A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

Mass spectrometry detection of inhaled drug in distal fibrotic lung.

BACKGROUND: Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease. METHODS: Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography-tandem Mass Spectrometry. RESULTS: Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants. CONCLUSIONS: In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route. Trial registration A prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120).

Holocene shifts in the assembly of plant and animal communities implicate human impacts.

Understanding how ecological communities are organized and how they change through time is critical to predicting the effects of climate change. Recent work documenting the co-occurrence structure of modern communities found that most significant species pairs co-occur less frequently than would be expected by chance. However, little is known about how co-occurrence structure changes through time. Here we evaluate changes in plant and animal community organization over geological time by quantifying the co-occurrence structure of 359,896 unique taxon pairs in 80 assemblages spanning the past 300 million years. Co-occurrences of most taxon pairs were statistically random, but a significant fraction were spatially aggregated or segregated. Aggregated pairs dominated from the Carboniferous period (307 million years ago) to the early Holocene epoch (11,700 years before present), when there was a pronounced shift to more segregated pairs, a trend that continues in modern assemblages. The shift began during the Holocene and coincided with increasing human population size and the spread of agriculture in North America. Before the shift, an average of 64% of significant pairs were aggregated; after the shift, the average dropped to 37%. The organization of modern and late Holocene plant and animal assemblages differs fundamentally from that of assemblages over the past 300 million years that predate the large-scale impacts of humans. Our results suggest that the rules governing the assembly of communities have recently been changed by human activity.

Multimodal imaging of drug and excipients in rat lungs following an inhaled administration of controlled-release drug laden PLGA microparticles.

Controlled-release formulations, in the form of micro- or nanoparticles, are increasingly attractive to the pharmaceutical industry for drug delivery. For respiratory illnesses, controlled-release microparticle formulations provide an opportunity to deliver a higher percentage of an inhaled medicament dose to the lung, thus potentially reducing the therapeutic dose, frequency of dosing, and minimising side-effects. We describe the use of a multimodal approach consisting of MALDI MS imaging, 3D depth profiling TOF-SIMS analysis, and histopathology to monitor the distribution of drug and excipients in sections taken from excised rat lungs following an inhaled administration of drug-laden microparticles. Following a single dose, the administered drug was detected in the lung via both MALDI MS and TOF-SIMS over a range of time points. Both imaging techniques enabled the characterisation of the distribution and retention of drug particles and identified differences in the capabilities of both imaging modalities. Histochemical staining of consecutive sections was used to provide biological context to the findings and will also be discussed in this presentation. We demonstrate how this multimodal approach could be used to help increase our understanding of the use of controlled release microparticles.

Isotopic niche variation from the Holocene to today reveals minimal partitioning and individualistic dynamics among four sympatric desert mice.

Species interact with each other and their environment over a range of temporal scales, yet our understanding of resource partitioning and the mechanisms of species coexistence is largely restricted to modern time-scales of years to decades. Furthermore, the relative magnitudes of inter- vs. intraspecific variation in resource use are rarely considered, despite the potential for the latter to influence a species' ability to cope with changing environmental conditions. Modern desert rodent communities are thought to be strongly structured by competitive interactions, with niche partitioning of food resources hypothesized to explain the coexistence of multiple sympatric granivores. Yet the stability of niche dynamics over extended temporal scales within desert rodent communities is unknown. I examined the isotopic niche dynamics of four common sympatric desert mice (three granivores: Chaetodipus formosus, Perognathus longimembris and Reithrodontomys megalotis, and one omnivore: Peromyscus maniculatus) in the Smoke Creek Desert of northwestern Nevada using 13 C and 15 N isotopes obtained from "Modern" (2008-2013 CE), "Historical" (1989-2005 CE) and Holocene fossil specimens spanning the last c. 7,500 years. I found significant variation in niche position, niche breadth and interspecific niche overlap of these species through time. The niche breadth dynamics of the cricetids (P. maniculatus and R. megalotis) were positively correlated with one another, while the niche breadth dynamics of the heteromyid C. formosus were negatively correlated with those of all other species. Body size, dietary functional group, palaeoenvironmental trends and time-averaging provided little explanatory power. Importantly, Modern and Historical patterns of resource use and partitioning differed from Holocene baselines in terms of decreased niche overlap and in the absolute and relative position of each species' niche in at least one isotopic axis. These observations suggest that each species' resource use changed individualistically over the Holocene, hence niche dynamics are poorly explained by the hypothesis of temporally stable species interactions at millennial time-scales. Furthermore, changes to the resource base over the last century (likely due to the spread of invasive cheatgrass) may be increasing resource partitioning in the Modern, pushing species past their baseline ranges of resource use variation.

Energy flow and functional compensation in Great Basin small mammals under natural and anthropogenic environmental change.

Research on the ecological impacts of environmental change has primarily focused at the species level, leaving the responses of ecosystem-level properties like energy flow poorly understood. This is especially so over millennial timescales inaccessible to direct observation. Here we examine how energy flow within a Great Basin small mammal community responded to climate-driven environmental change during the past 12,800 y, and use this baseline to evaluate responses observed during the past century. Our analyses reveal marked stability in energy flow during rapid climatic warming at the terminal Pleistocene despite dramatic turnover in the distribution of mammalian body sizes and habitat-associated functional groups. Functional group turnover was strongly correlated with climate-driven changes in regional vegetation, with climate and vegetation change preceding energetic shifts in the small mammal community. In contrast, the past century has witnessed a substantial reduction in energy flow caused by an increase in energetic dominance of small-bodied species with an affinity for closed grass habitats. This suggests that modern changes in land cover caused by anthropogenic activities--particularly the spread of nonnative annual grasslands--has led to a breakdown in the compensatory dynamics of energy flow. Human activities are thus modifying the small mammal community in ways that differ from climate-driven expectations, resulting in an energetically novel ecosystem. Our study illustrates the need to integrate across ecological and temporal scales to provide robust insights for long-term conservation and management.

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse.

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.

Do coursework summative assessments predict clinical performance? A systematic review.

BACKGROUND: Two goals of summative assessment in health profession education programs are to ensure the robustness of high stakes decisions such as progression and licensing, and predict future performance. This systematic and critical review aims to investigate the ability of specific modes of summative assessment to predict the clinical performance of health profession education students. METHODS: PubMed, CINAHL, SPORTDiscus, ERIC and EMBASE databases were searched using key terms with articles collected subjected to dedicated inclusion criteria. Rigorous exclusion criteria were applied to ensure a consistent interpretation of 'summative assessment' and 'clinical performance'. Data were extracted using a pre-determined format and papers were critically appraised by two independent reviewers using a modified Downs and Black checklist with level of agreement between reviewers determined through a Kappa analysis. RESULTS: Of the 4783 studies retrieved from the search strategy, 18 studies were included in the final review. Twelve were from the medical profession and there was one from each of physiotherapy, pharmacy, dietetics, speech pathology, dentistry and dental hygiene. Objective Structured Clinical Examinations featured in 15 papers, written assessments in four and problem based learning evaluations, case based learning evaluations and student portfolios each featured in one paper. Sixteen different measures of clinical performance were used. Two papers were identified as 'poor' quality and the remainder categorised as 'fair' with an almost perfect (k = 0.852) level of agreement between raters. Objective Structured Clinical Examination scores accounted for 1.4-39.7% of the variance in student performance; multiple choice/extended matching questions and short answer written examinations accounted for 3.2-29.2%; problem based or case based learning evaluations accounted for 4.4-16.6%; and student portfolios accounted for 12.1%. CONCLUSIONS: Objective structured clinical examinations and written examinations consisting of multiple choice/extended matching questions and short answer questions do have significant relationships with the clinical performance of health professional students. However, caution should be applied if using these assessments as predictive measures for clinical performance due to a small body of evidence and large variations in the predictive strength of the relationships identified. Based on the current evidence, the Objective Structured Clinical Examination may be the most appropriate summative assessment for educators to use to identify students that may be at risk of poor performance in a clinical workplace environment. Further research on this topic is needed to improve the strength of the predictive relationship.

The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice.

Mutations in fukutin-related protein (FKRP) underlie a group of muscular dystrophies associated with the hypoglycosylation of α-dystroglycan (α-DG), a proportion of which show central nervous system involvement. Our original FKRP knock-down mouse (FKRP(KD)) replicated many of the characteristics seen in patients at the severe end of the dystroglycanopathy spectrum but died perinatally precluding its full phenotyping and use in testing potential therapies. We have now overcome this by crossing FKRP(KD) mice with those expressing Cre recombinase under the Sox1 promoter. Owing to our original targeting strategy, this has resulted in the restoration of Fkrp levels in the central nervous system but not the muscle, thereby generating a new model (FKRP(MD)) which develops a progressive muscular dystrophy resembling what is observed in limb girdle muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) is a bifunctional glycosyltransferase previously shown to hyperglycosylate α-DG. To investigate the therapeutic potential of LARGE up-regulation, we have now crossed the FKRP(MD) line with one overexpressing LARGE and show that, contrary to expectation, this results in a worsening of the muscle pathology implying that any future strategies based upon LARGE up-regulation require careful management.

Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.

BACKGROUND: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. RESULTS: Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. CONCLUSIONS: This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.

Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse.

Loss of dystrophin protein due to mutations in the DMD gene causes Duchenne muscular dystrophy. Dystrophin loss also leads to the loss of the dystrophin glycoprotein complex (DGC) from the sarcolemma which contributes to the dystrophic phenotype. Tyrosine phosphorylation of dystroglycan has been identified as a possible signal to promote the proteasomal degradation of the DGC. In order to test the role of tyrosine phosphorylation of dystroglycan in the aetiology of DMD, we generated a knock-in mouse with a phenylalanine substitution at a key tyrosine phosphorylation site in dystroglycan, Y890. Dystroglycan knock-in mice (Dag1(Y890F/Y890F)) had no overt phenotype. In order to examine the consequence of blocking dystroglycan phosphorylation on the aetiology of dystrophin-deficient muscular dystrophy, the Y890F mice were crossed with mdx mice an established model of muscular dystrophy. Dag1(Y890F/Y890F)/mdx mice showed a significant improvement in several parameters of muscle pathophysiology associated with muscular dystrophy, including a reduction in centrally nucleated fibres, less Evans blue dye infiltration and lower serum creatine kinase levels. With the exception of dystrophin, other DGC components were restored to the sarcolemma including α-sarcoglycan, α-/ß-dystroglycan and sarcospan. Furthermore, Dag1(Y890F/Y890F)/mdx showed a significant resistance to muscle damage and force loss following repeated eccentric contractions when compared with mdx mice. While the Y890F substitution may prevent dystroglycan from proteasomal degradation, an increase in sarcolemmal plectin appeared to confer protection on Dag1(Y890F/Y890F)/mdx mouse muscle. This new model confirms dystroglycan phosphorylation as an important pathway in the aetiology of DMD and provides novel targets for therapeutic intervention.

Integrating long-acting reversible contraceptives into primary care internal medicine practices: A clinical innovation to reduce wait time.

BACKGROUND: Long-acting reversible contraception (LARC) has long been regarded as highly effective and safe. However, access is limited and lengthy when specialty referrals are required. OBJECTIVES: To integrate LARC services into an urban internal medicine primary care practice to decrease wait time for LARC procedures. DESIGN/METHODS: This pre-post with control group study took place at two large urban academic primary care practices (Practices A and B) and included patients ages 18 to 45 years assigned female sex at birth. Pre-implementation baseline data were collected retrospectively from 2019 to 2020 by identifying subjects who requested LARC insertion or removal via their primary care practice and were referred to Obstetrics and Gynecology (Ob/Gyn) for the procedure. Wait time was noted from time of initial request in the medical record to time of procedure. Practice A developed an integrated primary care LARC program in which one of their LARC-trained providers began offering these procedures within their own practice. All other providers within the practice were educated on how to counsel patients about the devices and procedures. Practice B did not have an in-house LARC provider and continued referring patients to Ob/Gyn. Post-implementation data were collected prospectively 2021-2022. RESULTS: Ninety-one patients in Practice A experienced a significant decrease in wait time (87 vs 21 days, p < 0.001) over the observation period, with a majority undergoing procedures on their first visit with the in-house LARC provider. Wait time for the 54 patients in Practice B remained unchanged (57 vs 47 days, p = .59), often requiring multiple specialty visits. CONCLUSION: Integrating LARC services into a primary care internal medicine practice can significantly reduce wait times for these procedures with the potential to contribute to increased reproductive and menstrual autonomy.

Impaired Arithmetic Fact Retrieval in an Adult with Developmental Dyscalculia: Evidence from Behavioral and Functional Brain Imaging Data.

Developmental dyscalculia (DD) is a developmental disorder characterized by arithmetic difficulties. Recently, it has been suggested that the neural networks supporting procedure-based calculation (e.g., in subtraction) and left-hemispheric verbal arithmetic fact retrieval (e.g., in multiplication) are partially distinct. Here we compared the neurofunctional correlates of subtraction and multiplication in a 19-year-old student (RM) with DD to 18 age-matched controls. Behaviorally, RM performed significantly worse than controls in multiplication, while subtraction was unaffected. Neurofunctional differences were most pronounced regarding multiplication: RM showed significantly stronger activation than controls not only in left angular gyrus but also in a fronto-parietal network (including left intraparietal sulcus and inferior frontal gyrus) typically activated during procedure-based calculation. Region-of-interest analyses indicated group differences in multiplication only, which, however, did not survive correction for multiple comparisons. Our results are consistent with dissociable and processing-specific, but not operation-specific neurofunctional networks. Procedure-based calculation is not only associated with subtraction but also with (untrained) multiplication facts. Only after rote learning, facts can be retrieved quasi automatically from memory. We suggest that this learning process and the associated shift in activation patterns has not fully occurred in RM, as reflected in her need to resort to procedure-based strategies to solve multiplication facts.

Computed tomographic arthrography, gross anatomy and histology demonstrate a communication between synovial invaginations in the proximal aspect of the third interosseous muscle and the carpometacarpal joint in horses.

This descriptive anatomical study investigates the relationship between the third interosseous muscle, also known as the suspensory ligament, and the carpometacarpal joint in forelimbs of horses, with the hypothesis that there was a direct synovial communication between these structures as shown by computed tomographic arthrography, histology, and gross anatomy sections. Computed tomography of the carpus and metacarpal region was performed on two groups. Group 1 consisted of eight cadaver limbs undergoing computed tomographic arthrography following injection of a mixture of positive contrast medium, saline, and color-pigmented fluid solution into the middle carpal joint. Group 2 consisted of eight forelimbs assessed using plain computed tomography. The images were interpreted subjectively for contrast medium distribution and objectively by comparing Hounsfield values of the proximal suspensory ligament at 0.5 cm intervals starting at the origin and extending 3 cm distal to the proximal subchondral bone plate of the third metacarpal bone. Of the 16 limbs, two were sectioned for gross anatomy and one was documented histologically. The proximal suspensory ligament was visualized with clear margins on computed tomography images. The positive contrast medium was found within the lateral and medial lobes of the suspensory ligament in all eight (100%) limbs. Hounsfield units within the suspensory ligament following contrast injection were significantly higher than in those in the plain CT group between 0.5 and 2.5 cm distal to the proximal subchondral bone plate of the third metacarpal bone (p < 0.05). The gross anatomy sections showed color pigmentation within the suspensory ligament correlating to the contrast medium distribution evident on computed tomography images. Histology confirmed a synovial lined cavity within the suspensory ligament. The demonstration of a direct synovial communication between the internal structure of the proximal suspensory ligament and the carpometacarpal joint in horses offers further explanation for commonly encountered interactions of diagnostic local anesthesia of the carpal and subcarpal regions. When performing diagnostic or therapeutic injections into the middle carpal joint, the likely effect on the proximal suspensory ligament should be considered. Furthermore, as the proximal suspensory ligament was identified clearly on CT images, further studies are needed to elucidate the utility of CT in clinical cases with suspected soft tissue pathology in the subcarpal region.

Environmental change and declining resource availability for small-mammal communities in the Great Basin.

Changes in climate and land use can impact natural systems across all levels of ecological organization. Most documented and anticipated effects consider species' properties, including phenologies, geographic distributions, and abundances. Responses of higher-level aggregate community or ecosystem properties have not been considered as they are assumed to be relatively stable due to compensatory dynamics and diversity-stability relationships. However, this assumption may not be as fundamental as previously thought. Here we assess stability in the aggregate properties of total abundance, biomass, and energy consumption for small-mammal communities in the Great Basin, using paired historical and modern survey data spanning nearly a century of environmental change. Results show marked declines in each aggregate property independent of spatial scale, elevation, or habitat type, and a reallocation of available biomass and energy favoring diet and habitat generalists. Because aggregate properties directly reflect resource availability, our findings indicate a regionwide decline in resources of 50% over the past century, which may signal a resource crisis. This work illustrates the power of using aggregate properties as indicators of ecological conditions and environmental change at broad spatial and temporal scales.

Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.

When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use a range of mathematical models and treatment strategies to investigate the tradeoff between controlling cell populations and delaying the emergence of resistance. These models extend game theoretic and competition models with four additional components: 1) an Allee effect where cell populations grow more slowly at low population sizes, 2) healthy cells that compete with cancer cells, 3) immune cells that suppress cancer cells, and 4) resource competition for a growth factor like androgen. In comparing maximum tolerable dose, intermittent treatment, and adaptive therapy strategies, no therapeutic choice robustly breaks the three-way tradeoff among the three therapeutic aims. Almost all models show a tight tradeoff between time to emergence of resistant cells and cancer cell burden, with intermittent and adaptive therapies following identical curves. For most models, some adaptive therapies delay overall tumor growth more than intermittent therapies, but at the cost of higher cell populations. The Allee effect breaks these relationships, with some adaptive therapies performing poorly due to their failure to treat sufficiently to drive populations below the threshold. When eradication is impossible, no treatment can simultaneously delay emergence of resistance, limit total cancer cell numbers, and minimize treatment. Simple mathematical models can play a role in designing the next generation of therapies that balance these competing objectives.

Standardized and reproducible measurement of decision-making in mice.

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here, we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We adopted a task for head-fixed mice that assays perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path toward achieving reproducibility in neuroscience through collaborative open-science approaches.

In science, it is of vital importance that multiple studies corroborate the same result. Researchers therefore need to know all the details of previous experiments in order to implement the procedures as exactly as possible. However, this is becoming a major problem in neuroscience, as animal studies of behavior have proven to be hard to reproduce, and most experiments are never replicated by other laboratories. Mice are increasingly being used to study the neural mechanisms of decision making, taking advantage of the genetic, imaging and physiological tools that are available for mouse brains. Yet, the lack of standardized behavioral assays is leading to inconsistent results between laboratories. This makes it challenging to carry out large-scale collaborations which have led to massive breakthroughs in other fields such as physics and genetics. To help make these studies more reproducible, the International Brain Laboratory (a collaborative research group) et al. developed a standardized approach for investigating decision making in mice that incorporates every step of the process; from the training protocol to the software used to analyze the data. In the experiment, mice were shown images with different contrast and had to indicate, using a steering wheel, whether it appeared on their right or left. The mice then received a drop of sugar water for every correction decision. When the image contrast was high, mice could rely on their vision. However, when the image contrast was very low or zero, they needed to consider the information of previous trials and choose the side that had recently appeared more frequently. This method was used to train 140 mice in seven laboratories from three different countries. The results showed that learning speed was different across mice and laboratories, but once training was complete the mice behaved consistently, relying on visual stimuli or experiences to guide their choices in a similar way. These results show that complex behaviors in mice can be reproduced across multiple laboratories, providing an unprecedented dataset and open-access tools for studying decision making. This work could serve as a foundation for other groups, paving the way to a more collaborative approach in the field of neuroscience that could help to tackle complex research challenges.