Wild Mice Research Articles

The gut bacterial and parasitic microbiome of wild mice in Ishikawa Prefecture

The gut bacterial and parasitic microbiome of wild mice in Ishikawa Prefecture

Phenotypic and Developmental Dissection of an Instance of the Island Rule.

Organismal body weight correlates with morphology, life history, physiology, and behavior, making it perhaps the most telling single indicator of an organism's evolutionary and ecological profile. Island populations provide an exceptional opportunity to study body weight evolution. In accord with the "island rule," insular small-bodied vertebrates often evolve larger sizes, whereas insular large-bodied vertebrates evolve smaller sizes. To understand how island populations evolve extreme sizes, we adopted a developmental perspective and compared a suite of traits with established connections to body size in the world's largest wild house mice from Gough Island and mice from a smaller-bodied mainland strain. We pinpoint 24-hour periods during the third and fifth week of age in which Gough mice gain exceptionally more weight than mainland mice. We show that Gough mice accumulate more visceral fat beginning early in postnatal development. During a burst of weight gain, Gough mice shift toward carbohydrates and away from fat as fuel, despite being more active than and consuming equivalent amounts of food as mainland mice. Our findings showcase the value of developmental phenotypic characterization for discovering how body weight evolves in the context of broader patterns of trait evolution.

Intact, recombinant, and spliced forms of endogenous mouse mammary tumor viruses in inbred and wild mice.

Endogenous retroviruses (ERVs) are copies of viral genomes inserted into host chromosomes, producing a fossil record of past infections and virus-host co-adaptations. ERVs of mouse mammary tumor viruses (Mtvs) were found in all common laboratory strains, all Mus musculus subspecies, and a sister species, Mus spretus. Most laboratory mouse Mtvs predate inbred strain origins and were acquired by M. musculus domesticus, but although widely shared among strains, none of these were found in wild mice. Among wild mouse Mtvs, only one showed a broad geographic distribution. All M. musculus subspecies carry Mtvs with a large envelope deletion corresponding to the processed mRNA for the viral rem gene; such Mtvs likely derive from spliced viral mRNA. The Mtv sag gene responsible for resistance to exogenous infection is under purifying selection and has been subject to recombination, whereas the Mtv envelope and its cellular receptor show no evidence of genetic conflicts.

Establishment and application of a wild neonatal mouse model infected with an Echovirus 30 isolate

BackgroundEchovirus 30 (E30) is a significant pathogen associated with various illnesses such as viral meningitis, viral myocarditis. Currently, there are no specific drugs or vaccines targeting this virus. An appropriate animal model is imperative for assessing drug and vaccine efficacy.MethodsThis investigation aimed to establish a neonatal mouse model using a clinical isolate E30/A538 and apply it to screen anti-E30 drugs. The study involved evaluating the susceptibility of different mouse strains to the isolate, determining the infectious dose, transmission route, and optimal age of the mice. This model was then used to assess antiviral efficacy.ResultsNeonatal ICR mice infected intracranially with 5LD50 of E30/A538 at one-day-old displayed clinical symptoms such as tremors, lethargy, limb paralysis, and mortality. Importantly, the E30/A538-infected mice exhibited brain neuron apoptosis and severe myocardial necrolysis, closely resembling human infections. Elevated levels of viral RNA and positive antigen presence were predominantly detected in the brains and hearts of infected mice. Using this model to assess antiviral efficacy, it was demonstrated that interferon-α2a inhibited E30/A538 replication in vivo, mitigated histopathological changes in the brain, spinal cord, and myocardium, and enhanced the survival rate of neonatal mice.ConclusionsIn summary, this research established a wild neonatal mouse model of E30/A538 isolate infection that mirrors the characteristics of human infection. The model demonstrated the efficacy of interferon-α2a in combating E30. This model would serve as a foundation for investigating the pathogenesis of E30, as well as for assessing the efficacy of vaccines and other antiviral treatments against E30.

Recent genetic drift in the co-diversified gut bacterial symbionts of laboratory mice

Laboratory mice (Mus musculus domesticus) harbor gut bacterial strains that are distinct from those of wild mice but whose evolutionary histories are unclear. Here, we show that laboratory mice have retained gut bacterial lineages that diversified in parallel (co-diversified) with rodent species for > 25 million years, but that laboratory-mouse gut microbiota (LGM) strains of these ancestral symbionts have experienced accelerated accumulation of genetic load during the past ~ 120 years of captivity. Compared to closely related wild-mouse gut microbiota (WGM) strains, co-diversified LGM strains displayed significantly faster genome-wide rates of nonsynonymous substitutions, indicating elevated genetic drift—a difference that was absent in non-co-diversified symbiont clades. Competition experiments in germ-free mice further indicated that LGM strains within co-diversified clades displayed significantly reduced fitness in vivo compared to WGM relatives to an extent not observed within non-co-diversified clades. Thus, stochastic processes (e.g., bottlenecks), not natural selection in the laboratory, have been the predominant evolutionary forces underlying divergence of co-diversified symbiont strains between laboratory and wild house mice. Our results show that gut bacterial lineages conserved in diverse rodent species have acquired novel mutational burdens in laboratory mice, providing an evolutionary rationale for restoring laboratory mice with wild gut bacterial strain diversity.

Computer reconstruction of gene networks controlling anxiety levels in humans and laboratory mice

Anxiety is a normotypic human condition, and like any other emotion has an adaptive value. But excessively high or low anxiety has negative consequences for adaptation, which primarily determines the importance of studying these two extreme conditions. At the same time, it is known that the perception of aversive stimuli associated with anxiety leads to changes in the activity of the brain’s cingulate cortex. The advantage of animals as models in studying the genetic bases of anxiety in humans is in the ability to subtly control the external conditions of formation of a certain state, the availability of brain tissues, and the ability to create and study transgenic models, including through the use of differentially expressed genes of small laboratory animals from the family Muridae with low and high anxiety. Within the framework of the translational approach, a three-domain potential gene network, which is associated with generalized anxiety in humans, was reconstructed using mouse models with different levels of anxiety by automatically analyzing the texts of scientific articles. One domain is associated with reduced anxiety in humans, the second with increased anxiety, and the third is a dispatcher who activates one of the two domains depending on the status of the organism (genetic, epigenetic, physiological). Stages of work: (I) A list of genes expressed in the cingulate cortex of the wild type CD-1 mouse line from the NCBI GEO database (experiment GSE29014). Using the tools of this database, differences in gene expression levels were revealed in groups of mice with low and high (relatively normal) anxiety. (II) Search for orthologs of DEG in humans and mice associated with anxiety in the OMA Orthology database. (III) Computer reconstruction using the ANDSystem cognitive system based on (a) human orthologous genes from stage (III), (b) human genes from the MalaCards database associated with human anxiety. The proven methods of the translational approach for the reconstruction of gene networks for behavior regulation can be used to identify molecular genetic markers of human personality traits, propensity to psychopathology.

Concerning Mercury (Hg) Levels in the Hair of Children Inhabiting a Volcanically Active Area

Background: Gaseous elemental mercury (Hg0 or GEM) is an atmospheric form of mercury (Hg)—a toxic heavy metal—that is naturally released in volcanic environments. Research with wild mice demonstrates that chronic exposure to a hydrothermal volcanic environment leads to the bioaccumulation of Hg in the lungs, but also in both the central (CNS) and peripheric (PNS) nervous systems, with marked indications of neurotoxicity. Studies addressing human exposure to volcanogenic Hg0 are scarce, hence its risks are still unknown. This study aims to evaluate the level of exposure to Hg0 in children living in a volcanically active environment. Methodology and main findings: Two groups of school-aged children (from 6 to 9 years old) were part of this study: one with children inhabiting a hydrothermal area (exposed group) and another with children inhabiting an area without volcanic activity (non-exposed group). Hair samples were collected from each individual for Hg level analysis. It was found that the levels of Hg in the hair of exposed children were 4.2 times higher than in that of non-exposed children (≈1797.84 ± 454.92 ppb vs. 430.69 ± 66.43 ppb, respectively). Conclusion: Given the vast health risks Hg poses, the need to monitor the health of populations inhabiting volcanically active areas is highlighted. Because little is known about the fate, modifications, and effects of Hg0 in the human body, particularly regarding its effects on the nervous system in children, the development of further research within the scope is strongly encouraged.

Avid lysosomal acidification in fibroblasts of the Mediterranean mouse Mus spretus.

Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have discovered that challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in selected species of the genus Mus. We found that cells from M. musculus, mice adapted to human environments, had weak lysosomal acidification and high expression and activity of the lysosomal enzyme β-galactosidase, a classic marker of cellular senescence. Cells of wild relatives, especially the Mediterranean mouse M. spretus, had more robustly performing lysosomes and dampened β-galactosidase levels. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately provide a blueprint for interventions that ameliorate lysosome breakdown in stress and disease.

Secretory leukocyte protease inhibitor influences periarticular joint inflammation in B. burgdorferi-infected mice.

Lyme disease, caused by Borrelia burgdorferi , is the most common tick-borne infection in the United States. Arthritis is a major clinical manifestation of infection, and synovial tissue damage has been attributed to the excessive pro-inflammatory responses. The secretory leukocyte protease inhibitor (SLPI) promotes tissue repair and exerts anti-inflammatory effects. The role of SLPI in the development of Lyme arthritis in C57BL/6 mice, which can be infected with B. burgdorferi , but only develop mild joint inflammation, was therefore examined. SLPI -deficient C57BL/6 mice challenged with B. burgdorferi had a higher infection load in the tibiotarsal joints and marked periarticular swelling, compared to infected wild type control mice. The ankle joint tissues of B. burgdorferi -infected SLPI -deficient mice contained significantly higher percentages of infiltrating neutrophils and macrophages. B. burgdorferi -infected SLPI -deficient mice also exhibited elevated serum levels of IL-6, neutrophil elastase, and MMP-8. Moreover, using a recently developed BASEHIT (BActerial Selection to Elucidate Host-microbe Interactions in high Throughput) library, we found that SLPI directly interacts with B. burgdorferi . These data demonstrate the importance of SLPI in suppressing periarticular joint inflammation in Lyme disease.

Effects of nonlinear impulsive controls and seasonality on hantavirus infection.

Effects of nonlinear impulsive controls and seasonality on hantavirus infection.

Impacts of predation risk on learning and memory of free-living mice.

In predator-prey interactions, responses to predation risk typically involve behavioural, morphological or physiological changes. Laboratory-based studies have also shown changes in prey cognition (i.e. learning and memory), with individuals often showing impairment. However, an ecological perspective predicts that wild animals should conserve their cognitive ability, given that many risk responses require robust cognition. Here, we simulated predation risk and used a field-adapted version of the Morris Water Maze (MWM) to investigate how chronic predation risk affects cognition in wild white-footed mice (Peromyscus leucopus). We found that 24 days' exposure to predation risk did not impair learning. However, those exposed to risk had a 25% reduction of their short-term memory. Twelve days post-risk exposure, we found no performance differences between risk-exposed and control mice. Additionally, risk-exposed mice displayed greater exploration with a higher probability of completing the MWM in their initial trial. Given that prey integrate multiple pieces of information to shape their behaviour, the lack of learning impairment and altered exploration strategies may help mice respond to predation risk. However, the tendency of memory impairment suggests there are consequences for cognition when experiencing increased predation risk.

Phenotypic and Developmental Dissection of an Instance of the Island Rule.

Organismal body weight correlates with morphology, life history, physiology, and behavior, making it perhaps the most telling single indicator of an organism's evolutionary and ecological profile. Island populations provide an exceptional opportunity to study body weight evolution. In accord with the "island rule," insular small-bodied vertebrates often evolve larger sizes, whereas insular large-bodied vertebrates evolve smaller sizes. To understand how island populations evolve extreme sizes, we adopted a developmental perspective and compared a suite of traits with established connections to body size in the world's largest wild house mice from Gough Island and mice from a smaller-bodied mainland strain. We pinpoint 24-hour periods during the third and fifth week of age in which Gough mice gain exceptionally more weight than mainland mice. We show that Gough mice accumulate more visceral fat beginning early in postnatal development. During a burst of weight gain, Gough mice shift toward carbohydrates and away from fat as fuel, despite being more active than and consuming equivalent amounts of food as mainland mice. Our findings showcase the value of developmental phenotypic characterization for discovering how body weight evolves in the context of broader patterns of trait evolution.

The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration

BackgroundMetabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions.MethodsPDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome.ResultsThe dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development.ConclusionsThese results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape.

Effects of behavioural types on the problem‐solving performance of wild house mice under controlled and semi‐natural conditions

Animals often face challenges that require them to come up with solutions to novel problems or to find new solutions to existing ones; i.e. they need to innovate. However, not all individuals in a population are equally likely to solve novel problems, and it is unclear which individual characteristics make a successful innovator. Theoretical frameworks suggest the importance of intrinsic (e.g. individual characteristics) and extrinsic (e.g. study condition) factors on problem‐solving performance. Such frameworks have been empirically tested in model, highly neophobic species, leaving the generality of these processes unclear. We examined whether behavioural traits such as exploration and risk‐taking are linked to problem‐solving behaviour, using two replicated populations (n = 121) of wild house mice Mus musculus domesticus living under semi‐natural conditions. There, we presented a battery of four problem‐solving setups that individuals could access voluntarily, and we tested the mice for risk‐taking and exploration. Furthermore, after acclimatising to cages, we tested a subset (n = 50) of the same individuals in controlled conditions, to validate the cross‐context stability of cognitive performance and potential influences of behaviours. We placed single individuals overnight in arenas containing another four novel problem‐solving setups. Contrasting most existing literature, we found no direct effects of behavioural type on the likelihood to problem‐solve in either condition. However, there was an indirect effect, with shyer individuals visiting the problems more, which improved their likelihood of solving them. Additionally, mice were more likely to solve alone, and individuals were not consistent across conditions. Our findings suggest that exploration and risk‐taking do not affect the ability to problem‐solve across different conditions, but impact the non‐cognitive steps that lead to the final performance. Also, individuals did not perform consistently across conditions, questioning the ecological validity of measures taken under controlled, artificial conditions when they do not reflect the animals' natural experience.

Characteristic visual phenotypes in Korean wild mice (KWM/Hym)

Abstract Background In the last few decades, numerous efforts have been made to develop a better mouse model to overcome the current limitations of laboratory inbred mouse models such as have a weaker and simpler immune status. As part of these efforts, in Korea, the Hallym university medical genetics research team has been developing a new inbred strain of Korean wild mouse KWM/Hym. It was suggested that this strain, which is derived from wild mice, might be useful for genetic research and may become a valuable tool for overcoming some limitations seen in inbred mice that are currently used in the laboratory. Furthermore, for this study, we aimed to determine the visual phenotype of this unique strain KWM/Hym, and consider whether and if they are suitable for visual research. To analyze their visual phenotype, we performed the functional and morphological examinations in KWM/Hym mice and compared the results with laboratory mice which are the most common background strain. Results KWM/Hym had a thin corneal phenotype, thin but well-ordered retina due to their light body weight characteristic, and normal visual function similar to control mice. Unexpectedly, the KWM/Hym mice developed cataracts only at around 25 weeks old. Conclusions We suggest Korean wild mouse KWM/Hym is useful for visual experiments and could be an animal model of eye disease in humans.

Effects of Directive 2010/63/EU on research on wild-sourced animals: a review of publication trends in studies on captive wild mice (Apodemus sp.).

Most animals used in experimentation are small mammals. In the EU, Directive 2010/63/EU regulates the use of laboratory animals for experimental purposes. However, there are few guidelines for the use of wild-sourced animals, which cover permits, experimentation, transport, maintenance, and setting free after experiments. To evaluate the effect of the Directive on the study of wild-sourced animals, we conducted a systematised literature review focusing on three widespread rodents of the genus Apodemus: Apodemus agrarius, A. flavicollis and A. sylvaticus. We selected studies performed across the EU, published before (2000-August 2010), during (September 2010-2012) and after implementation of the Directive (2013-2022). From those, we collected data on three main topics: i) authorisation; ii) care and accommodation and iii) methods of killing. We found that after implementation of the Directive a higher proportion of published studies provided information about authorisation. In contrast, there was no significant difference over time in the information given about the care and accommodation of animals or methods of killing. As such, our analysis suggests that there is still room for improvement to achieve consistency across journals publishing research involving wild-sourced small mammals. Specifically, editors should require the provision of detailed information by authors regarding proper animal care (e.g. more detailed care and accommodation protocols). To harmonise the information requested by different editorial boards, we recommend the addition of specific guidelines in the Directive regarding wild animals, particularly on their proper accommodation, manipulation, enrichment and veterinary control.

Wild-Mouse-Derived Gut Microbiome Transplantation in Laboratory Mice Partly Alleviates House-Dust-Mite-Induced Allergic Airway Inflammation

Laboratory mice are instrumental for preclinical research but there are serious concerns that the use of a clean standardized environment for specific-pathogen-free (SPF) mice results in poor bench-to-bedside translation due to their immature immune system. The aim of the present study was to test the importance of the gut microbiota in wild vs. SPF mice for evaluating host immune responses in a house-dust-mite-induced allergic airway inflammation model without the influence of pathogens. The wild mouse microbiome reduced histopathological changes and TNF-α in the lungs and serum when transplanted to microbiota-depleted mice compared to mice transplanted with the microbiome from SPF mice. Moreover, the colonic gene expression of Gata3 was significantly lower in the wild microbiome-associated mice, whereas Muc1 was more highly expressed in both the ileum and colon. Intestinal microbiome and metabolomic analyses revealed distinct profiles associated with the wild-derived microbiome. The wild-mouse microbiome thus partly reduced sensitivity to house-dust-mite-induced allergic airway inflammation compared to the SPF mouse microbiome, and preclinical studies using this model should consider using both ‘dirty’ rewilded and SPF mice for testing new therapeutic compounds due to the significant effects of their respective microbiomes and derived metabolites on host immune responses.

Potential radiosensitive germline biomarkers in the testes of wild mice after the Fukushima accident.

We investigated potential germline-specific radiosensitive biomarkers in the testes of large Japanese field mice (Apodemus speciosus) exposed to low-dose-rate (LDR) radiation after the Fukushima accident. Fukushima wild mice testes were analysed via RNA-sequencing to identify genes differentially expressed in the breeding and non-breeding seasons when compared to controls. Results revealed significant changes during the breeding season, with Lsp1 showing a considerable upregulation, while Ptprk and Tspear exhibited significant reductions. Conversely, in the non-breeding season, Fmo2 and Fmo2 (highly similar) were significantly upregulated in radiation-exposed Fukushima mice. qPCR analysis results were consistent with transcriptome sequencing, detecting Lsp1 and Ptprk regulation in the testes of Fukushima mice. While differences in gene expression were observed, these do not imply any causal association between the identified biomarkers and chronic LDR exposure, as other factors such as the environment and developmental age may contribute. This study provides valuable insights into the reproductive biology is affected by environmental radiation and highlights the value of assessing the effects of chronic LDR radiation exposure on testicular health in wild mice.

Mutations in Tau’s Proline Rich Domain Affect its Protein Interactions

AbstractBackgroundEpileptic activity is increasingly recognized as a contributor to Alzheimer’s Disease (AD) pathology. In AD models, endogenous tau contributes to epileptic activity and associated cognitive deficits through mechanisms that are not fully understood. Increased attention is being directed towards tau’s interactions with proteins that regulate neuronal activity, particularly tau’s proline rich domain and its binding to SH3‐containing proteins. However, the impact of mutations in tau’s proline‐rich region on other protein interactions remains unclear.MethodWe assessed mutations in tau’s proline rich domain in two mouse lines: AxxA6 (P‐to‐A substitutions in 6th PxxP motif in tau) and R221A (R‐to‐A substitution at amino acid corresponding to 221 in human 2N4R tau). These mutations block tau’s interactions with SH3‐containing proteins, including PLCγ1 and p85α/PI3K. Co‐immunoprecipitation (Co‐IP) of tau from cortical brain tissue was confirmed and analyzed by mass spectrometry. We compared protein abundance ratios to wild type tau mice within each mouse line. Significant (p<.05) tau‐baited protein interactions were further explored within literature and the String Database.ResultThe R221A line produced 143 and 120 significant proteins within the heterozygous and homozygous groups, respectively. Many identified proteins are strongly associated with processes such as microtubule organization, postsynaptic structure, and mitochondrial functions. The AxxA6 line produced 158 and 126 significant proteins within the heterozygous and homozygous groups, respectively. Many identified proteins are involved in cellular trafficking and are strongly associated with processes such as glutamate catabolic processes and microtubule protein localization. Notably, many proteins identified in both lines are involved in prion disease and vascular endothelial growth factor (VEGF) signaling pathways.ConclusionCo‐IP mass spectrometry of the R221A and AxxA6 mouse lines revealed that mutations in tau’s proline rich domain to affect tau’s interactions with multiple proteins. Of the significant proteins, multiple are related to microtubule, metabolic, synaptic, and mitochondrial activity, and many are found within prion disease pathways and VEGF signaling pathways. Interestingly, PLCγ1 and p85α/PI3K, are also implicated in VEGF signaling pathways. These findings highlight the importance of further investigating the possible relationships between noted cellular processes and biological pathways and tau‐protein interactions in familial AD.

Impact of Surgical Mouse Model of Large Arterial Stiffening on Cognition

AbstractBackgroundIn humans, larger artery stiffening is associated with increased tau phosphorylation and neurodegeneration. However, because arterial stiffness often co‐occurs with other age‐related conditions like hypertension, atherosclerosis, and diabetes, it is nearly impossible to distill the underlying mechanisms specifically linking arterial stiffening to abnormal brain function. We leveraged a surgical mouse model of larger artery stiffening and used it concurrently with a transgenic Alzheimer’s disease (AD) mouse model of tau pathology to investigate the impact of larger artery stiffening on cognition. Large arterial stiffening typically occurs during middle age, so this model was tested in 5‐month old mice.Method5‐month old, male and female, P301S (n = 6) and wild‐type littermate controls (n = 11) underwent a carotid calcification surgery, where both carotid arteries was exposed to 0.3 mol/L CaCl2 (or saline as a control) for 20 minutes. Carotid compliance, shown as change in diameter within a cardiac cycle, was measured in vivo using M‐Mode Doppler Ultrasound imaging before and after surgery. Three weeks post‐surgery, mice underwent behavioral testing, including locomotor activity, elevated zero maze, Morris Water maze, Y‐maze, novel object recognition, and nest building.ResultCaCl2 exposure led to decreased post‐operatively compliance of the carotid artery as measured by a significantly decreased change in carotid diameter compared to saline treated mice in both left and right arteries (A. n = 8‐9; p = 0.0003. B. n = 8‐9; p = 0.015) (Figure 1). Preliminary data suggest the carotid calcification surgery impairs ability to learn the position of the escape platform in the Morris water maze in the wild type control mice (Figure 2). Data are not currently sufficiently powered to establish whether the same effect will also be observed in the P301S mice (n = 5‐6 per group WT, 3 per group P301S).ConclusionThe carotid calcification surgery significantly decreased compliance of the carotid artery in vivo and demonstrated successful stiffening of the large artery. The preliminary data suggest this reduced compliance impairs cognition, specifically spatial learning abilities, but whether the effect is greater in P301S mice is unclear. This model will further be used to investigate whether the carotid calcification surgery accelerates development of tau pathology seen in the P301S mice.