Mouse Populations Research Articles

DIETARY RESTRICTION OF ISOLEUCINE INCREASES THE HEALTHSPAN AND LIFESPAN OF GENETICALLY HETEROGENEOUS MICE

Abstract Low protein (LP) diets promote health and longevity in diverse species, andreducing dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine recapitulates these effects in C57BL/6J mice, promoting metabolic health in both sexes, and increases lifespan while reducing frailty in males. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in C57BL/6J males. Here, we tested the hypothesis that specifically restricting dietary isoleucine could promote healthy aging in adult genetically heterogenous UM-HET3 mice. We find that isoleucine restriction (IleR) improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism, blunting age-related molecular changes in males and, to a lesser extent, in females. Finally, we find that IleR reduces frailty and extends both the median and maximum lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice and suggest that reducing dietary levels of isoleucine, or drug regimens that mimic this effect, may be a novel intervention to promote healthy aging.

Chargaff's second parity rule lies at the origin of additive genetic interactions in quantitative traits to make omnigenic selection possible.

Francis Crick's central dogma provides a residue-by-residue mechanistic explanation of the flow of genetic information in living systems. However, this principle may not be sufficient for explaining how random mutations cause continuous variation of quantitative highly polygenic complex traits. Chargaff's second parity rule (CSPR), also referred to as intrastrand DNA symmetry, defined as near-exact equalities G ≈ C and A ≈ T within a single DNA strand, is a statistical property of cellular genomes. The phenomenon of intrastrand DNA symmetry was discovered more than 50 years ago; at present, it remains unclear what its biological role is, what the mechanisms are that force cellular genomes to comply strictly with CSPR, and why genomes of certain noncellular organisms have broken intrastrand DNA symmetry. The present work is aimed at studying a possible link between intrastrand DNA symmetry and the origin of genetic interactions in quantitative traits. Computational analysis of single-nucleotide polymorphisms in human and mouse populations and of nucleotide composition biases at different codon positions in bacterial and human proteomes. The analysis of mutation spectra inferred from single-nucleotide polymorphisms observed in murine and human populations revealed near-exact equalities of numbers of reverse complementary mutations, indicating that random genetic variations obey CSPR. Furthermore, nucleotide compositions of coding sequences proved to be statistically interwoven via CSPR because pyrimidine bias at the 3rd codon position compensates purine bias at the 1st and 2nd positions. According to Fisher's infinitesimal model, we propose that accumulation of reverse complementary mutations results in a continuous phenotypic variation due to small additive effects of statistically interwoven genetic variations. Therefore, additive genetic interactions can be inferred as a statistical entanglement of nucleotide compositions of separate genetic loci. CSPR challenges the neutral theory of molecular evolution-because all random mutations participate in variation of a trait-and provides an alternative solution to Haldane's dilemma by making a gene function diffuse. We propose that CSPR is symmetry of Fisher's infinitesimal model and that genetic information can be transferred in an implicit contactless manner.

Genomic inbreeding measures applied to a population of mice divergently selected for birth weight environmental variance.

This study aimed to compare different inbreeding measures estimated from pedigree and molecular data from two divergent mouse lines selected for environmental birth weight during 26 generations. Furthermore, the performance of different approaches and both molecular and pedigree data sources for estimating Ne were tested in this population. A total of 1,699 individuals were genotyped using a high-density genotyping array. Genomic relationship matrices were used to calculate molecular inbreeding: Nejati-Javaremi (F NEJ), Li and Horvitz (F L&H), Van Raden method 1 (F VR1) and method 2 (F VR2), and Yang (F YAN). Inbreeding based on runs of homozygosity (F ROH) and pedigree inbreeding (F PED) were also computed. F ROH, F NEJ, and F L&H were also adjusted for their average values in the first generation of selection and named F ROH0, F NEJ0, and F L&H0. ∆F was calculated from pedigrees as the individual inbreeding rate between the individual and his parents (∆F PEDt) and individual increases in inbreeding (∆F PEDi). Moreover, individual ∆F was calculated from the different molecular inbreeding coefficients (∆F NEJ0, ∆F L&H, ∆F L&H0, ∆F VR1, ∆F VR2, ∆F YAN, and ∆F ROH0). The Ne was obtained from different ∆F, such as Ne PEDt, Ne PEDi, Ne NEJ0, Ne L&H, Ne L&H0, Ne VR1, Ne VR2, Ne YAN, and Ne ROH0. Comparing with F PED , F ROH , F NEJ and F VR2 overestimated inbreeding while F NEJ0 , F L&H , F L&H0 , F VR1 and F YAN underestimated inbreeding. Correlations between inbreeding coefficients and ∆F were calculated. F ROH had the highest correlation with F PED (0.89); F YAN had correlations >0.95 with all the other molecular inbreeding coefficients. Ne PEDi was more reliable than Ne PEDt and presented similar behaviour to Ne L&H0 and Ne NEJ0. Stable trends in Ne were not observed until the 10th generation. In the 10th generation Ne PEDi was 42.20, Ne L&H0 was 45.04 and Ne NEJ0 was 45.05 and in the last generation these Ne were 35.65, 35.94 and 35.93, respectively F ROH presented the highest correlation with F PED, which addresses the identity by descent probability (IBD). The evolution of Ne L&H0 and Ne NEJ0 was the most similar to that of Ne PEDi. Data from several generations was necessary to reach a stable trend for Ne, both with pedigree and molecular data. This population was useful to test different approaches to computing inbreeding coefficients and Ne using molecular and pedigree data.

Genetics and diet explain sex differences in glucose metabolism and cognitive function

AbstractBackgroundDiabetes and cognitive impairment occur together more often than would be expected by chance [1–6]. Individuals diagnosed with type 2 diabetes have a 1.4–2.2‐fold higher risk of dementia than those without diabetes [2,6,7]. Epidemiological research has demonstrated shared risk factors, metabolic disorders, and comorbidities[5,8], shared genetics[9], and evidence of causality assessing glycemic traits [4,10–12]. We set out to determine how glucose metabolism modifies normal aging‐related cognitive decline in comparison to Alzheimer’s Disease (AD)‐related decline, given genetic diversity and controlled diet (GxD).MethodWe studied an innovative, genetically diverse mouse population (AD‐BXDs, Fig. 1) to determine GxD effects on metabolic function and the transition to cognitive impairment [13]. The data were collected longitudinally from a cohort of ∼650 AD‐BXD mice (39 unique strains) fed either a low‐fat chow diet or a high‐fat, high sucrose diet (HFD:45% fat,17.5% sucrose). Glucose metabolism was assessed by measuring the area under the curve of an intraperitoneal glucose tolerance test (IPGTT). In general, faster clearance of glucose (smaller area under the curve) reflects better glycemic control. Contextual fear memory (CFM) at 6 and 14 months of age was the measure of cognitive function. We used multivariable linear regression to model the relationship between overall CFM and an IPGTT by strain effect.ResultWe found that there was heterogeneity in IPGTT by sex, strain, and diet, accounting for more than 50% of the variation explained (Fig. 2). Females generally exhibit faster glucose metabolism than males (Fig.2, left), while the magnitude of the effect of sex and diet on IPGTT differs by strain (Fig. 2, x‐axis). For our research question of how glucose metabolism affects cognitive function, we identified strains that exhibited resilience to cognitive dysfunction as predicted by their glucose metabolism, with a broad‐sense heritability of 0.81 (Fig. 3). These early findings establish a foundation to identify quantitative trait loci (QTLs) and GxD‐type QTLS based on glucose tolerance and cognitive function associations.ConclusionBy examining the effect of diet on AD‐BXD strains and incorporating metabolic measures associated with diabetes, we will be able to evaluate and validate cause in these relationships for the first time.

Cochlear transcriptome analysis of an outbred mouse population (CFW).

Age-related hearing loss (ARHL) is the most common cause of hearing loss and one of the most prevalent conditions affecting the elderly worldwide. Despite evidence from our lab and others about its polygenic nature, little is known about the specific genes, cell types, and pathways involved in ARHL, impeding the development of therapeutic interventions. In this manuscript, we describe, for the first time, the complete cell-type specific transcriptome of the aging mouse cochlea using snRNA-seq in an outbred mouse model in relation to auditory threshold variation. Cochlear cell types were identified using unsupervised clustering and annotated via a three-tiered approach-first by linking to expression of known marker genes, then using the NSForest algorithm to select minimum cluster-specific marker genes and reduce dimensional feature space for statistical comparison of our clusters with existing publicly-available data sets on the gEAR website, and finally, by validating and refining the annotations using Multiplexed Error Robust Fluorescence In Situ Hybridization (MERFISH) and the cluster-specific marker genes as probes. We report on 60 unique cell-types expanding the number of defined cochlear cell types by more than two times. Importantly, we show significant specific cell type increases and decreases associated with loss of hearing acuity implicating specific subsets of hair cell subtypes, ganglion cell subtypes, and cell subtypes within the stria vascularis in this model of ARHL. These results provide a view into the cellular and molecular mechanisms responsible for age-related hearing loss and pathways for therapeutic targeting.

Transcriptomes and metabolism define mouse and human MAIT cell populations.

Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes that respond to microbial metabolites. We defined MAIT cell populations in different organs and characterized the developmental pathway of mouse and human MAIT cells in the thymus using single-cell RNA sequencing and phenotypic and metabolic analyses. We showed that the predominant mouse subset, which produced IL-17 (MAIT17), and the subset that produced IFN-γ (MAIT1) had not only greatly different transcriptomes but also different metabolic states. MAIT17 cells in different organs exhibited increased lipid uptake, lipid storage, and mitochondrial potential compared with MAIT1 cells. All these properties were similar in the thymus and likely acquired there. Human MAIT cells in lung and blood were more homogeneous but still differed between tissues. Human MAIT cells had increased fatty acid uptake and lipid storage in blood and lung, similar to human CD8 T resident memory cells, but unlike mouse MAIT17 cells, they lacked increased mitochondrial potential. Although mouse and human MAIT cell transcriptomes showed similarities for immature cells in the thymus, they diverged more strikingly in the periphery. Analysis of pet store mice demonstrated decreased lung MAIT17 cells in these so-called "dirty" mice, indicative of an environmental influence on MAIT cell subsets and function.

Anterior Open Bite Malocclusion: From Clinical Treatment Strategies towards the Dissection of the Genetic Bases of the Disease Using Human and Collaborative Cross Mice Cohorts.

Anterior open bite malocclusion is a complex dental condition characterized by a lack of contact or overlap between the upper and lower front teeth. It can lead to difficulties with speech, chewing, and biting. Its etiology is multifactorial, involving a combination of genetic, environmental, and developmental factors. Genetic studies have identified specific genes and signaling pathways involved in jaw growth, tooth eruption, and dental occlusion that may contribute to open bite development. Understanding the genetic and epigenetic factors contributing to skeletal open bite is crucial for developing effective prevention and treatment strategies. A thorough manual search was undertaken along with searches on PubMed, Scopus, Science Direct, and Web of Science for relevant studies published before June 2022. RCTs (clinical trials) and subsequent observational studies comprised the included studies. Orthodontic treatment is the primary approach for managing open bites, often involving braces, clear aligners, or other orthodontic appliances. In addition to orthodontic interventions, adjuvant therapies such as speech therapy and/or physiotherapy may be necessary. In some cases, surgical interventions may be necessary to correct underlying skeletal issues. Advancements in technology, such as 3D printing and computer-assisted design and manufacturing, have improved treatment precision and efficiency. Genetic research using animal models, such as the Collaborative Cross mouse population, offers insights into the genetic components of open bite and potential therapeutic targets. Identifying the underlying genetic factors and understanding their mechanisms can lead to the development of more precise treatments and preventive strategies for open bite. Here, we propose to perform human research using mouse models to generate debatable results. We anticipate that a genome-wide association study (GWAS) search for significant genes and their modifiers, an epigenetics-wide association study (EWAS), RNA-seq analysis, the integration of GWAS and expression-quantitative trait loci (eQTL), and micro-, small-, and long noncoding RNA analysis in tissues associated with open bite in humans and mice will uncover novel genes and genetic factors influencing this phenotype.

Host Genetic Background Effect on Body Weight Changes Influenced by Heterozygous Smad4 Knockout Using Collaborative Cross Mouse Population.

Obesity and its attendant conditions have become major health problems worldwide, and obesity is currently ranked as the fifth most common cause of death globally. Complex environmental and genetic factors are causes of the current obesity epidemic. Diet, lifestyle, chemical exposure, and other confounding factors are difficult to manage in humans. The mice model is helpful in researching genetic BW gain because genetic and environmental risk factors can be controlled in mice. Studies in mouse strains with various genetic backgrounds and established genetic structures provide unparalleled opportunities to find and analyze trait-related genomic loci. In this study, we used the Collaborative Cross (CC), a large panel of recombinant inbred mouse strains, to present a predictive study using heterozygous Smad4 knockout profiles of CC mice to understand and effectively identify predispositions to body weight gain. Male C57Bl/6J Smad4+/- mice were mated with female mice from 10 different CC lines to create F1 mice (Smad4+/-x CC). Body weight (BW) was measured weekly until week 16 and then monthly until the end of the study (week 48). The heritability (H2) of the assessed traits was estimated and presented. Comparative analysis of various machine learning algorithms for predicting the BW changes and genotype of mice was conducted. Our data showed that the body weight records of F1 mice with different CC lines differed between wild-type and mutant Smad4 mice during the experiment. Genetic background affects weight gain and some lines gained more weight in the presence of heterozygous Smad4 knockout, while others gained less, but, in general, the mutation caused overweight mice, except for a few lines. In both control and mutant groups, female %BW had a higher heritability (H2) value than males. Additionally, both sexes with wild-type genotypes showed higher heritability values than the mutant group. Logistic regression provides the most accurate mouse genotype predictions using machine learning. We plan to validate the proposed method on more CC lines and mice per line to expand the literature on machine learning for BW prediction.

Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2−/− mice. Compared to wild-type mice, female Asah2−/− mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

Long-Term Stability of Harvest Mouse Population

The Eurasian harvest mouse (Micromys minutus) is a tiny rodent of the Palearctic and Indomalayan regions, with a distinct regional species status in Europe and irregularly varying local numbers. We analysed the population of M. minutus in Lithuania (Northern Europe) based on trapping data from 1975 to 2022 and owl pellet data from 1986 to 2009. Based on both datasets, the proportion of this species in the small mammal community was similar, 1.13% and 0.62%, respectively. The proportions have remained stable across all decades. Relative abundance was 1.19 ± 0.19 individuals per 1000 trap days, stable over the long term and across the country. Irregular fluctuations in abundance were observed in some of the sites surveyed. The highest average RA was recorded in open sedge habitats, meadows and marshes. The absolute highest RA was 88 individuals per 1000 trap days in floodplain meadows after a major flood. Although the negative impact of habitat anthropogenisation has been confirmed, M. minutus does not require special conservation measures in Lithuania.

Tdsa: An R package for time‐dependent sensitivity analysis

Abstract Sensitivity analysis of ecological and epidemiological models is often used to identify the best targets of opportunity for control or management, for example, which subpopulations should be prioritised for vaccination or protection. However, effectiveness of a management action depends not just on which system component is targeted but also on when an action is taken. Traditional methods of model sensitivity analysis apply to time‐invariant parameter perturbations, which limits their ability to address questions about the timing of management interventions. A semianalytic method for performing time‐dependent sensitivity analysis (TDSA) has been recently introduced to address this need (Ng et al., in press). However, some of the steps typically require substantial time and effort. We have developed an R package, tdsa, that automates all steps required for TDSA by using numerical rather than analytic differentiation of model terms to evaluate the sensitivity equations. By avoiding analytic differentiation, the package substantially reduces user effort and risk of human error and increases the generality of TDSA by making it possible to analyse nonparametric or equation‐free models. The results of TDSA may be sensitive to assumptions of the system model. By reducing the effort needed to perform TDSA, the tdsa package facilitates comparison of results under different model assumptions, hence allowing for more robust conclusions. We illustrate this using an example involving the transmission of Morogoro virus in the Natal multimammate mouse, under different assumptions about how the contact rate depends on mouse population density. By automating most of the mathematical and programming steps of the semianalytical approach, the tdsa package makes TDSA accessible to a wide range of users with varying quantitative expertise.

OA2‐AM23‐MN‐19 | Genetic Loci Containing Immunoregulatory IFIT Genes are Associated with RBC Alloimmunization in an Outbred Mouse Population

OA2‐AM23‐MN‐19 | Genetic Loci Containing Immunoregulatory IFIT Genes are Associated with RBC Alloimmunization in an Outbred Mouse Population

Seasonal and sex-specific changes in the gastrointestinal tracts of Peromyscus maniculatus.

Functional traits are phenotypic characteristics that contribute to fitness of individuals in dynamic and changing environments. In mammals, both categorical and continuous (e.g., quantitative) functional traits have been extensively utilized as proxies for diet, locomotion, and other aspects of species ecology, but there has been less focus on form and function of soft tissues. This is particularly true for the digestive system, which varies in size and complexity across Class Mammalia and plays a major role in the energetics of species. To guide more effective utilization of gastrointestinal (GI) morphology as a functional proxy in small mammal ecology, we examined how GI tracts (lengths and masses of four GI sections) varied within a population of deer mice (Peromyscus maniculatus) in the Southern Appalachian Mountains of North Carolina, United States. We collected samples of adult P. maniculatus monthly for 1 year and measured GI tracts to quantify variation with respect to seasonality and trophic level, providing insight into plasticity in this soft tissue trait over time. We found that season had a significant effect on the total length and wet mass of the GI tract, with January mice having the longest GI tracts and lengths being shortest in the summer. The relative shortening of the GI tract in summer corresponded with a partial trophic increase detected by stable isotope signatures. GI length and wet mass also were affected by reproduction, but males and females responded in sex-specific ways to demands of reproduction, with reproductively active males having shorter and lighter GI tracts than nonreproductively active males. Our study provides proof-of-concept for understanding population-level plasticity in a rarely collected soft tissue trait, which may also be complementary to standard craniodental measurements as a functional dietary proxy to understand mammalian ecology and community assembly.

Genic constraint against nonsynonymous variation across the mouse genome

BackgroundSelective constraint, the depletion of variation due to negative selection, provides insights into the functional impact of variants and disease mechanisms. However, its characterization in mice, the most commonly used mammalian model, remains limited. This study aims to quantify mouse gene constraint using a new metric called the nonsynonymous observed expected ratio (NOER) and investigate its relationship with gene function.ResultsNOER was calculated using whole-genome sequencing data from wild mouse populations (Mus musculus sp and Mus spretus). Positive correlations were observed between mouse gene constraint and the number of associated knockout phenotypes, indicating stronger constraint on pleiotropic genes. Furthermore, mouse gene constraint showed a positive correlation with the number of pathogenic variant sites in their human orthologues, supporting the relevance of mouse models in studying human disease variants.ConclusionsNOER provides a resource for assessing the fitness consequences of genetic variants in mouse genes and understanding the relationship between gene constraint and function. The study’s findings highlight the importance of pleiotropy in selective constraint and support the utility of mouse models in investigating human disease variants. Further research with larger sample sizes can refine constraint estimates in mice and enable more comprehensive comparisons of constraint between mouse and human orthologues.

Exploring Early-Stage Retinal Neurodegeneration in Murine Pigmentary Glaucoma: Insights From Gene Networks and miRNA Regulation Analyses.

Glaucoma is a group of heterogeneous optic neuropathies characterized by the progressive degeneration of retinal ganglion cells. However, the underlying mechanisms have not been understood completely. We aimed to elucidate the genetic network associated with the development of pigmentary glaucoma with DBA/2J (D2) mouse model of glaucoma and corresponding genetic control D2-Gpnmb (D2G) mice carrying the wild type (WT) Gpnmb allele. Retinas isolated from 13 D2 and 12 D2G mice were subdivided into 2 age groups: pre-onset (1-6months: samples were collected at approximately 1-2, 2-4, and 5-6months) and post-onset (7-15months: samples were collected at approximately 7-9, 10-12, and 13-15months) glaucoma were compared. Differential gene expression (DEG) analysis and gene-set enrichment analyses were performed. To identify micro-RNAs (miRNAs) that target Gpnmb, miRNA expression levels were correlated with time point matched mRNA expression levels. A weighted gene co-expression network analysis (WGCNA) was performed using the reference BXD mouse population. Quantitative real-time PCR (qRT-PCR) was used to validate Gpnmb and miRNA expression levels. A total of 314 and 86 DEGs were identified in the pre-onset and post-onset glaucoma groups, respectively. DEGs in the pre-onset glaucoma group were associated with the crystallin gene family, whereas those in the post-onset group were related to innate immune system response. Of 1329 miRNAs predicted to target Gpnmb, 3 miRNAs (miR-125a-3p, miR-3076-5p, and miR-214-5p) were selected. A total of 47 genes demonstrated overlapping with the identified DEGs between D2 and D2G, segregated into their time-relevant stages. Gpnmb was significantly downregulated, whereas 2 out of 3 miRNAs were significantly upregulated (P < 0.05) in D2 mice at both 3-and 10-month time points. These findings suggest distinct gene-sets involved in pre-and post-glaucoma in the D2 mouse. We identified three miRNAs regulating Gpnmb in the development of murine pigmentary glaucoma.

The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18–20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug’s short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1β, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring.

Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat

Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress.

Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity.

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.

Zoonotic implications of white-footed mice habitat selection and territoriality in fragmented landscapes.

White-footed mouse (Peromyscus leucopus) populations can thrive in fragmented suburban and urban parks and residential spaces and play a pivotal role in the spread and prevalence of tick-borne diseases. We collected spatial data on 58 individual mice living at the intersection of county park land and residential land in suburban Howard County, MD, U.S.A. We analyzed mouse density, home-range size and overlap, and a Bayesian mixed-effects model to identify the habitats where they were found relative to where they were caught, as well as a resource selection function for general habitat use. We found that as mouse density increased, home-range size decreased. The overlap indices and the resource selection function supported territoriality coupled with site-specific space use in these suburban mouse populations. While mice occurred in open areas, forest edge, and forest, they showed a strong preference for forested areas. Interestingly, mice captured only 30 to 40 m into the forest rarely used the nearby private yards or human structures and this has direct implications for the placement of rodent-targeted tick control treatments. Our study supports the need for zoonotic disease management frameworks that are based on site-specific land cover characteristics as well as specific management objectives.

From chip to SNP: Rapid development and evaluation of a targeted capture genotyping-by-sequencing approach to support research and management of a plaguing rodent.

The management of invasive species has been greatly enhanced by population genetic analyses of multilocus single-nucleotide polymorphism (SNP) datasets that provide critical information regarding pest population structure, invasion pathways, and reproductive biology. For many applications there is a need for protocols that offer rapid, robust and efficient genotyping on the order of hundreds to thousands of SNPs, that can be tailored to specific study populations and that are scalable for long-term monitoring schemes. Despite its status as a model laboratory species, there are few existing resources for studying wild populations of house mice (Mus musculus spp.) that strike this balance between data density and laboratory efficiency. Here we evaluate the utility of a custom targeted capture genotyping-by-sequencing approach to support research on plaguing house mouse populations in Australia. This approach utilizes 3,651 hybridization capture probes targeting genome-wide SNPs identified from a sample of mice collected in grain-producing regions of southeastern Australia genotyped using a commercially available microarray platform. To assess performance of the custom panel, we genotyped wild caught mice (N = 320) from two adjoining farms and demonstrate the ability to correctly assign individuals to source populations with high confidence (mean >95%), as well as robust kinship inference within sites. We discuss these results in the context of proposed applications for future genetic monitoring of house mice in Australia.