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PubMed2024

Bulk serum extracellular vesicles from stressed mice show a distinct proteome and induce behavioral and molecular changes in naive mice.

Chronic stress can trigger several pathologies including mood disorders for which no clear diagnostic molecular markers have been established yet. Attractive biomarker sources are extracellular vesicles (EVs). Evs are released by cells in health and disease and contain genetic material, proteins and lipids characteristic of the cell state. Here we show that Evs recovered from the blood of animals exposed to a repeated interrupted stress protocol (RIS) have a different protein profile compared to those obtained from control animals. Proteomic analysis indicated that proteins differentially present in bulk serum Evs from stressed animals were implicated in metabolic and inflammatory pathways and several of them were previously related to psychiatric disorders. Interestingly, these serum Evs carry brain-enriched proteins including the stress-responsive neuronal protein M6a. Then, we used an in-utero electroporation strategy to selectively overexpress M6a-GFP in brain neurons and found that M6a-GFP could also be detected in bulk serum Evs suggesting a neuronal origin. Finally, to determine if these Evs could have functional consequences, we administered Evs from control and RIS animals intranasally to naïve mice. Animals receiving stress EVs showed changes in behavior and brain M6a levels similar to those observed in physically stressed animals. Such changes could therefore be attributed, or at least in part, to EV protein transfer. Altogether these findings show that EVs may participate in stress signaling and propose proteins carried by EVs as a valuable source of biomarkers for stress-induced diseases.

Animals↗

PubMed2020

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1-XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15-fold in peripheral lymphocytes from 4- to 5-month-old Ercc1-/∆ and 2.5-year-old wild-type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4- to 5-month-old Ercc1-/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence-associated β-galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1-/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1-/∆ and aged WT mice support the conclusion that the DNA repair-deficient mice accurately model the age-related accumulation of senescent cells, albeit six-times faster.

Aging↗

PubMed2026

Effects of Short-Term Energy Limitation at Different Levels With Normal Protein Intake on Hepatic Lipid Metabolism and the Gut Microbiota in Overweight/Obese Mice.

This study investigated the sex-specific effects of graded short-term energy limitation (EL) with normal protein intake on hepatic lipid metabolism and the gut microbiota in overweight/obese mice. Mice were allocated to a normal control (NC) group, a high-fat diet model (MC) group, and groups receiving 20%, 30% or 40% EL (n = 8 per group). All mice underwent blood biochemistry, liver biochemistry, histological, liver metabolomic, and fecal microbiota community genomic analyses. Relative to the NC group, both male and female MC mice developed varying degrees of insulin resistance, dyslipidaemia, and sex hormone dysregulation. However, disrupted hepatic lipid metabolism was detected solely in male mice, in association with changes in key lipid-metabolizing enzymes and metabolites; female mice showed only disturbed total cholesterol (TC) metabolism, which was linked to alterations in the cholesterol synthesis rate-limiting enzyme HMGCR. With normal protein intake, 20%, 30%, and 40% EL reduced hepatic triglyceride and TC synthesis in overweight/obese male mice by suppressing the expression of the key lipogenic enzyme DGAT and the activities of ACC and HMGCR (p < 0.05). An effect on the lipolytic enzymes CPT1 and CYP7A1 was detected only at 30% EL (p < 0.05), and hepatic metabolite profiles varied with the degree of EL. In female mice, only 40% EL significantly decreased TC synthesis by inhibiting both HMGCR expression and enzymatic activity (p < 0.05). Furthermore, irrespective of sex, short-term EL (all levels) with normal protein intake reduced the gut Firmicutes/Bacteroidetes ratio in overweight/obese mice (p < 0.05). In conclusion, graded short-term EL with adequate protein intake exerts differential effects on hepatic lipid metabolism and the gut microbiota in overweight/obese mice, with pronounced sex-specific differences.

energy limitation↗

PubMed2025

Adrenomedullin overexpression protects mice from experimental bronchopulmonary dysplasia and associated pulmonary hypertension.

Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). Adm deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether Adm overexpression can mitigate this lung disease is unclear. Thus, we tested the hypothesis that Adm overexpression attenuates hyperoxia (HO)-induced murine experimental BPD-PH by using a novel transgenic mouse that overexpresses Adm globally (Admhi/hi mice). One-day-old Admhi/hi mice or their wild-type littermates (Adm+/+ mice) were exposed to HO ([Formula: see text] 70%) for 14 days and allowed to recover in normoxia (NO, [Formula: see text] 21%) for an additional 14 days. Controls were maintained in NO for 28 days. On postnatal day (P) 14, we harvested the lungs to determine the extent of Adm expression and apoptosis. On P28, we quantified alveolarization, lung vascularization, and PH. HO-exposed Adm+/+ mice demonstrated increased lung apoptosis, decreased alveolarization and lung vascularization, and indices of PH, indicating that neonatal HO exposure causes BPD-PH. However, Adm overexpression attenuated experimental BPD-PH, as evident by the decreased extent of hyperoxia-induced lung apoptosis and inflammation, alveolar and vascular simplification, pulmonary vascular remodeling, and PH in Admhi/hi mice than in Adm+/+ mice. Collectively, our results demonstrate that Adm overexpression attenuates HO-induced murine experimental BPD-PH, emphasizing the therapeutic potential of Adm for BPD-PH in preterm infants.NEW & NOTEWORTHY The deficiency of the proangiogenic peptide, adrenomedullin (Adm), exacerbates the severe infantile lung disorder, bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), in mice. However, whether Adm therapy can mitigate this disease is unclear. Our study, conducted with a rigorous methodology, suggests a potential solution. Using a novel mouse that overexpresses Adm to overcome the pharmacological limitations of the peptide, we demonstrate that Adm can mitigate this disorder, highlighting the therapeutic potential of Adm for human BPD-PH.

Animals↗

PubMed2026

Effects of aerobic exercise on inflammation and gut microbiota in obese mice: a metagenomic and metabolomic analysis.

BACKGROUND: Aerobic exercise can ameliorate insulin resistance (IR). However, the mechanism by which aerobic exercise regulates the gut microbiome to ameliorate IR and obesity remains unexplored. METHODS: Obese models were established by feeding C57BL/6 male mice a high-fat diet. A total of 26 mice were randomly divided into control group (group A, N = 8) and high-fat diet group (HFD group, N = 18). Successfully modeled mice were further assigned to model group (group B, N = 8) and exercise group (group C, N = 8). Group C underwent a 6-week treadmill exercise program (12 m/min, 60 min per day, 5 days per week). After intervention, colon tissue morphology was observed through hematoxylin-eosin staining, serum lipids and inflammatory indicators levels were detected by ELISA. The changes in the intestinal microbiota of the mice were also examined using metagenomic sequencing and UPLC-MS non-targeted metabolomics. RESULTS: Compared with the group A, the body weight, TC, TG, LDL-C, blood glucose, insulin, and IR in the group B significantly increased (P < 0.01), while the levels of pro-inflammatory cytokines TXNIP, TNF-α, NLRP3, IL-1β, and IL-18 significantly increased (P < 0.05 or P < 0.01). Compared with the group B, aerobic exercise reduced the body weight, TC, blood glucose, insulin, IR, TXNIP, TNF-α and other indicators in obese mice (P < 0.05 or P < 0.01). Moreover, aerobic exercise can regulate the imbalance of the intestinal flora in obese mice and ameliorate the disorder of metabolites. The metabolic pathways including arachidonic acid metabolism and histidine metabolism showed the most significant differences after the intervention of aerobic exercise. CONCLUSIONS: In conclusion, aerobic exercise can ameliorate glucose and lipid metabolism, IR, inflammatory response, and regulate the intestinal microecology and metabolic disorders in obese mice. The mechanism may be closely related to enhancing the diversity of intestinal flora, regulating the metabolism of arachidonic acid and histidine.

Animals↗

PubMed2003

Characterization and development of T-Cell immune responses in B-cell-deficient (Igh-6(-/-)) mice with Salmonella enterica serovar Typhimurium infection.

Infection of mice with Salmonella enterica serovar Typhimurium induces strong Th1 T-cell responses that are central to the control of the infection. In the present study, we examined the role of B cells in the development of Th1 T-cell responses to Salmonella by using gene-targeted B-cell-deficient mice (Igh-6(-/-) mice). The development of Th1 T-cell responses in Igh-6(-/-) mice was impaired in the early stage of a primary infection. This impairment persisted throughout the course of the disease. The ability of T cells to produce the Th1 cytokine gamma interferon and the frequency at which they did so were lower in Igh-6(-/-) mice than in control mice. We also observed a transient switch toward Th2 cytokine production in Igh-6(-/-) mice. Thus, B cells are important for the induction of protective Th1 T-cell responses in the early phase of a Salmonella infection. Activated B cells express high levels of major histocompatibility complex and costimulatory molecules and are nearly as effective as dendritic cells in their antigen-presenting cell (APC) activity. However, their importance as APCs in infection and their role in initiating and/or maintaining T-cell responses are unknown. Here, we show that B cells upregulate costimulatory molecules upon in vitro stimulation with S. enterica serovar Typhimurium and that they can present Salmonella antigens to Salmonella-specific CD4(+) T cells. Our results show that B cells are important for the development of T-cell responses in the early stage of a Salmonella infection and that this property may be due to their ability to present antigens to T cells.

Animals↗

PubMed2026

Sex-specific differences in liver DNA methylation patterns and epigenetic aging in mice.

Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This study investigated whether aged male and female mice display distinct liver DNA methylation patterns and differences in epigenetic aging. Liver samples were collected from 17 aged c57BL/6 mice (6 males, 11 females). Genomic DNA was extracted and bisulfite-converted before targeted enrichment of 2,045 murine age-associated CpG loci. Biological age (DNAge) was estimated using a previously developed DNA methylation-based predictor generated through elastic net regression. The difference (ΔDNAge) between DNAge and chronological age was computed. Sex-specific differences were assessed by comparing site-specific methylation ratios, ΔDNAge values, and through principal component analysis (PCA) and multiple linear regression. Twelve CpG sites across six genes (Fam84b, Zswim6, Hsf4, Mn1, Qprt, and Rapgefl1) showed significant sex-associated differences in methylation. Fam84b demonstrated the largest and most consistent sex-associated effect, with all three associated CpG sites showing higher methylation in males (regression coefficients: -0.204, -0.281, and -0.294). Zswim6 exhibited consistent lower methylation ratios in females, whereas the other genes showed higher methylation in females. There were no sex differences in biological age or ΔDNAge (P = 0.596). Although the epigenetic clock did not reveal differences between sexes in aging, aged mice did exhibit sex-specific liver methylation patterns different from those reported in younger mice, suggesting that sex-dependent epigenetic changes may emerge later in life and may reflect sexual dimorphism in liver function with age.NEW & NOTEWORTHY Males and females are known to age differently and develop certain diseases at different rates. Here, we examined the livers of aged male and female mice to see if they show different DNA methylation patterns. We found that aged male and female mice had distinct DNA methylation patterns at specific genes. Interestingly, most of these methylation differences were not present in younger mice, suggesting that sex differences in the genome may change with age.

Animals↗

PubMed2026

Therapeutic effect and anti-inflammatory mechanism of modified Shoutai pills against lipopolysaccharide-induced miscarriage in mice.

OBJECTIVE: To elucidate the anti-inflammatory mechanisms of modified Shoutai pills (, MSTP) in miscarriages, we performed transcriptome sequencing on the decidua and placental tissues of pregnancy mice. METHODS: The therapeutic effects and anti-inflammatory mechanisms of MSTP were studied in mice with lipopolysaccharide (LPS)-induced miscarriage. First, the effects of MSTP on pregnancy outcomes and the maternal-fetal interface, in LPS-induced miscarriage mice were examined. RNA sequencing was used to further investigate gene expression changes in LPS-induced miscarriage mice and to assess the effects of MSTP intervention. Finally, the expression levels of inflammation-related genes in the decidua and placental tissues were determined using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A high dose of MSTP significantly decreased the resorption rate (P < 0.05) and reduced apoptosis of the decidua and placental tissues in mice. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that inflammatory and immune-related signals were enriched. qRT-PCR results confirmed that in decidual and placental tissues, MSTP reduced the gene expression levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), c-Jun N-terminal kinase 1, p38, and tumor necrosis factor-α. CONCLUSIONS: In this study, we demonstrated that MSTP effectively prevented embryo loss with an anti-inflammatory mechanism through downregulation of the TLR4-NF-κB/ MAPK signaling pathway, in LPS-induced miscarriage mice model. To our knowledge, this is the first study to reveal the therapeutic mechanism of MSTP in LPS-induced miscarriage in mice.

Animals↗

PubMed2026

Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment. METHODS: To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism. RESULTS: Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion. CONCLUSIONS: These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.

Animals↗

PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗

PubMed2026

Tfr2 is necessary for acute iron-dependent hepcidin induction in mice with Tfr1-deficient hepatocytes.

In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homolog, transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cre mice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by liberated Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, Hamp mRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that "liberated" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and Tfr2 and Hfe exhibit nonredundant functions under chronic iron loading but act cooperatively to induce hepcidin in response to an acute iron challenge.

Animals↗

PubMed2022

A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that γδ T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their γδ T cell populations, and by investigating the functional contributions of particular γδ T cells subsets, using Vγ-gene targeted NOD mice. We found evidence that NOD Vγ4+ γδ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD Vγ1+ cells promote diabetes development. Enhanced Vγ1+ cell numbers in NOD mice, in particular those biased to produce IFNγ, appear to favor diabetic disease. Within NOD mice deficient in particular γδ T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the γδ T cells that were missing. Our results indicate that while certain γδ T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.

Mice↗

PubMed2024

Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Animals↗

PubMed2025

Genetic structure and demographic history of house mice in western Europe inferred using whole-genome sequences.

The western house mouse, Mus musculus domesticus, is a human commensal and an outstanding model organism for studying a wide variety of traits and diseases. However, we have few genomic resources for wild mice and only a rudimentary understanding of the demographic history of house mice in Europe. Here, we sequenced 59 whole genomes of mice collected from England, Scotland, Wales, Guernsey, northern France, Italy, Portugal and Spain. We combined this dataset with 24 previously published sequences from southern France, Germany and Iran and compared patterns of population structure and inferred demographic parameters for house mice in western Europe to patterns seen in humans. Principal component and phylogenetic analyses identified three genetic clusters in western European mice. Admixture and f-branch statistics identified historical gene flow between these genetic clusters. Demographic analyses suggest a shared history of population bottlenecks prior to 20 000 years ago. Estimated divergence times between populations of house mice from western Europe ranged from 1500 to 5500 years ago, in general agreement with the zooarchaeological record. These results correspond well with key aspects of contemporary human population structure and the history of migration in western Europe, highlighting the commensal relationship of this important genetic model.

Animals↗

PubMed2021

RNA-seq Analysis of Peri-Implant Tissue Shows Differences in Immune, Notch, Wnt, and Angiogenesis Pathways in Aged Versus Young Mice.

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch, and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

AGING↗

PubMed2026

Diet-dependent effects of an environmentally relevant dose of polyethylene and polyethylene terephthalate on white adipose tissue and systemic insulin resistance in mice.

As human exposure to micro- and nanoplastics (NPs) is unavoidable, it remains unclear whether dietary composition can modulate their health impacts. To address this, we investigated the metabolic effects of two common yet understudied polymers, polyethylene (PE) and polyethylene terephthalate (PET), in mice with either healthy or energy-dense diet. C57BL/6 J male mice were exposed to an environmentally relevant dose of PE or PET (100 nm, 25 mg/kg BW/day) for 29 weeks under either a normal diet (ND) or a high-fat diet (HFD). The metabolic consequence of NP exposure was highly diet-dependent. In ND-fed mice, PE and PET reduced white adipose tissue (WAT) mass, with PET inducing metabolic changes that toward a lipodystrophy-like state. Conversely, in HFD-fed mice, both polymers impaired systemic insulin sensitivity. Regardless of diet, PE and PET promoted immunoglobin G (IgG) accumulation in epididymal WAT, with PE-exposed lean mice exhibited the most robust IgG elevation, WAT fibrosis and impaired adipogenesis. These findings demonstrate that chronic, environmentally relevant PE or PET exposure disrupts metabolic health in male mice under both dietary contexts. While dietary composition dictates the specific metabolic phenotype, it does not prevent adverse outcomes. This complicates lifestyle-based mitigation strategies and underscores the urgent need for environmental source controls.

Insulin Sensitivity↗

PubMed2023

Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

UNLABELLED: Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1 . Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occurs alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. SIGNIFICANCE STATEMENT: We generated mouse models that express mutations in high-confidence genes linked to Tourette disorder (TD). These models show sensorimotor and cognitive behavioral phenotypes resembling TD-like behaviors. Sensorimotor gating deficits and repetitive motor behaviors are attenuated by drugs that act on dopamine. Reward learning and striatal dopamine is enhanced. Brain development is grossly normal, including cortical layering and patterning of major axon tracts. Further, no signs of striatal interneuron loss are detected. Interestingly, behavioral phenotypes in affected females can be more pronounced than in males, despite male sex bias in the diagnosis of TD. These novel mouse models with construct, face, and predictive validity provide a new resource to study neural substrates that cause tics and related behavioral phenotypes in TD.

Preprint↗

PubMed2026

Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.

Obesity is often associated with sex-dependent metabolic complications, to which altered intestinal barrier function and gut microbiota contribute. Glutamine supplementation has previously shown beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize, in male and female mice, the effects of oral glutamine supplementation during high-fat-diet-induced obesity. Male and female C57BL/6 mice received a standard (SD) or high-fat diet (HFD; 60 % kcal from fat) for 14 weeks (W14). From W12 onward, mice received glutamine in drinking water (2 g/kg/day) or no supplementation. Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic inflammatory response, cecal microbiota and inflammatory/endocrine adipose response were assessed. In both male and female mice, glutamine supplementation failed to improve body weight and body composition. However, glutamine reduced glucose intolerance in HFD-fed males (AUC reduced by 14.57 %) that was associated with a partial restoration of plasma resistin and insulin and a trend toward limiting adipose inflammatory response. In males, glutamine did not affect gut microbiota composition and colonic response. Conversely, in HFD-fed females, glutamine supplementation led to gut microbiota changes (increase in Bacteroidota and Pseudomonadota phyla; increase in Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (Il1b, Tlr4, Myd88, Irf3), increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. Finally, HFD-fed mice exhibited sex-specific responses to glutamine supplementation with protective effects in males and harmful effects in females that need to be further deeply explored.

Animals↗