show that the ascorbate-TET axis limits excessive myelopoiesis, promotes balanced hematopoiesis, and is essential for surviving malaria. Hematopoietic-specific ascorbate depletion promoted myelopoiesis. The effects of ascorbate were mediated by TET2/TET3 activity in myeloid progenitors. Combined ascorbate and TET2 depletion markedly skewed hematopoiesis to the myeloid lineage and impaired erythropoiesis. Ascorbate is commonly depleted in infections, but the functional significance of this remains unclear. In the absence of ascorbate and TET2, mice infected with Plasmodium parasites could clear the pathogen, but had exacerbated myeloid and impaired erythroid response, anemia, and tissue damage and they succumbed to infection, indicating compromised disease tolerance. Therefore ascorbate and TET2 promote balanced hematopoiesis to impart tolerance to malaria.

immunology↗

bioRxiv2026

Mice sense Moon and Sun

Life on earth has always been exposed to the fluctuating Earth's magnetic field, but a magnetic sense affecting behavior has been debated for mammals. We here report that mice, kept under constant laboratory conditions, showed fluctuations in spontaneous behavioral activity with a periodicity of ~14 and ~28 days. This was confirmed in nine cohorts from four facilities on two continents, covering 3 to 41 months. Such oscillations were also maintained in brain Bmal1 knockout mice lacking circadian rhythms, suggesting independence of the circadian clock. The behavioral activity peaked around full and new Moon, and showed a strong alignment with the periodic geomagnetic fluctuations originating in the Earth's iono- and magnetosphere that are modulated by solar rotation and the orbital motion of the Moon. In the ultradian range, this alignment persisted in CRY1/2 knockout mice, suggesting that solar-lunar-driven geomagnetic fluctuations can modulate behavior rhythms independently of CRY1/2.

neuroscience↗

bioRxiv2026

Nocturnin drives mitochondrial NADP(H)/NAD(H) rhythms to regulate steroid rhythm amplitude and time metabolism

Circadian rhythms are conserved biological timekeeping mechanisms crucial for the temporal compartmentalization of metabolic processes. However, the molecular pathways by which circadian rhythms are regulated within metabolism are not fully understood. Nocturnin (NOCT) is a highly rhythmic, clock-controlled NADP(H) phosphatase that has been implicated in numerous metabolic phenotypes. While it is known that NOCT significantly impacts the cellular NADP(H) and NAD(H) pools in vitro, NOCTs impact on their concentrations and rhythmicity in vivo has not yet been established. In fact, the rhythmicity of NADH, NADP+, and NADPH have yet to be quantified in mammalian nucleated cells. Here, we determined both the whole cell and mitochondrial NAD(H) and NADP(H) rhythms in wild-type and Noct-/-mouse livers. Unexpectedly, we found a robust rhythm in the mitochondrial NADP(H)/NAD(H) ratio that is antiphase to the respective whole cell rhythm. While loss of NOCT increases the amplitude of the whole cell NADP(H)/NAD(H) rhythm, the mitochondrial rhythm is completely damped in Noct-/-mice. The constitutively higher relative NADP(H) within Noct-/-mitochondria drives steroidogenesis, leading to an increased amplitude of plasma corticosterone. Both the acute increase in plasma corticosterone and the disruption of mitochondrial cofactor rhythms caused by loss of NOCT lead to widespread changes in hepatic metabolism. Collectively, we found that NOCTs control of mitochondrial NADP(H)/NAD(H) rhythms is a novel regulator of steroid amplitude and downstream metabolic rhythms.

physiology↗

bioRxiv2026

Two Stages of Dynamic Metabolic and Transcriptomic Remodeling During the Adaptation to Caloric Restriction in Male C57BL/6J

The molecular basis of caloric restriction (CR) has been defined primarily at a metabolic steady state, leaving the initiating events that drive the transition from ad libitum feeding to an adapted CR state largely unresolved. Here, we combine continuous indirect calorimetry with longitudinal bulk RNA-seq of liver and inguinal white adipose tissue (iWAT) sampled at six circadian timepoints across four stages of adaptation to 30% CR in male C57BL/6J mice. We show that whole-body metabolic adaptation proceeds through two discrete adaptive phases separated by a threshold at approximately 14 days; during this initial transition, consolidated feeding attenuates ketogenesis, establishing a distinct whole-body metabolic phenotype prior to long-term adaptation. To elucidate the molecular mechanisms underlying these physiological shifts, weighted gene co-expression network analysis (WGCNA) was performed, revealing that hepatic transcriptional remodeling is organized proportionally to fasting duration, whereas iWAT remodeling remains restricted to specific circadian timepoints. Because systemic adaptation requires coordinated inter-tissue communication, we conducted a cartographic analysis to evaluate network topology and inter-modular connectivity. This approach identifies restricted populations of early kinless and connector hub genes, nucleated by Casp3 in the liver and Lpl in iWAT, whose structural integration is established prior to the broader transcriptional remodeling observed at later timepoints. Functional annotation indicates the hepatic hub network is enriched for mitochondrial bioenergetics and FOXO/TP53-mediated transcription, while the iWAT hub network exhibits a bifurcated enrichment spanning ribosomal biosynthesis and immune-regulatory signaling. Although these tissues exhibit distinct transcriptional profiles, projecting both datasets onto a shared phenotypic eigenspace reveals a unified systemic response; as CR is maintained, dynamically regulated transcripts in both liver and iWAT converge on an adiponectin-coupled state. Ultimately, the identification of adiponectin as an integrative signal coordinating chronic adaptation across metabolically distinct tissues delineates the temporal sequence of early CR adaptation; furthermore, it establishes a mechanistic framework defining how early molecular and physiological shifts converge to achieve steady-state metabolic homeostasis.

systems biology↗

bioRxiv2025

A Novel Cell-Type Specific Circadian Reporter Mouse Reveals Self-Sustained Food Entrainable Nature in Enteric Neurons

Global luciferase reporter gene technology is an important real-time readout for the analysis of circadian oscillations. However, because nearly all cells in the body possess cell-autonomous circadian oscillators, developing cell-type-specific reporter systems is essential to dissect how these oscillators interact within complex multicellular tissues and are modulated by brain-body circadian signals. The intestine is a complex organ composed of diverse cell types with distinct origins and functions, and it exhibits robust daily rhythms in physiological activities driven by intrinsic circadian clocks. While the circadian regulation of the mucosal compartment, including the intestinal epithelium, has been relatively well characterized, the mechanisms governing the circadian rhythms in the cells of the muscularis externa remain largely unexplored. Here, we report a novel Cre-dependent Per2-luciferase reporter mouse that enables precise measurement of circadian oscillations in specific peripheral cell populations ex vivo and demonstrate its utility in revealing the hierarchical circadian chrono-architecture within the intestine. Ex vivo gut explants from mice expressing the reporter in one of five major cell types of the muscularis externa--enteric neurons (ENs), enteric glial cells (EGCs), interstitial cells of Cajal (ICCs), smooth muscle cells (SMCs), and muscularis macrophages (MMs)--exhibited robust, self-sustained circadian bioluminescence rhythms, indicating that all of these cell types possess cell-autonomous circadian oscillators. Notably, ENs in the small intestine entrained more rapidly to feeding schedules than did those in the colon, revealing regional differences in food entrainment among the gut clocks. Moreover, the clocks of ENs, SMCs, and MMs shifted their phase in response to daytime-restricted feeding, whereas ICC clocks remained unaffected even after three weeks of restricted feeding. These findings demonstrate that distinct intestinal cell types possess unique entrainment properties and that feeding rhythms can induce heterogeneous phase shifts within the gut clocks. Given that circadian disruption, such as that caused by shift work, contributes to intestinal disorders, this reporter system could provide a powerful platform to dissect the mechanisms linking intercellular circadian desynchrony to intestinal homeostasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/688705v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@11250fforg.highwire.dtl.DTLVardef@18397f2org.highwire.dtl.DTLVardef@6ccd24org.highwire.dtl.DTLVardef@10fffef_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA cell-type-specific circadian reporter mouse enables dissection of the chronoarchitecture of complex multicellular organs (e.g., the intestine) C_LIO_LIAll five major intestinal cell types contain autonomous circadian oscillators peaking at night C_LIO_LIEnteric neurons in small intestine entrain to feeding cycles faster than that in colon C_LIO_LIInterstitial cells of Cajal in both the small intestine and colon do not entrain to feeding cycles C_LIO_LIChemogenetic activation of enteric neurons mimics food entrainment, shifting their circadian phase. C_LI

neuroscience↗

bioRxiv2025

Timing of immune checkpoint blockade shapes anti-tumor immunity via a clock-dependent chemokine axis

Circadian clocks regulate immunity, yet how they shape the tumor immune microenvironment and influence cancer immunotherapy remains unclear. Here, we show that tumor immune infiltration and immune checkpoint inhibitor efficacy vary by time of day in mice, driven by intrinsic clocks in dendritic cells and CD8+ T cells. Time-of-day modulates the abundance, spatial organization, and cytokine-chemokine production of tumor-infiltrating immune cells. Mechanistically, dendritic cell clocks control expression of Cx3cl1, driving recruitment of CX3CR1+CD8+ T cells and thereby reshaping the tumor immune microenvironment to enhance immunotherapy efficacy. Disruption of this axis abolishes time-of-day-dependent differences in treatment response. These findings identify a circadian mechanism of immune cell recruitment to tumors and provide mechanistic insight into clinical observations linking treatment timing to immunotherapy outcomes. One sentence summaryTime of day determines cancer immunotherapy efficacy through a circadian clock-dependent chemokine axis.

immunology↗

bioRxiv2025

Time-Restricted Feeding Extends Healthspan in Female and Lifespan in Male C57BL/6J Mice

Time-restricted feeding (TRF) aligned with an organisms circadian rhythm has been shown to improve health, but its long-term effects on healthspan and lifespan in mammals, especially under normal dietary conditions, remain unclear. Here, we examined the impact of 12-hour (h) and 8h nightly TRF windows in male and female mice fed regular chow. TRF improved multiple health measures, including behavioral rhythmicity, body weight and composition, frailty, and disease onset. These effects were most pronounced in the 8h-TRF group, which exhibited voluntary caloric restriction in addition to time restriction. A composite Healthspan Index revealed that TRF extended healthspan in both sexes, though the benefits were more prolonged in females relative to their total lifespan. Median lifespan was significantly extended in males under 8h-TRF by 12%, whereas females showed no significant lifespan extension, highlighting sex-specific responses to TRF.

physiology↗

bioRxiv2024

Circadian rhythms mediate malaria transmission potential

Malaria transmission begins when infected female Anopheles mosquitos deposit Plasmodium parasites into the mammalian hosts skin during a bloodmeal. The salivary gland-resident sporozoite parasites migrate to the bloodstream, subsequently invading and replicating within hepatocytes. As Anopheles mosquitos are more active at night, with a 24-hour rhythm, we investigated whether their salivary glands are under circadian control, anticipating bloodmeals and modulating sporozoite biology for host encounters. Here we show that approximately half of the mosquito salivary gland transcriptome, particularly genes essential for efficient bloodmeals such as anti-blood clotting factors, exhibits circadian rhythmic expression. Furthermore, we demonstrate that mosquitoes prefer to feed during nighttime, with the amount of blood ingested varying cyclically throughout the day. Notably, we show a substantial subset of the sporozoite transcriptome cycling throughout the day. These include genes involved in parasite motility, potentially modulating the ability to initiate infection at different times of day. Thus, although sporozoites are typically considered quiescent, our results demonstrate their transcriptional activity, revealing robust daily rhythms of gene expression. Our findings suggest a circadian evolutionary relationship between the vector, parasite and mammalian host that together modulate malaria transmission.

microbiology↗

bioRxiv2023

The circadian molecular clock in the suprachiasmatic nucleus is necessary but not sufficient for fear entrainment in the mouse

Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock. One-Sentence SummaryCyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary but not sufficient for fear-entrainment.

neuroscience↗

bioRxiv2023

An extra-circadian function for human CLOCK in the neocortex

Core circadian-related proteins such as the transcription factor CLOCK are ubiquitously expressed and important for regulating molecular pathways underlying circadian rhythms. Previous work has suggested that CLOCK has evolved human neocortex-specific gene regulation and therefore may have extra-circadian functions. To test this in vivo, we generated a mouse model that recapitulates human cortical expression of CLOCK. The CLOCK humanized (HU) mice show enhanced cognitive flexibility, which is associated with the alteration in spatiotemporal expression of CLOCK. Cell type specific genomic profiling of HU mice identified upregulated genes related to dendritic growth and spine formation in excitatory neurons. Consistent with this result, we found that excitatory neurons in HU mice have increased complexity of dendritic branching and spine density, as well as a greater frequency of excitatory postsynaptic currents, suggesting an increase in neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-induced neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK evolved extra-circadian gains of function via altered spatiotemporal gene expression and these functions may underlie human brain specializations.

neuroscience↗

bioRxiv2022

Extensive Soma-Soma Plate-Like Contact Sites (Ephapses) Connect Suprachiasmatic Nucleus Neurons

AO_SCPLOWBSTRACTC_SCPLOWThe hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for mammalian circadian rhythms. As such, this ensemble of cell-autonomous neuronal oscillators with divergent periods must maintain coordinated oscillations. To investigate ultrastructural features enabling such synchronization, 805 coronal ultrathin sections of mouse SCN tissue were imaged with electron microscopy and aligned into a volumetric stack, from which selected neurons within the SCN core were reconstructed in silica. We found that clustered SCN core neurons were physically connected to each other via multiple large soma-to-soma plate-like contacts. In some cases, a sliver of a glial process was interleaved. These contacts were large, covering on average [~]21% of apposing neuronal somata. It is possible that contacts may be the electrophysiological substrate for synchronization between SCN neurons. Such plate-like contacts may explain why synchronization of SCN neurons is maintained even when chemical synaptic transmission or electrical synaptic transmission via gap junctions is blocked. Such ephaptic contact-mediated synchronization among nearby neurons may therefore underlie the wave-like oscillations of circadian core clock genes and calcium signals observed in the SCN. SO_SCPLOWIGNIFICANCEC_SCPLOWThree-dimensional reconstruction of SCN tissue via serial electron microscopy revealed a novel structural feature of SCN neurons that may account for inter-neuronal synchronization that persists even when usual mechanisms of neuronal communication are blocked. We found that SCN core neurons are connected by multiple soma-soma contact specializations, ultrastructural elements that could enable synchronization of tightly packed neurons organized in clustered networks. This extensive network of plate-like soma-soma contacts among clustered SCN neurons may provide insight into how [~]20,000 autonomous neuronal oscillators with a broad range of intrinsic periods remain synchronized in the absence of ordinary communication modalities, thereby conferring the resilience required for the SCN to function as the mammalian circadian pacemaker.

neuroscience↗

bioRxiv2022

Gut Microbes and the Liver Circadian Clock Partition Glucose and Lipid Metabolism

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes also exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we show hierarchical, bi-directional communication between the liver circadian clock, gut microbes, and glucose homeostasis in mice. The liver clock, but not the forebrain clock, requires gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expands proportions and abundances of oscillating microbial features by two-fold relative to controls. The liver clock is the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provide secondary cues that dampen these rhythms, resulting in reduced utilization of lipids as fuel relative to carbohydrates. Together, the liver clock transduces signals from gut microbes necessary to regulate glucose and lipid metabolism and meet energy demands over 24 hours. HighlightsThe liver circadian clock is autonomous from the central clock in metabolic regulation Liver clock and gut microbes interact to direct hepatic glucose and lipid metabolism Reciprocating host-microbe interactions drive rhythmic hepatic transcription Perturbed liver Bmal1 results in chaotic downstream oscillators and metabolism

physiology↗

bioRxiv2020

Natural Antisense Transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock

Circadian transcriptome studies identified a novel transcript at the Period2 (Per2) locus, which we named Per2AS. Per2AS is a long non-coding RNA transcribed from the antisense strand of Per2, and is expressed rhythmically and anti-phasic to Per2 mRNA. Previously, we mathematically tested the hypothesis that Per2AS and Per2 mutually inhibit each others expression by forming a double negative feedback loop, and found that Per2AS expands the oscillatory domain. In this study, we have experimentally tested this prediction by perturbing the expression of Per2AS in mouse fibroblasts. We found that Per2AS represses Per2 pre-transcriptionally in cis and regulates the amplitude of the circadian clock, but not period or phase. Unexpectedly, we also found that Per2 positively regulates Per2AS post-transcriptionally, indicating that Per2AS and Per2 form a single negative feedback loop. Because knock-down of Per2 does not recapitulate the phenotypes of Per2AS perturbation and Per2AS also activates Bmal1 in trans, we propose that Per2AS regulates the amplitude of the circadian clock without producing a protein by rewiring the molecular clock circuit.

molecular biology↗

bioRxiv2020

An essential role for MEF2C in the cortical response to loss of sleep

Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function. One Sentence SummaryMEF2C is critical to the response to sleep loss.

neuroscience↗

bioRxiv2019

CNOT1 mediates phosphorylation via Protein kinase A on the circadian clock

At the core of the mammalian circadian feedback loop, CLOCK (NPAS2)-BMAL1 is the positive element to activate transcription of downstream genes encoding the negative elements PERs and CRYs. Here we show that CNOT1 associates with both CLOCK and BMAL1, promotes their phosphorylation and increases their protein stability, and in turn inhibits the transcriptional activity of CLOCK-BMAL1. Expression of either CLOCK, BMAL1 or CNOT1 could interact with endogenous Protein Kinase A (PKA) as assessed by co-immunoprecipitation (Co-IP) and kinase assays. PKA could phosphorylate CLOCK and BMAL1 and this was promoted by CNOT1. Genetic deletion of PKA-C by CRISPR-Cas9 results in a longer period of the circadian rhythm; while overexpression of PKA-C induces a shorter period. Furthermore, we demonstrate that CNOT1 associates with CLOCK and BMAL1 in the mouse liver and promotes their phosphorylation. PER2, but not CRY2, is also a PKA target. Our results suggest that CNOT1 and PKA play a critical role in the mammalian circadian clock, revealing a conserved function in eukaryotic circadian regulations.

developmental biology↗

bioRxiv2018

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease.

neuroscience↗

bioRxiv2018

Tissue-specific BMAL1 cistromes reveal that enhancer-enhancer interactions regulate rhythmic transcription

AbtsractThe mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of thousands of genes. Consistent with the various biological functions under clock control, rhythmic gene expression is tissue-specific despite an identical clockwork mechanism in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, due to differences in chromatin accessibility between tissues and co-binding of tissue-specific transcription factors. Our results also indicate that BMAL1 ability to drive tissue-specific rhythmic transcription not only relies on the activity of BMAL1 cis-regulatory elements (CREs), but also on the activity of neighboring CREs. Characterization of the physical interactions between BMAL1 CREs and other CREs in the mouse liver reveals that interactions are quite stable, and that BMAL1 controls rhythmic transcription by regulating the activity of other CREs. This supports that much of BMAL1 target gene transcription depends on BMAL1 capacity to rhythmically regulate a network of enhancers.

genetics↗

bioRxiv2017

Forward Genetic ENU Mutagenesis Screen for Mouse Models of Chronic Fatigue Identifies a Novel Mutation in Slc2a4 (GLUT4)

In a screen of voluntary wheel-running behavior designed to identify genetic mouse models of chronic fatigue in ENU mutagenized C57BL/6J mice, we discovered two lines that showed aberrant wheel-running patterns. These lines both stem from a single original founder identified as a low body-weight candidate in a recessive screen. Progeny from both of these lines showed the abnormal wheel-running behavior, with affected mice showing significantly lower daily activity levels than unaffected mice. They also exhibited low amplitude circadian rhythms, consisting of lower activity levels during the normal active phase, and increased levels of activity during the rest or light phase, but only a modest alteration in free-running period. Their activity is not consolidated into longer bouts, but is frequently interrupted with periods of inactivity throughout the dark phase of the light-dark (LD) cycle. As seen with the low body weight, expression of the behavioral phenotypes in offspring of strategic crosses was consistent with a recessive heritance pattern. Mapping of these phenotypic abnormalities showed linkage to a single locus on chromosome 11, and whole exome sequencing (WES) identified a single point mutation in the Slc2a4 gene encoding the GLUT4 insulin-responsive glucose transporter. The single nucleotide change (A to T) was found in the distal end of exon 10, and results in a premature stop (Y440*). To our knowledge, this is the first time a mutation in this gene has been shown to result in extensive changes in general behavioral patterns.\n\nSIGNIFICANCE STATEMENTChronic fatigue is a debilitating and devastating disorder with widespread consequences for both the patient and the persons around them, but effective treatment strategies are lacking. The identification of novel genetic mouse models of chronic fatigue may prove invaluable for the study of its underlying physiological mechanisms and for the testing of treatments and interventions. A novel mutation in Slc2a4 (GLUT4) was identified in a forward mutagenesis screen because affected mice showed abnormal daily patterns and levels of wheel running consistent with chronic fatigue. This new mouse model may shed light on the pathophysiology of chronic fatigue.

genetics↗