Biology subjects

Bains, R. S.

Publications and source records attributed to Bains, R. S..

8 recordsLinked to original sources

bioRxiv2026

Using machine learning to automate the analysis of an olfactory habituation-dishabituation task in mice

IntroductionImproving the efficiency and accuracy of annotation and extraction of performance data from mouse behavioural tasks will improve both the throughput and scientific value of preclinical research. MethodsHere, we present and validate an automated pipeline for the annotation and quantification of performance in a mouse olfactory habituation-dishabituation task, using a single side-view camera, resulting in occluded body parts. We created a pipeline for task analysis, combining DeepLabCut, for pose-estimation, and SimBA, for behavioural classification to automatically quantify odour interaction (sniffing time) in a three-odour (water, familiar mouse social odour, novel mouse social odour) variant of the task. We used a subset of previously published, fully manually annotated datasets to train the models and unseen videos from the same study to validate the utility of our machine learning pipeline. Results and conclusionOur analysis pipeline estimated behavioural performance in the task with high accuracy, and the data produces similar technical and biological results to manual methods when analysed by linear mixed modelling. Thus, we validated the utility of our new pipeline for the automated scoring of this mouse sensory task.

animal behavior and cognition↗

bioRxiv2025

The Preclinical Animal Network (PCAN): Integrative high-throughput phenotyping of standardized mouse models for Prader-Willi syndrome

The Preclinical Animal Network (PCAN) is a collaborative resource established to advance translational research and therapeutic development for Prader-Willi syndrome (PWS), a rare neurodevelopmental disorder caused by loss of paternally expressed genes on chromosome 15q11-q13. PCAN integrates standardized, high-throughput phenotyping of approximately 1,000 mice across six engineered lines carrying paternal deletions of Ndn, Magel2, Snord116, Ipw, and multigenic loci. Using validated experimental pipelines spanning metabolic, behavioral, and developmental domains, we captured comprehensive phenotypic profiles by applying a statistical variance-decomposition framework to partition genetic and environmental contributions. This analysis provides robust genotype-phenotype maps, revealing shared and model-specific phenotypic effects while accounting for key confounding factors. The PCAN resource provides a framework for evaluating PWS-relevant phenotypes and benchmarking therapeutic strategies. By providing open access to its mouse models, datasets and analytical resources, PCAN enables the research community to apply standardized, reproducible workflows and accelerate the development of targeted, mechanism-based treatments.

genetics↗

bioRxiv2025

Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction

Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell spontaneous activity. We report that changes in synaptic innervation and intrinsic Purkinje cell activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of Purkinje cell dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different Purkinje cell populations in SCA.

neuroscience↗

bioRxiv2024

Long-read transcriptomic identification of synaptic adaptation to amyloid pathology in the App(NL-G-F) knock-in mouse model of the earliest phase of Alzheimer's disease

Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimers disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the AppNL-G-F knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-{beta}. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-{beta} at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the AppNL-G-F knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-{beta} during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.

genetics↗

bioRxiv2023

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

FUS (Fused in sarcoma) is a ubiquitously expressed DNA/RNA binding protein. Mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. While most studies have focused on the role of FUS in motor neuron degeneration, little is known about the effect of FUS mutations in the whole body, and the impact of FUS mutations in the correct development of the nervous system. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the FUSDelta14 mutation in homozygosity. RNA sequencing was conducting in six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) to identify the genes and pathways altered by the FUSDelta14 mutant protein in the systemic transcriptome. Additionally, brain structural magnetic resonance imaging (MRI) and histological characterisation was conducted in young mice to study the role of FUS mutation in the brain development. FUS mutant protein was upregulated and mislocalised in the cytoplasm in most cells of the tissues analysed. We identified few genes commonly altered in all tissues by this mutation, although most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We demonstrated that the disease aetiology of FUS mutations can include neurodevelopmental and systemic alterations, which should be taken into consideration in the clinic.

neuroscience↗

bioRxiv2023

Comprehensive longitudinal study of home-cage activity, including climbing, reveals new complex phenotypic profile in the N171-82Q HD mouse model with implications for refined preclinical studies.

Monitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. In this study, we focus on non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. We show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used mouse model of neurodegeneration. In addition, performing such measurements in the home-cage environment, over several 24-hour periods, allows for the collection of comprehensive behavioral and activity data, which reveals prolific sexual dimorphism and biphasic changes in locomotor activity. Here we present data from home-cage analysis, which reveals the complexity of unprovoked behavior in both wild-type and mutant mice. This has the potential to greatly enhance the characterization of mouse strains, detect early and subtle signs of disease and increase reproducibility in preclinical studies.

neuroscience↗

bioRxiv2020

Aberrant synaptic release underlies sleep/wake transition deficits in a mouse Vamp2 mutant

Sleep-wake transitions are modulated through extensive subcortical networks although the precise roles of their individual components remain elusive. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterised by a reduced propensity to transition between all sleep states while a profound loss in total REM sleep time was evident. The causative mutation, an Ile102Asn substitution in VAMP2, was associated with substantial synaptic changes while in vitro electrophysiological investigations with fluorescence imaging revealed a diminished probability of vesicular release in mutants. We conclude that the synaptic efficiency of the entire subcortical brain network determines the likelihood that an animal transitions from one vigilance state to the next.

neuroscience↗

bioRxiv2018

Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Summary statementIn this study, we show that the loss of the epilepsy-related gene Frrs1l in mice causes a dramatic reduction in AMPA receptor levels at the synapse. This change elicits severe motor and coordination disabilities, hyperactivity, cognitive defects, behavioural seizures and abnormal electroencephalographic (EEG) patterns.\n\nAbstractLoss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis and assembly, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in glycosylation deficits in GLUA2 and GLUA4 AMPA receptor proteins, leading to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.

neuroscience↗