Biology subjects

Lerch, J. P.

Publications and source records attributed to Lerch, J. P..

51 records · Page 3Linked to original sources

bioRxiv2020

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and genes that regulate chromatin modify and control events regulating the formation of neural connections. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. For this work, a novel preclinical mouse model of Arid1b deficiency was created and molecularly validated to characterize and define neuroanatomical, behavioural and transcriptional phenotypes. Brains of adult Arid1b+/- mice had a smaller cerebellum along with a larger hippocampus and corpus callosum. In addition, a notable sex dependence was observed throughout development; males had an early emergence of the neuroanatomical phenotype around postnatal day 7, whereas females had a delayed emergence of the phenotype around postnatal day 40. Behavioural assays relevant to NDD were conducted during neonatal development and adulthood to evaluate general health, anxiety-like, motor, cognitive, and social behaviours in Arid1b+/- mice. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but surprisingly not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. This study represents a full investigation of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

neuroscience↗

bioRxiv2020

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Autism Spectrum Disorder (ASD) and Developmental Delay (DD). To investigate how Cul3 mutations impact brain development, we generated haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified neuronal cytoskeleton and Rho signaling as primary targets of Cul3 mutation during early brain development.

neuroscience↗

bioRxiv2020

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death.

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the cortex, the formation of inhibitory networks occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The molecular mechanisms that select GABAergic interneurons to survive or die are unknown. Here we report that the clustered Protocadherins regulate GABAergic cell survival in the developing brain. Deletion of the Pcdh-gamma genes (Pcdhgs) from GABAergic neurons in mice causes a severe loss of inhibitory neurons in multiple brain regions and results in motor deficits and seizure activities. By focusing on the neocortex and cerebellar cortex, we demonstrate that GABAergic interneuron loss results from elevated apoptosis during the postnatal wave of Bax-dependent programmed cell death. Pro-survival AKT signals are reduced in Pcdhg-deficient interneurons, diminishing the intrinsic capacity of interneurons to compete and incorporate into developing networks. We propose that the Pcdhgs mediate selective GABAergic interneuron survival to contribute to the formation of balanced inhibitory networks.

neuroscience↗

bioRxiv2019

Reduced axonal caliber and white matter changes in a rat model of Fragile X syndrome with a deletion of a K Homology domain of Fmr1.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene that are known to cause neuroanatomical alterations. The morphological underpinnings of these alterations have not been elucidated. Furthermore, while alterations have been identified in both male and female individuals, neuroanatomy in female rodent models has not been assessed. We identified structural differences in regions that are also altered in FXS in male and female rat models, including the splenium of the corpus callosum. Interestingly, different sets of regions were disrupted in male and female rat models and, remarkably, male rats had higher brain-wide diffusion than female rats overall. We found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and suggest a potential mechanism for how its loss causes white matter dysfunction in FXS.

neuroscience↗

bioRxiv2019

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

genomics↗

bioRxiv2019

Sex-Biased Trajectories of Amygdalo-Hippocampal Morphology Change Over Human Development

The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes - low vs. high areal expansion, and early vs. late growth deceleration. These results bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females and discover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence.\n\nSIGNIFICANCE STATEMENTThe amygdala and hippocampus are implicated in several developmentally-dynamic and sex-biased psychiatric disorders, but the spatiotemporal organization and sex-biased patterning of amygdalo-hippocampal maturation remains unclear in humans. Here, by integrating new methods for analysis of longitudinal neuroimaging data, we resolve the developmental milestones and spatial gradients that organize human amygdalo-hippocampal maturation. Each structures volume follows a tri-phasic, curvilinear growth trajectory which - for the amygdala - shows rapid male-female size divergence in mid-adolescence through delayed growth deceleration in males. Spatially fine-grained shape analyses localize these sex differences, and further reveal highly orchestrated shape changes across the amygdala and hippocampus that are organized by two topographical gradients. These data provide a new framework for understanding amygdalo-hippocampal organization in human development.

neuroscience↗

bioRxiv2019

Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

Mutations in the ATRX chromatin remodeler are associated with syndromic and non-syndromic intellectual disability. Emerging evidence points to key roles for ATRX in preserving neuroprogenitor cell genomic stability, whereas ATRX function in differentiated neurons and memory processes are still unresolved. Here, we show that Atrx deletion in mouse forebrain glutamatergic neurons causes distinct hippocampal structural defects identified by magnetic resonance imaging. Ultrastructural analysis revealed fewer presynaptic vesicles and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. These synaptic defects are associated with impaired long-term contextual memory in male, but not female mice. Mechanistically, we identify ATRX-dependent and sex-specific alterations in synaptic gene expression linked to Mir137 levels, a known regulator of presynaptic processes and spatial memory. We conclude that ablation of Atrx in excitatory forebrain neurons leads to sexually dimorphic outcomes on miR-137 and on spatial memory, identifying a promising therapeutic target for neurological disorders caused by ATRX dysfunction.\n\nSummary statementAblation of the ATRX chromatin remodeler specifically in forebrain excitatory neurons of mice causes male-specific deficits in long-term spatial memory associated with miR-137 overexpression, transcriptional changes and structural alterations corresponding to pre- and post-synaptic abnormalities.

neuroscience↗

bioRxiv2019

Altered structural brain asymmetry in autism spectrum disorder: large-scale analysis via the ENIGMA Consortium

BackgroundLeft-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely due to limited sample sizes and low statistical power.\n\nMethodsWe investigated 1,774 subjects with ASD and 1,809 controls, from 54 datasets, for differences in the asymmetry of thickness and surface area of 34 cerebral cortical regions. We also examined global hemispheric measures of cortical thickness and area asymmetry, and volumetric asymmetries of subcortical structures. Data were obtained via the ASD Working Group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas.\n\nResultsASD was significantly associated with reduced leftward asymmetry of total hemispheric average cortical thickness, compared to controls. Eight regional thickness asymmetries, distributed over the cortex, also showed significant associations with diagnosis after correction for multiple comparisons, for which asymmetry was again generally lower in ASD versus controls. In addition, the medial orbitofrontal surface area was less rightward asymmetric in ASD than controls, and the putamen volume was more leftward asymmetric in ASD than controls. The largest effect size had Cohens d = 0.15. Most effects did not depend on age, sex, IQ, or disorder severity.\n\nConclusionAltered lateralized neurodevelopment is suggested in ASD, affecting widespread cortical regions with diverse functions. Large-scale analysis was necessary to reliably detect, and accurately describe, subtle alterations of structural brain asymmetry in this disorder.

neuroscience↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗

bioRxiv2018

Non-monotonic regulation of gene expression, neural progenitor fate and brain growth by the chromatin remodeller CHD8

Heterozygous CHD8 mutations are associated with autism and macrocephaly with high penetrance in the human population. The reported mutations may have loss-of-function (haploinsufficient), hypomorphic or dominant negative effects on protein function. To determine the effects of reducing CHD8 protein function below haploinsufficient levels on brain development, we established a Chd8 allelic series in the mouse. Chd8 heterozygous mice exhibited relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. In comparison, mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia, and significantly altered expression of over 2000 genes. Autism-associated genes were downregulated and neural progenitor proliferation genes upregulated. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, affecting genes and pathways that largely overlapped with those dysregulated in the mild hypomorphs. By contrast, homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in the induction of p53 target genes, cell cycle exit, apoptosis and pronounced brain hypoplasia. Intriguingly, increased progenitor proliferation in hypomorphs was primarily restricted to TBR2+ intermediate progenitors, suggesting critical roles for CHD8 in regulating the expansion of this population. Given the importance of these progenitors in human cortical growth, this observation suggests that human brain development might be more sensitive to CHD8 deficiency than the mouse. We conclude that brain development is acutely sensitive to CHD8 dosage and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage can result in non-linear effects on gene transcription and brain growth.

neuroscience↗

bioRxiv2018

Genetic and behavioural requirements for structural brain plasticity

1Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.

neuroscience↗

bioRxiv2017

Normative Brain Size Variation and the Remodeling of Brain Shape in Humans

Evolutionary and developmental increases in primate brain size have been accompanied by systematic shifts in the proportionality of different primate brain systems. However, it remains unknown if and how brain patterning varies across the more than 2-fold inter-individual variation in brain size that occurs amongst typically-developing humans. Using in vivo neuroimaging data from 2 independent cohorts totaling nearly 3000 individuals, we find that larger-brained humans show preferential areal expansion within specific fronto-parietal cortical networks (default mode, dorsal attentional) and related subcortical regions, at the expense of primary sensory/motor systems. This targeted areal expansion recapitulates cortical remodeling across evolution, manifests by early childhood and is linked to molecular signatures of heightened metabolic cost. Our results define a new organizing principle in human brain patterning which governs the highly-coordinated remodeling of human brain shape as a function of naturally-occurring variations in brain size.\n\nOne Sentence SummaryA hodologically and metabolically expensive brain network is preferentially expanded in larger-brained humans.

neuroscience↗

bioRxiv2017

Structural covariance of brain region volumes is associated with both structural connectivity and transcriptomic similarity

An organizational pattern seen in the brain, termed structural covariance, is the statistical association of pairs of brain regions in their anatomical properties. These associations, measured across a population as covariances or correlations usually in cortical thickness or volume, are thought to reflect genetic and environmental underpinnings.\n\nHere, we examine the biological basis of structural volume covariance in the mouse brain. We first examined large scale associations between brain region volumes using an atlas-based approach that parcellated the entire mouse brain into 318 regions over which correlations in volume were assessed, for volumes obtained from 153 mouse brain images via high-resolution MRI. We then used a seed-based approach and determined, for 108 different seed regions across the brain and using mouse gene expression and connectivity data from the Allen Institute for Brain Science, the variation in structural covariance data that could be explained by distance to seed, transcriptomic similarity to seed, and connectivity to seed.\n\nWe found that overall, correlations in structure volumes hierarchically clustered into distinct anatomical systems, similar to findings from other studies and similar to other types of networks in the brain, including structural connectivity and transcriptomic similarity networks. Across seeds, this structural covariance was significantly explained by distance (17% of the variation, up to a maximum of 49% for structural covariance to the visceral area of the cortex), transcriptomic similarity (13% of the variation, up to maximum of 28% for structural covariance to the primary visual area) and connectivity (15% of the variation, up to a maximum of 36% for structural covariance to the intermediate reticular nucleus in the medulla) of covarying structures. Together, distance, connectivity, and transcriptomic similarity explained 37% of structural covariance, up to a maximum of 63% for structural covariance to the visceral area. Additionally, this pattern of explained variation differed spatially across the brain, with transcriptomic similarity playing a larger role in the cortex than subcortex, while connectivity explains structural covariance best in parts of the cortex, midbrain, and hindbrain. These results suggest that both gene expression and connectivity underlie structural volume covariance, albeit to different extents depending on brain region, and this relationship is modulated by distance.

neuroscience↗

bioRxiv2017

Mouse MRI shows brain areas larger in males emerge earlier than those larger in females

2Sex differences exist in behaviours, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. We used manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulated findings on canonically dimorphic areas, demonstrating the ability of MEMRI to study neuroanatomical sex differences. We discovered, upon whole-brain volume correction, that neuroanatomical regions larger in males develop early in life, while regions larger in females develop in peripubertal life. Furthermore, we found groups of areas with shared sexually dimorphic developmental trajectories that reflect behavioural and functional networks, and expression of genes involved with sex processes. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

neuroscience↗

bioRxiv2017

Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.

neuroscience↗