Biology subjects

Ellegood, J.

Publications and source records attributed to Ellegood, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Brain structural and genetic correlates of motor coordination and learning behaviours: modelling developmental coordination disorder

Developmental coordination disorder (DCD) is a common neurodevelopmental condition characterized by impaired motor coordination and learning, yet its neurobiological and genetic bases remain poorly understood. Here, we leverage the BXD recombinant inbred mouse panel to model the polygenic architecture of DCD and link behaviour, brain structure, and genotype. High-resolution ex vivo MRI across 14 strains revealed that DCD-like mice have modestly reduced total brain volume, with a distinct neuroanatomical profile characterized by enlarged cortical regions alongside reduced cerebellar, thalamic, and other subcortical volumes. These structural differences closely mirror findings reported in human DCD. Across strains, variation in brain structure strongly correlated with motor behaviours, with coordinated patterns linking increased cortical and decreased subcortical volumes to poorer motor coordination, while more focal associations were observed for motor learning. Multivariate analysis identified a dominant brain-behaviour axis capturing this cortical-subcortical trade-off. Quantitative trait locus (QTL) mapping revealed multiple loci influencing regional brain volumes, including a prominent locus on chromosome 12 regulating cerebellar structures, but did not identify single loci driving the main multivariate brain-behaviour relationships, consistent with a distributed genetic architecture. Together, these findings demonstrate that DCD-like motor impairments arise from coordinated alterations across distributed brain systems under polygenic control. This work establishes a translational framework linking genetic variation to brain organization and motor function, and suggests that DCD reflects the extreme of a continuous spectrum of neurobiological variation rather than a discrete condition.

neuroscience↗

bioRxiv2026

Gonadal and sex chromosomal contributions to sex differences in mammalian brain organization

Sex differences in brain development may contribute to well-known sex differences in behavior and neuropsychiatric risk - making it important to comprehensively map and mechanistically annotate normative sex differences in brain organization. Most sex differences in mammalian brain organization have previously been attributed to differential effects of gonadal hormones based on outcomes from rodent endocrine manipulations at canonical subcortical foci of male-biased brain volume. However, a systematic quantification of both gonadal and sex chromosome dosage (SCD) contributions across all regions of sex-biased brain volume has been lacking. Here, using structural neuroimaging scans from wild-type (n=670) and transgenic mice that dissociate gonadal, X-, and Y-chromosome effects (n=181), we show that: many more brain regions are volumetrically sex-biased than previously recognized; gonadal effects dominate throughout this expanded map of sex differences; several regions also show prominent SCD contributions to anatomical sex differences, which can both reinforce or counteract gonadal effects in a regionally specific manner. Targeted single nucleus RNA sequencing at a region of female-biased cerebellar volume reveals that combined gonadal and SCD effects also drive sex-biased cellular gene expression. These findings revise our understanding of the spatial distribution and causal basis of sex-differences in the mammalian brain, illuminating a key axis of biological variation in health and disease.

neuroscience↗

bioRxiv2025

Altered brain structure in an ATRX-deficient mouse model of autism spectrum disorder

Mutations in the ATRX gene are a primary cause of ATR-X syndrome, which is characterized by intellectual disability, autism, and a range of brain structural abnormalities, including microcephaly. We previously showed that mice with conditional ATRX ablation in forebrain excitatory neurons display deficits in fear memory and autism-related behaviors, with some effects exhibiting sexual dimorphism. In this study, we used high-resolution magnetic resonance imaging (MRI) to systematically characterize brain structural changes associated with these behavioral abnormalities. Whole-brain analysis revealed male-specific microcephaly, while subregional analysis identified significant reductions in hippocampal structures and increased volume of the caudal cortex in mutant animals of both sexes. We also identified structural alterations in regions retaining ATRX expression, such as the thalamus, midbrain, cerebellum, and several fiber tracts. These findings suggest that ATRX loss disrupts the coordinated development of interconnected brain regions. Overall, our results implicate impaired cortico-thalamic-cerebellar connectivity as a potential neural substrate underlying the autistic-like behaviors observed in this mouse model, providing new insights into the neurobiological basis of ATR-X syndrome. LAY SUMMARYChanges in a gene called ATRX are known to affect brain development and are linked to intellectual disability and autism. In our previous work, we found that removing this gene early in brain development caused mice to show behaviors like those seen in people with autism. In this study, we used detailed brain scans to see if these behavioral changes were linked to differences in brain structure. We found that male mice without ATRX had smaller brains and bodies, while female mice did not show the same brain size reduction. However, both male and female mice had smaller areas of the brain important for memory and movement, and larger areas involved in thinking and sensing. We also saw changes in parts of the brain where ATRX was still present, suggesting that early changes in one area can affect how the whole brain develops. These findings help us understand how early disruptions in brain development might lead to autism-related behaviors.

neuroscience↗

bioRxiv2025

Assigning Targetable Molecular Pathways to Transdiagnostic Subgroups Across Autism and Related Neurodevelopmental Disorders

The heterogeneity of autism and related neurodevelopmental conditions has impeded accurate prognoses and treatment discovery. Using translational neuroimaging across 135 mouse models (3,515 mice) and two human MRI datasets (n = 1,234 and n = 1,015), we derived participant subgroups from shared neuroanatomical features. These subgroups did not distinguish autism, ADHD, or OCD diagnoses and only modestly differentiated cognitive and behavioural phenotypes. Instead, they mapped onto four molecular pathways: (1) synaptic function; (2) MAPK and Wnt signalling; (3) chromatin modification and cellular stress responses; and (4) broader chromatin, immune, and second-messenger signalling pathways. This framework bridges preclinical models and idiopathic human neurodevelopmental conditions, linking patients to biologically relevant molecular mechanisms.

neuroscience↗

bioRxiv2025

Biological subtyping of autism via cross-species fMRI

It is frequently assumed that the phenotypic heterogeneity in autism spectrum disorder reflects underlying pathobiological variation. However, direct evidence in support of this hypothesis is lacking. Here, we leverage cross-species functional neuroimaging to examine whether variability in brain functional connectivity reflects distinct biological mechanisms. We find that fMRI connectivity alterations in 20 distinct mouse models of autism (n=549 individual mice) can be clustered into two prominent hypo- and hyperconnectivity subtypes. We show that these connectivity profiles are linked to distinct signaling pathways, with hypoconnectivity being associated with synaptic dysfunction, and hyperconnectivity reflecting transcriptional and immune-related alterations. Extending these findings to humans, we identify analogous hypo- and hyperconnectivity subtypes in a large, multicenter resting state fMRI dataset of n=940 autistic and n=1036 neurotypical individuals. Remarkably, hypo- and hyperconnectivity autism subtypes are replicable across independent cohorts (accounting for 25.1% of all autism data), exhibit distinct functional network architecture, are behaviorally dissociable, and recapitulate synaptic and immune mechanisms identified in corresponding mouse subtypes. Our cross-species investigation, thus, decodes the heterogeneity of fMRI connectivity in autism into distinct pathway-specific etiologies, offering a new empirical framework for targeted subtyping of autism.

neuroscience↗

bioRxiv2025

Perinatal environmental enrichment affects murine neonates' brain structure before their active engagement with environment

Early life experiences shape individuals. Environmental enrichment, an experimental paradigm used to study the effect of increased environmental complexity and novelty in animal models, has long been recognised for its broad effect on nervous system function and behaviour. In adult rodents, structural changes in the brain due to enriched environments are well documented, notably in the hippocampus. However, the effect of environmental enrichment on the developing brain during early life is not well understood. This study aims to investigate how environmental enrichment affects brain development during the critical perinatal period, and how such effects compare to those observed during adulthood. We use high-resolution MRI to measure the brain structure of mouse neonates at postnatal day 7, born either in an enriched or a standard environment. We show that rodents exhibit brain structure differences as early as postnatal day 7. However, the regional changes observed differ from those in adulthood: hippocampal changes are limited, but changes in the hindbrain, the dorsal striatum, and the medial habenula are strong. Given the lack of direct interaction between neonates and the environment at P7, we hypothesised that maternal care may mediate these effects. We show that maternal care differs between enriched and standard environments, that maternal care correlates with brain structure changes in the neonates, and that maternal care and enriched environment affect brain structure similarly. This suggests that early changes in brain structure due to environmental enrichment are at least partly mediated by maternal care. This study provides novel insight into the differential effect of enriched environment on early brain development in rodents.

neuroscience↗

bioRxiv2024

A cross-species analysis of neuroanatomical covariance sex difference in humans and mice

Structural covariance in brain anatomy is thought to reflect inter-regional sharing of developmental influences - although this hypothesis has proved hard to causally test. Here, we use neuroimaging in humans and mice to study sex-differences in anatomical covariance - asking if regions that have developed shared sex differences in volume also show shared sex differences in volume covariance. This study design illuminates both the biology of sex-differences and theoretical models for anatomical covariance - benefitting from tests of inter-species convergence. We find that volumetric structural covariance is stronger in adult females compared to adult males for both wild-type mice and healthy human subjects: 98% of all comparisons with statistically significant covariance sex differences in mice are female-biased, while 76% of all such comparisons are female-biased in humans (q < 0.05). In both species, a regions covariance and volumetric sex-biases have weak inverse relationships to each other: volumetrically male-biased regions contain more female-biased covariations, while volumetrically female-biased regions have more male-biased covariations (mice: r = -0.185, p = 0.002; humans: r = -0.189, p = 0.001). Our results identify a conserved tendency for females to show stronger neuroanatomical covariance than males, evident across species, which suggests that stronger structural covariance in females could be an evolutionarily conserved feature that is partially related to volumetric alterations through sex. SIGNIFICANCE STATEMENTStructural covariance is a potent readout of coordinated brain development, but hard to probe experimentally. We use sex differences as a naturally occurring test for developmental theories of structural covariance - adopting a cross-species approach for validation and translational benefit. Brain MRI reveals two conserved features of anatomical covariance across humans and mice: (i) tighter inter-regional coordination of brain development in females as evidenced by stronger volume covariance; (ii) a tendency for female-biased covariance to involve regions that are smaller in females - suggesting a previously unknown counterbalancing between these two distinct modes of sex-biased brain organization. These findings advance understanding of coordinated brain development and sex difference in a cross-species framework - facilitating future translational research on both topics.

neuroscience↗

bioRxiv2024

Left-Right Brain-Wide Asymmetry of Neuroanatomy in the Mouse Brain

Left-right asymmetry of the human brain is widespread through its anatomy and function. However, limited microscopic understanding of it exists, particularly for anatomical asymmetry where there are few well-established animal models. In humans, most brain regions show subtle, population-average regional asymmetries in thickness or surface area, alongside a macro-scale twisting called the cerebral petalia in which the right hemisphere protrudes anteriorly past the left. Here, we ask whether neuroanatomical asymmetries can be observed in mice, leveraging 6 mouse neuroimaging cohorts from 5 different research groups ([~]3,500 animals). We found an anterior-posterior pattern of volume asymmetry with anterior regions larger on the right and posterior regions larger on the left. This pattern appears driven by similar trends in surface area and positional asymmetries, with the results together indicating a small brain-wide twisting pattern, similar to the human cerebral petalia. Furthermore, the results show no apparent relationship to known functional asymmetries in mice, emphasizing the complexity of the structure-function relationship in brain asymmetry. By establishing a signature of anatomical brain asymmetry in mice, we aim to provide a foundation for future studies to probe the mechanistic underpinnings of brain asymmetry seen in humans - a feature of the brain with extremely limited understanding. Significance StatementThe human brain shows significant left-right anatomical asymmetry. Understanding its microscopic basis has implications for studies of autism and schizophrenia, evolution, embryonic brain development, and the relationship between structure and function in the brain. One of the biggest challenges to understanding this aspect of the brain is that animal models are limited. Here we show a brain-wide twisting pattern of asymmetry in the mouse brain using over 3,500 animals from six independent cohorts. These findings provide a basis for using mice to interrogate the microscopic underpinnings of anatomical asymmetry in humans and a roadmap for exploring anatomical asymmetry in additional species.

neuroscience↗

bioRxiv2024

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency. TeaserInhibitors targeting NMDA receptors may represent viable therapies for KDM5B neurodevelopmental disorders

neuroscience↗

bioRxiv2023

The universe is asymmetric, the mouse brain too.

Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

neuroscience↗

bioRxiv2023

Comparative neuroimaging of sex differences in human and mouse brain anatomy

In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-biased brain development in mammals, there have been no attempts to formally compare mouse and human sex differences across the whole brain to ascertain how well they translate. Addressing this question would shed critical light on use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use cross-species structural magnetic resonance imaging to carry out the first comparative neuroimaging study of sex-biased neuroanatomical organization of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous brain regions (r=0.30; e.g.: M>F amygdala, hippocampus, bed nucleus of the stria terminalis, and hypothalamus and F>M anterior cingulate, somatosensory, and primary auditory cortices). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-biased brain development in mice to brain regions that best echo sex-biased brain development in humans.

neuroscience↗

bioRxiv2023

Lifespan Changes in Brain Structure and Cognitive Performance Associated with Normal Aging in Mice

IntroductionAs the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. MethodsYoung (2m, n=10), middle-age (10m, n=10) and old (22m, n=9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume, residualized for total brain volume, and associations between volume and cognitive performance on the Y-maze task were tested. General linear models with total brain volume as a covariate, and logistic regression for sample wide associations were employed respectively, correcting for multiple comparisons. Structural covariance networks were generated using the R package igraph. Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5-40%), using 5,000 (1,000 for degree) permutations with significance criteria of p<0.05 at [≥]5 consecutive density thresholds. ResultsWidespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area ({chi}2=2.325, pO_SCPLOWBHC_SCPLOW=0.044) and larger volume of the hippocampal formation ({chi}2=-2.180, pO_SCPLOWBHC_SCPLOW=0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. Conclusions/ImplicationsThese findings offer a foundational account of age effects on brain volume, structural brain networks, and cognition in mice, informing future work in facilitating translation between rodent models and human brain aging.

neuroscience↗

bioRxiv2022

Host genetics maps to behaviour and brain structure in mice

Gene-environment interactions in the postnatal period have a long-term impact on neurodevelopment. To effectively model neurodevelopment in the mouse, we incorporated several validated behavioural tests to develop a behavioural pipeline that measures translationally relevant milestones of development in mice. The behavioral phenotype of 1060 wild type and genetically-modified mice was examined in parallel with structural brain imaging. The influence of genetics, sex, and early life stress on behaviour and neuroanatomy was determined using traditional statistical and machine learning methods. The results demonstrated that neuroanatomical diversity was primarily associated with genotype whereas behavioural phenotypic diversity was observed to be more susceptible to gene-environment interactions.

neuroscience↗

bioRxiv2022

Organization of thalamocortical structural covariance and a corresponding 3D atlas of the mouse thalamus

For information from sensory organs to be processed by the brain, it is usually passed to appropriate areas of the cerebral cortex. Almost all of this information passes through the thalamus, a relay structure that reciprocally connects to the vast majority of the cortex. The thalamus facilitates this information transfer through a set of thalamocortical connections that vary in cellular structure, molecular profiles, innervation patterns, and firing rates. Additionally, corticothalamic connections allow for intracortical information transfer through the thalamus. These efferent and afferent connections between the thalamus and cortex have been the focus of many studies, and the importance of cortical connectivity in defining thalamus anatomy is demonstrated by multiple studies that parcellate the thalamus based on cortical connectivity profiles. Here, we examine correlated morphological variation between the thalamus and cortex, or thalamocortical structural covariance. For each voxel in the thalamus as a seed, we construct a cortical structural covariance map that represents correlated cortical volume variation, and examine whether high structural covariance is observed in cortical areas that are functionally relevant to the seed. Then, using these cortical structural covariance maps as features, we subdivide the thalamus into six non-overlapping regions (clusters of voxels), and assess whether cortical structural covariance is associated with cortical connectivity that specifically originates from these regions. We show that cortical structural covariance is high in areas of the cortex that are functionally related to the seed voxel, cortical structural covariance varies along cortical depth, and sharp transitions in cortical structural covariance profiles are observed when varying seed locations in the thalamus. Subdividing the thalamus based on structural covariance, we additionally demonstrate that the six thalamic clusters of voxels stratify cortical structural covariance along the dorsal-ventral, medial-lateral, and anterior-posterior axes. These cluster-associated structural covariance patterns are prominently detected in cortical regions innervated by fibers projecting out of their related thalamic subdivisions. Together, these results advance our understanding of how the thalamus and the cortex couple in their volumes. Our results indicate that these volume correlations reflect functional organization and structural connectivity, and further provides a novel segmentation of the mouse thalamus that can be used to examine thalamic structural variation and thalamocortical structural covariation in disease models.

neuroscience↗

bioRxiv2021

Genetic Mouse Models of Autism Spectrum Disorder Present Subtle Heterogenous Cardiac Abnormalities.

BackgroundAutism Spectrum Disorder (ASD) and Congenital Heart Disease (CHD) are strongly linked on a functional and genetic level. Most work has been focused on neurodevelopmental abnormalities in CHD. Conversely, cardiac abnormalities in ASD have been less studied. In this work we investigate the prevalence of cardiac comorbidities relative to genetic contributors of ASD. MethodsUsing high frequency ultrasound imaging, we screened 9 mouse models with ASD-related genetic alterations (Arid1b(+/-), Chd8(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Shank3 {Delta}exon 4-9(+/-), Shank3 {Delta}exon 4-9(-/-), Fmr1(-/-), Vps13b(+/-)), and pooled wild-type littermates (WT). Using a standardised imaging protocol, we measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, Peak E and A velocity ratio of mitral inflow, Velocity Time Integral (VTI) through the ascending aorta. ResultsMutant groups presented small-scale alterations in cardiac structure and function compared to WTs. A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in measures of structure (LV chamber diameter and anterior wall thickness, HR, AoD). When compared to WTs, they differed in both structure and function (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmrl(-/-), Arid1b(+/-). Among mutant groups, the groups differing most from others were 16p11.2 (deletion), Sgsh(+/-), Fmrl(-/-). Our results broadly recapitulate the associated clinical findings. LimitationsVarious genetically driven cardiac abnormalities occur early in life, so repeating this work in non-adult mice may be valuable. To identify possible sex differences, we must extend this work to female mice. The downsampling procedure used (total correlation calculation) must be verified. Only indirect comparison between our results and clinical literature is possible due to differing study designs. ConclusionsThe characteristic heterogeneity of ASD was recapitulated in the observed cardiac phenotype. The type of measures (morphological, functional) mutant groups differ in can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal cardiac abnormalities can impact normal development.

neuroscience↗

bioRxiv2021

Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation

BackgroundThe amygdala (AMY) is a key brain region of the limbic system that plays a critical role in emotion processing and stress response. Functional magnetic resonance imaging (fMRI) studies identified abnormal AMY activation in psychiatric illnesses including major depressive disorder (MDD). Stress exposure is a major precipitating factor of MDD episodes which are associated with AMY hyperactivity. Preclinical studies using of pharmacologic, opto- and chemogenetic approaches to activate AMY neurons have consistently demonstrated that acute AMY hyperactivation induces anxiety-like behaviors in mice. However, it remains unknown if chronic hyperactivation of the amygdala (cHOA) is sufficient to induce chronic stress-like deficits or is a susceptibility factor for chronic stress-induced behavioral, volumetric and synaptic deficits. MethodsUsing designer receptor exclusively activated by designer drug (DREADD) approach, basolateral amygdala (BLA) neurons of Camk2a-cre mice infected with a virus driving the expression of the Gq-coupled DREADD were activated with clozapine-N-oxide (in drink water for 5 weeks). Mice were then exposed to chronic restraint stress (CRS; 1X/day for 1hr) for 2 weeks. All mice were behaviorally assessed in the Phenotyper (PT), and sucrose consumption tests (SCT) each week and in the novelty supressed feeding (NSF, once at the end of the experiment). Animals were then perfused for ex vivo-MRI and puncta density analysis. ResultsWe found that mice with cHOA displayed a progressive increase in baseline anxiety-like deficits in the PT test and slightly more marked deficits following CRS compared to controls, but not statistically different from animals subjected to CRS alone. Also, cHOA did not exacerbate CRS effect in the NSF. No significant cAH effect was found in the SCT before or after CRS. MRI analysis revealed no statistical charges between groups, while increased synaptic puncta density was found in cHOA mice subjected to CRS compared to cHOA or CRS alone. ConclusionWe demonstrate that cAH is sufficient to induce anxiety and may exacerbate CRS effects on anxiety and synaptic measures. Results also suggest that cHOA was not sufficient to induce depressive-like behavior and was not a vulnerability factor for stress-induced depressive-like behavior in mice. Altogether, our findings imply that a strong causal link between AMY hyperactivity and elevated anxiety, but not depressive-like behaviors and provide critical information to clinical research focused on using AMY activity level as a biomarker in stress-related illnesses.

neuroscience↗

bioRxiv2021

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

BackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/-) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. ResultsDdx3x+/- mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

neuroscience↗

bioRxiv2021

Examining the effect of chronic intranasal oxytocin administration on the neuroanatomy and behavior of three autism-related mouse models

1Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the 16p11.2 deletion, Shank3 (exon 4-9) knockout, and Fmr1 knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwent in vivo longitudinal and high-resolution ex vivo imaging with MRI. The scans included three in vivo T1-weighted, 90um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolution ex vivo scan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in the Fmr1 mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.

developmental biology↗