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This article reappraises brain function by reconsidering the role of cerebral fluid dynamics in cognition. Tracing a lineage from early modern thinkers like Descartes-who invoked hydraulic metaphors and 'animal spirits'-to J.C. Bose's pioneering studies on electro-mechanical plant physiology, and culminating in contemporary findings on cerebrospinal fluid (CSF), extracellular space (ECS), and neurovascular coupling, we reveal a forgotten yet vital computational substrate. We argue that alongside the well-studied digital operations of neural circuits exists a slower, analog, evolutionarily older layer of electrofluidic computation. This system-comprised of ionic diffusion, convective CSF flow, and vascular modulation-not only supports but dynamically shapes neural activity. The brain emerges as an electromechanical ecology of electric pulses and fluid flows, where the mind is both a pattern of neural activity and a choreography of fluid flows.
Somatostatin analogues reduce liver and kidney cyst volume in autosomal dominant polycystic kidney disease (ADPKD), but randomized trials have not demonstrated a consistent benefit on kidney function decline. We tested whether the analogue lanreotide slows glomerular filtration rate (GFR) decline over three years in adults with ADPKD stages 2/3. In this randomized, double-blind, placebo-controlled trial, we enrolled adults with ADPKD and measured GFR (mGFR) 30-89 mL/min/1.73 m2. Patients were randomized to receive monthly injections of lanreotide 120 mg or 0.9% sodium chloride placebo for three years. The primary endpoint was mGFR slope (iohexol clearance) assessed at baseline, weeks 72 and 144 and analyzed with a linear mixed-effects model (LMM). Secondary endpoints included annual estimated GFR decline (creatinine-based, assessed at 11 scheduled visits), kidney events, quality of life, and safety. Due to slow enrollment, recruitment stopped after 144 of 180 planned participants. All randomized participants were included in the analysis (intention-to-treat). The primary endpoint was not met: the model-derived annualized between-arm difference in mGFR trajectory was -0.3 ml/min/1.73 m2 per year (95% confidence interval -3.4 to 2.8). The time × lanreotide coefficient from the pre-specified creatinine-eGFR LMM was significant +1.2 ml/min/1.73 m2 per year (0.27 to 2.15); however, this signal was not replicated by cystatin C-eGFR nor urinary creatinine clearance, consistent with a non-GFR effect on creatinine physiology. Rates of kidney events and quality-of-life scores were similar between arms. Gastrointestinal adverse events were more frequent with lanreotide. Hypoglycemia occurred in 11.1% of lanreotide-treated versus 1.4% of placebo-treated participants. Lanreotide did not slow mGFR decline in adults with stage 2/3 ADPKD. The creatinine-eGFR signal is exploratory, not supported by muscle-mass-independent markers, and should be interpreted in the context of a negative primary endpoint. An unexpected hypoglycemia signal warrants proactive monitoring when considering lanreotide in this population.
Fontan-associated liver disease contributes to long-term morbidity and mortality. This study evaluated whether non-invasive liver fibrosis scores-aspartate transaminase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) and routine clinical hepatic synthetic function, specifically albumin-predict adverse outcomes when obtained 10 and 20 years after the Fontan procedure. We conducted a retrospective analysis of Fontan patients with laboratory data available at ≥10 years post-procedure. The primary adverse outcomes included death, heart transplantation, or Fontan failure. Failing Fontan physiology was defined as heart failure, poorly controlled ascites, plastic bronchitis, or treatment-resistant protein-losing enteropathy. Cox regression was used to evaluate associations between APRI, FIB-4, and albumin level with adverse outcomes. Outcomes of 98 patients surviving at 10 years (but <20 years), and 109 different patients surviving at 20 years were included. At least one adverse outcome occurred in 8% (8/98) of patients at 10 years and 12% (13/109) of patients at 20 years. Albumin <3.5 g/dL was associated with adverse outcomes at both 10 years (hazard ratio [HR] 8.54; p=0.02) and 20 years (HR 4.31; p=0.03). FIB-4 >1.45 but not APRI was significantly associated with adverse outcomes (HR 21.3; p=0.03) at 20 years. Low albumin and elevated FIB-4 scores, usually leveraged in evaluation of liver disease, are associated with more frequent adverse outcomes of death, heart transplantation, or Fontan failure. These markers may serve as simple, non-invasive prognostic tools in long-term follow-up.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) represents a multisystemic mitochondrial disease mainly triggered by heteroplasmic m.3243A > G mutation in mtDNA MT-TL1, the gene for tRNA^Leu(UUR). Here we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a female MELAS patient into induced pluripotent stem cells (iPSCs). This patient-specific iPSC line provides a valuable platform to investigate MELAS pathophysiology and screen therapeutic interventions targeting mitochondrial dysfunction in a genetically relevant context.
Diabetes mellitus is a chronic metabolic disorder characterised by impaired glucose homeostasis, resulting in persistent hyperglycaemia. Accurate and prompt diagnosis is essential for early intervention and prevention of long-term complications. Fasting blood glucose levels have traditionally been central to the diagnosis and monitoring of diabetes mellitus. However, growing evidence highlights the clinical relevance of non-fasting glucose measures, including postprandial glucose, random plasma glucose, and glycated haemoglobin (HbA1c) levels. Practical challenges, safety concerns, and evolving insights into glucose physiology have prompted renewed interest in flexible and context-driven approaches to glucose testing. This narrative review examines the physiological basis of fasting and non-fasting glucose regulation and critically evaluates their roles in diabetes screening, diagnosis, and monitoring. It also discusses the strengths and limitations of measuring fasting blood glucose, oral glucose tolerance, HbA1c, random plasma glucose, postprandial glucose, and continuous glucose monitoring. Special attention is given to pre-analytical and practical considerations, patient safety, and the ability of non-fasting measures to capture early metabolic dysfunction and real-world glycaemic exposure. This article reviews evidence supporting the prognostic value of postprandial hyperglycaemia and the expanding role of non-fasting monitoring tools. Non-fasting glucose testing offers substantial advantages in terms of accessibility, safety, and clinical relevance, and is well-suited for population screening and routine diabetes monitoring. Fasting glucose testing remains essential for specific diagnostic and research applications, particularly when strict metabolic standardisation is required. A context-driven framework that prioritises non-fasting approaches while reserving fasting tests for targeted indications provides a balanced and patient-centred strategy for contemporary diabetes care.
Agricultural expansion is one of the leading causes of biodiversity loss, yet the molecular and physiological mechanisms linking habitat modification to individual state remain understudied. Identifying mechanisms underlying organisms' responses to habitat modification is essential for accurately modelling cause-effect relationships. Using transcriptomics and blood-based assays, we show that young European rollers (Coracias garrulus) raised in cropland-dominated landscapes (CL) have nine genes significantly downregulated compared to conspecific young birds raised in mixed-use landscapes (mosaics of land uses including meadows, pastures, and fallows; ML), with overrepresented genes in the catalase complex, a key antioxidant system. Consistent with gene expression results, CL birds showed lower blood catalase activity than ML birds. CL birds also exhibited higher glutathione peroxidase activity and lower immunoglobulin Y than ML birds. Finally, we found no differences in SOD activity, DNA damage, haptoglobin, BKA, haemagglutination, and haemolysis between habitats. Overall, our results reveal small molecular and physiological differentiation between CL and ML habitats, primarily driven by specific components of immune-oxidative physiology. This study provides novel mechanistic insights into how habitat conditions can influence organisms during early life stages.
Almost since its discovery, tau protein has perplexed scientists and clinicians with its varied roles in physiology as well as its appearance as phosphorylated protein aggregates of various structures in many neurodegenerative diseases. Tau plays a role in microtubule stabilization, but from the earliest of studies, tau has also been observed to bind to RNA, with recent research suggesting tau has a higher affinity for some RNA species compared to microtubules. In the context of disease, tau dysfunction potentiates disruptions to RNA metabolism, including the perturbation of mRNA splicing, impairment of translation, de-repression of transposable elements, and alteration of RNA export and degradation. Tau aggregates directly sequester diverse RNA species and RNA binding proteins. Emerging evidence reinforces the characterization of tau as an RNA binding protein, highlighting questions about both the physiological and disease-related functions of this direct RNA binding. The disparate structure of tau in normal and various disease states makes teasing apart the various impacts on RNA and regulation a more difficult puzzle requiring future study. In this review, we summarize the evidence for tau's role in RNA biology, including as an RNA binding protein.
SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors constitute a conserved family of key regulators orchestrating plant growth and development, with well-documented roles in hormone signaling pathways, secondary metabolism, and abiotic stress responses across diverse plant taxa. Despite their importance, the characterization of individual SPL genes in cotton (Gossypium hirsutum) remains limited. Here, we present a comprehensive functional characterization of GhSPL13 through CRISPR/Cas12-mediated targeted gene disruption, coupled with integrative analyses encompassing developmental, physiological, and metabolomic parameters. GhSPL13 edited lines exhibited pronounced alterations in plant architecture, including enhanced axillary bud outgrowth, increased branching complexity, and significant increase of root length and biomass. These phenotypic changes were accompanied by the significant upregulation of the cytokinin biosynthetic gene GhIPT1. Under drought stress conditions, GhSPL13 edited lines demonstrated superior physiological response, characterized by elevated stomatal conductance, increased intercellular CO₂ concentration, enhanced photosynthetic rates, and higher total chlorophyll content relative to wild-type controls. Metabolomic profiling revealed substantial reprogramming of flavonoid and anthocyanin biosynthetic pathways in the mutants. Furthermore, promoter motif analysis identified conserved GTAC-centered SPL-binding cis-elements within key flavonoid biosynthesis genes, including GhDFR. Collectively, these findings outline a multifaceted role for GhSPL13 in modulating plant architecture, root development, cytokinin-mediated growth regulation, secondary metabolite biosynthesis, and drought adaptive physiology in cotton. This study provides critical insights into the SPL-mediated regulatory networks in Gossypium hirsutum and establishes a foundational framework for targeted genetic improvement of cotton for enhanced growth and stress response.
Contemporary management of refractory ventricular arrhythmias and electrical storm (ES) emphasizes antiarrhythmic therapy, autonomic modulation, sedation, catheter ablation, mechanical circulatory support, and heart transplantation. The stellate ganglion block (SGB) has been used for decades to treat refractory ventricular tachycardia (VT) and ventricular fibrillation (VF), and has gained more traction in the literature in recent years. The authors summarize the anatomy of the stellate ganglion, the mechanism of action of an SGB, and the physiology of VT, VF and ES. They then review current practices for the treatment of VT and VF and review the current literature supporting the use of SGB as treatment for refractory VT and VF. Finally, they describe practical considerations for the use of SGB for the treatment of VT and VF. Multiple observational studies, case series, retrospective studies, and meta-analyses in recent years have shown that SGB can be effective at reducing arrhythmia episodes in patients with refractory VT or VF; however, the quality of the available literature is weak because of the lack of randomized controlled trials. Despite this, the SGB may play a role as a bridge therapy in patients with refractory VT between initial stabilization and further long-term management.
As an abundant fungal colonizer of mammalian skin, Malassezia establishes mutualistic or pathogenic interactions with the host. Here we show that Malassezia furfur promotes skin homeostasis by maintaining epidermal integrity via tryptophan-derived metabolites that activate the aryl hydrocarbon receptor (AhR), a key regulator of keratinocyte differentiation and inflammation. M. furfur-derived tryptophan derivatives activated AhR in human epidermal equivalents and upregulated proteins important for skin structure and barrier activity in mouse epidermis. In a mouse model of atopic dermatitis, M. furfur colonization with tryptophan supplementation reduced inflammation and restored barrier function, while a fungal mutant defective in indole production was unable to do so. Mice lacking AhR specifically in keratinocytes failed to benefit from M. furfur-mediated barrier protection. These findings establish a previously unrecognized mutualistic role for Malassezia in skin physiology and expand our understanding of the skin microbiota's influence on barrier function and immune regulation.
Understanding what shapes variation in organisms' capacity to utilize novel resources is essential to predicting how species will respond to environmental change. For herbivores, exposure to toxic phytochemicals in novel plants may limit persistence in new habitats. We investigated the behavioral, physiological, genetic, and microbial consequences of diet switching in two closely related species of rodent herbivores that each consume differentially toxic plants in their native habitat, and that maintain different dietary strategies (i.e., relative dietary specialist versus relative generalist). In reciprocal laboratory feeding trials, we exposed wild-caught woodrats (genus Neotoma) to toxins characteristic of either familiar or novel plant secondary compounds. We measured changes in food and water intake, locomotor activity, gut microbial composition, and gene expression across the digestive tract following feeding trials. The dietary generalist responded minimally, but the specialist responded strongly when exposed to the novel diet. This response included behavioral and genetic components including increased water intake, reduction in locomotor activity, increased differential expression of detoxification genes, and a greater shift in gut microbial composition. The dietary specialist exhibited a strong response to diet switching that corresponded with ecologically relevant shifts in behavior and physiology that would have negative fitness consequences. Although the dietary specialist had a strong genetic and microbial response to novel plant secondary compounds, this response would likely be insufficient to overcome the immediate challenge of exposure to novel dietary toxins in the wild. Our results underscore the link between feeding strategy and the capacity to shift to novel dietary resources in response to environmental change.
Industrial settleable particulate matter (SePM) represents a significant yet underrecognized source of metallic contaminants in freshwater environments. This study investigated the acute effects of metallurgy-derived SePM on bullfrog tadpoles (Aquarana catesbeiana), with emphasis on cardiac physiology, oxidative stress, and tissue metal(loid) accumulation. Short-term exposure led to marked increases in both classical (Fe, Ag, Ba) and emerging (Ce, Ti, V) metals within cardiac tissue, with electron microscopy confirming intracellular nanoparticles (Fe, Al, Sn, Ni) in cardiomyocytes. SePM exposure triggered elevated heart rates, enhanced contractile force, ventricular remodeling, and disrupted redox balance, evidenced by increased lipid peroxidation and protein carbonylation. These physiological alterations increase energy expenditure, potentially compromising growth and delaying developmental progression. Our findings demonstrate that SePM acts a vector for the cross-compartmental transfer of metallic contaminants and directly induces toxicity in amphibian larvae. These findings highlight the urgent need for more stringent regulation and comprehensive monitoring of metallic particulate emissions to better protect aquatic organisms and ecosystem integrity.
To efficiently perceive sensory information and guide behavior, the brain organizes incoming sensory stimuli into internal maps that capture perceptual relatedness between stimuli. Whether these maps, typically assessed in scaling paradigms without feedback, also shape perceptual decisions during reinforcement-based conditions remains unclear. Here, we assess task-naïve perceptual maps from similarity judgments of pulsed sound stimuli, and compare them to perceptual maps obtained from multiple discrimination tasks in humans (n = 152) and mice (n = 11). We find that task-naïve maps predict how well humans discriminate sounds, how quickly they learn, and which stimulus features guide their choices. Moreover, naïve and task-based maps share key structures, suggesting a stable perceptual map architecture throughout learning. Remarkably, human task-based and task-naïve perceptual maps share key features and structures with the task-based perceptual maps of mice, indicating congruent structures of auditory perception across species. Together, our results indicate that perception relies on robust internal maps that provide a common framework to flexibly guide behavior in changing environments.
Mild intermittent hypoxia is emerging as a promising strategy to enhance healthspan, but the molecular mechanisms remain poorly defined. ADORA2B, a hypoxia-inducible adenosine receptor, is known to regulate metabolism and stress responses, yet its role in functional aging is unclear. Using Caenorhabditis elegans, we investigated the role of the ADORA2B ortholog ador-1 in mediating the healthspan effects of mild hypoxia. We exposed wild-type and ador-1 knockout worms to low-dose cobalt chloride (CoCl2) and assessed movement, speed, and lifespan metrics through automated imaging. Transcriptomic analyses via 3' RNA-seq and Gene Set Enrichment Analysis (GSEA) were performed to characterize underlying molecular responses. Mild hypoxia significantly extended healthspan in wild-type C. elegans, increasing sustained locomotor activity and distance traveled throughout adulthood. This benefit was markedly attenuated in ador-1 mutants, which displayed reduced baseline healthspan and a substantially blunted transcriptional response to CoCl2 treatment. Transcriptomic analyses identified coordinated regulation of canonical hypoxia-responsive genes, including acs-2, icl-1, adh-1, ftn-1 and ftn-2, consistent with activation of hypoxia-responsive transcriptional programs. GSEA revealed activation of pathways related to neuronal plasticity, muscle function and mitochondrial adaptation, together with transcriptional downregulation of ROS-related pathways. In contrast, hypoxia-treated ador-1 mutants exhibited suppression of pathways associated with ciliary function, immune responses, protein synthesis and cellular homeostasis CONCLUSIONS: ADORA2B is required for the coordinated transcriptional adaptation associated with hypoxia-induced healthspan extension in C. elegans. Loss of ador-1 is associated with impaired baseline healthspan and an attenuated response to hypoxic conditioning. These findings support a model in which successful hypoxic adaptation requires coordinated regulation of multiple biological systems.
Immune-stimulating antibody conjugates (ISACs) represent an emerging class of immunotherapeutics that combine tumor-targeted antibodies with innate immune agonists. However, current ISAC platforms often rely on heterogeneous conjugation strategies and poorly defined antibody architectures, making it difficult to disentangle how Fc glycosylation, payload presentation, and linker design collectively govern immune activation. Here we report a dual-enzymatic antibody editing strategy that integrates Fc glyco-engineering with site-specific payload conjugation to construct structurally defined immune-stimulating antibody conjugates. Using microbial transglutaminase-mediated conjugation at the Fc Q295 residue together with Endo-S2-mediated Fc glycan remodeling at N297, we generated trastuzumab-based ISACs with defined Fc glycoforms and linker architectures. Systematic evaluation reveals that Fc glycosylation state and payload presentation act as orthogonal and synergistic determinants of immune activation. In particular, an intact and afucosylated Fc glycan is essential for robust tumor-cell killing and cytokine induction, while cleavable linkers further enhance innate immune activation through efficient intracellular release of the TLR7/8 agonist. This work establishes a versatile chemical strategy for controlling antibody architecture and immune activation, providing a broadly applicable platform for the rational design of next-generation antibody therapeutics.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have garnered attention as cell-free therapeutics due to their regenerative and immunomodulatory potential. Human placenta-derived stromal cells (hPSCs) are a particularly promising source owing to their accessibility, scalability, and superior proliferative capacity-yet the functional behavior of their EVs, especially in inflammatory disease contexts, remains poorly defined. This study introduces a novel integrated approach, combining a 3D microcarrier bioreactor for scalable EV production with advanced 3D human airway disease models, to resolve how donor variability and inflammatory context shape the immunomodulatory activity of hPSC-EVs. hPSCs were expanded under Good Manufacturing Practice (GMP)-compliant conditions in both conventional 2D cultures and 3D stirred-tank bioreactors using microcarrier technology. EVs were isolated from conditioned media via tangential flow filtration and characterized by fluorescent nanoparticle tracking analysis (fNTA), flow cytometry and protein content. Functional effects of hPSCs and EVs were assessed in PBMC co-cultures and two human 3D airway models-cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS)-based on the Epithelix SmallAir™ platform, integrating primary airway epithelium and macrophages at the air-liquid interface. Inflammation was induced with TNF-α (CF) or LPS (ARDS), and EVs or hPSCs were administered to both apical and basal compartments. 3D culture significantly increased EV yield without compromising quality. A key finding was a substantial donor-dependent variability in both hPSC and EV activity, which translated into distinct, model-specific immunomodulatory profiles. Notably, EV- and hPSC-mediated responses diverged across immune and epithelial compartments, indicating that EVs do not simply recapitulate parental cell function. In the 3D models, despite substantial heterogeneity, induction of IL-10 and Arginase-1 (up to 25-fold) in the macrophage compartment emerged as a consistent trend across experimental conditions. In contrast, parental hPSCs showed broader but less predictable cytokine modulation, including variable TNF-α suppression and context-specific effects across donors. Our findings demonstrate that hPSC- and EV-mediated immunomodulation is highly context-dependent and cannot be predicted solely from donor identity or culture format. Rather than identifying a single optimal condition, this study highlights the need for larger donor cohorts and functional profiling in advanced human models and supports the use of EVs as distinct, cell-free immunomodulatory entities with compartment-specific activity. Together, this work provides a translational framework linking GMP-compliant EV manufacturing with functionally relevant human disease modeling.
Central respiratory chemoreceptors (CRCs) are critically important for maintaining normal systemic levels of pH and PCO2. Their specific identity has been controversial. It is widely acknowledged that CRCs must respond to small changes in pH via cell-autonomous (intrinsic) mechanisms. However most studies designed to identify CRCs have only blocked a limited subset of synaptic mechanisms. Here we used patch-clamp recordings to compare chemosensitivity of two candidates for CRCs: (1) Phox2b-expressing neurones of the retrotrapezoid nucleus (RTN) and (2) serotonin (5-HT)-producing neurones of the medullary raphe nuclei. We used acute dissociation to ensure responses were intrinsic. In response to a change in CO2 from 5% to 9% (pH 7.4 to ≈7.2) 48% of medullary 5-HT neurones (n = 118) increased their firing rate by more than 20% with a mean increase of 139%, whereas 16% of RTN neurones (n = 93) increased their firing rate by more than 20% with a mean increase of 46%. RTN neurones that expressed Neuromedin B (Nmb) (a proposed biomarker of RTN CRCs) were not more likely to have a larger pH response. After 3 days in culture many RTN neurones began to receive excitatory synaptic drive from 5-HT neurones and also responded to acidosis. These results support the conclusion that a subset of medullary 5-HT neurones are CRCs. Many RTN neurones may play a role in integration and relay of pH information from 5-HT neurones and other chemoreceptor sites but contribute less to direct pH sensation. KEY POINTS: Central respiratory chemoreceptors in the brainstem detect changes in CO2 and pH via intrinsic mechanisms and induce changes in breathing to maintain pH homoeostasis. The identity of these cells is controversial. We measured the pH response of two prominent candidates for these chemoreceptors after they were acutely isolated from all other cells to ensure that their responses were intrinsic. A small percentage of neurones from the retrotrapezoid nucleus had a small response to acidosis. A much larger percentage of serotonin neurones were stimulated by acidosis with a large increase in firing rate. Over the first few days in cultured neuronal preparations serotonin neurones formed synapses on retrotrapezoid neurones and stimulated them in response to acidosis. These results reveal that a large subset of serotonin neurones have properties consistent with central chemoreceptors, whereas a small number of retrotrapezoid neurones have a small response, and may be more important as relays of chemoreceptor information rather than as direct sensors of pH themselves.
Intracerebral hemorrhage (ICH) causes high rates of mortality and long-term disability, but there are no effective treatments currently. Two key pathologies of ICH are blood-brain barrier (BBB) damage and white matter injury. Previous studies show that oligodendrocytes (OLs) regulate BBB integrity and (re)myelination via the extracellular matrix (ECM). The receptors that mediate these functions, however, remain incompletely understood. Here, we investigated the function of OL-derived integrin-β1 under both homeostatic and ICH conditions using conditional knockout mice. The mutant mice were grossly normal with intact BBB and OL maturation/myelination under homeostatic conditions. After ICH, however, these mutants exhibited exacerbated brain injury, including larger hematoma volume, elevated brain edema, aggravated axonal injury, enhanced BBB damage, compromised OL differentiation/maturation, impaired remyelination, and worsened neurological dysfunction. Subsequent studies revealed that the enhanced BBB injury was mediated by both paracellular and transcellular mechanisms and associated with pericyte defects. These findings demonstrate that OL-derived integrin-β1 is dispensable under homeostatic conditions but strictly required for BBB repair and remyelination following hemorrhagic stroke.
Wakefulness produces sleep-promoting substances and the cerebrospinal fluid contains substances that reflect homeostatic sleep pressure. However, identities of such molecules, and the neural mechanisms for producing and sensing them, remain mysterious. Here we show that cerebrospinal fluid levels of tryptamine (TrpA) track homeostatic sleep pressure in nocturnal mice and diurnal pigs, reflecting physical activity history independently of light-dark cycles. We developed a ratiometric fluorescent sensor for TrpA and showed that TrpA is produced by wake-active monoaminergic nuclei in the diencephalon and brainstem and is secreted in an activity-dependent manner. We showed that released TrpA binds to G-protein-coupled receptor 139 (GPR139) and enhances neuronal excitability in the hypothalamic preoptic area to promote sleep. TrpA-GPR139 signaling was necessary for homeostatic sleep rebound and small-molecule GPR139 agonists promoted sleep duration and quality. Together, our study reveals TrpA as a signal related to sleep homeostasis and GPR139 as a druggable target against its disruption.