Publications by authors named "Jason P Lerch"

221 Publications

Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody mouse model.

Mol Psychiatry 2021 Jul 21. Epub 2021 Jul 21.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.

Immunoglobulin G (IgG) autoantibodies reactive to fetal brain proteins in mothers of children with ASD have been described by several groups. To understand their pathologic significance, we developed a mouse model of maternal autoantibody related ASD (MAR-ASD) utilizing the peptide epitopes from human autoantibody reactivity patterns. Male and female offspring prenatally exposed to the salient maternal autoantibodies displayed robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults. In the present study, neuroanatomical differences in adult MAR-ASD and control offspring were assessed via high-resolution ex vivo magnetic resonance imaging (MRI) at 6 months of age. Of interest, MAR-ASD mice displayed significantly larger total brain volume and of the 159 regions examined, 31 were found to differ significantly in absolute volume (mm) at an FDR of <5%. Specifically, the absolute volumes of several white matter tracts, cortical regions, and basal nuclei structures were significantly increased in MAR-ASD animals. These phenomena were largely driven by female MAR-ASD offspring, as no significant differences were seen with either absolute or relative regional volume in male MAR-ASD mice. However, structural covariance analysis suggests network-level desynchronization in brain volume in both male and female MAR-ASD mice. Additionally, preliminary correlational analysis with behavioral data relates that volumetric increases in numerous brain regions of MAR-ASD mice were correlated with social interaction and repetitive self-grooming behaviors in a sex-specific manner. These results demonstrate significant sex-specific effects in brain size, regional relationships, and behavior for offspring prenatally exposed to MAR-ASD autoantibodies relative to controls.
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http://dx.doi.org/10.1038/s41380-021-01215-wDOI Listing
July 2021

Cross-Diagnosis Structural Correlates of Autistic-Like Social Communication Differences.

Cereb Cortex 2021 Jun 3. Epub 2021 Jun 3.

Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario M4G 1R8, Canada.

Social communication differences are seen in autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), but the brain mechanisms contributing to these differences remain largely unknown. To address this gap, we used a data-driven and diagnosis-agnostic approach to discover brain correlates of social communication differences in ASD, ADHD, and OCD, and subgroups of individuals who share similar patterns of brain-behavior associations. A machine learning pipeline (regression clustering) was used to discover the pattern of association between structural brain measures (volume, surface area, and cortical thickness) and social communication abilities. Participants (n = 416) included children with a diagnosis of ASD (n = 192, age = 12.0[5.6], 19% female), ADHD (n = 109, age = 11.1[4.1], 18% female), or OCD (n = 50, age = 12.3[4.2], 42% female), and typically developing controls (n = 65, age = 11.6[7.1], 48% female). The analyses revealed (1) associations with social communication abilities in distributed cortical and subcortical networks implicated in social behaviors, language, attention, memory, and executive functions, and (2) three data-driven, diagnosis-agnostic subgroups based on the patterns of association in the above networks. Our results suggest that different brain networks may contribute to social communication differences in subgroups that are not diagnosis-specific.
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http://dx.doi.org/10.1093/cercor/bhab142DOI Listing
June 2021

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice.

Environ Health Perspect 2021 May 6;129(5):57002. Epub 2021 May 6.

Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.

Background: 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans.

Objectives: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression.

Methods: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD ( TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring.

Results: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3.

Discussion: Exposure to TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352.
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http://dx.doi.org/10.1289/EHP7352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101924PMC
May 2021

A fully segmented 3D anatomical atlas of a lizard brain.

Brain Struct Funct 2021 Jul 30;226(6):1727-1741. Epub 2021 Apr 30.

Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada.

As the relevance of lizards in evolutionary neuroscience increases, so does the need for more accurate anatomical references. Moreover, the use of magnetic resonance imaging (MRI) in evolutionary neuroscience is becoming more widespread; this represents a fundamental methodological shift that opens new avenues of investigative possibility but also poses new challenges. Here, we aim to facilitate this shift by providing a three-dimensional segmentation atlas of the tawny dragon brain. The tawny dragon (Ctenophorus decresii) is an Australian lizard of increasing importance as a model system in ecology and, as a member of the agamid lizards, in evolution. Based on a consensus average 3D image generated from the MRIs of 13 male tawny dragon heads, we identify and segment 224 structures visible across the entire lizard brain. We describe the relevance of this atlas to the field of evolutionary neuroscience and propose further experiments for which this atlas can provide the foundation. This advance in defining lizard neuroanatomy will facilitate numerous studies in evolutionary neuroscience. The atlas is available for download as a supplementary material to this manuscript and through the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/UJENQ ).
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http://dx.doi.org/10.1007/s00429-021-02282-zDOI Listing
July 2021

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density.

Neuropharmacology 2021 06 14;190:108562. Epub 2021 Apr 14.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada; Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada. Electronic address:

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p < 0.05). Reduced ACC correlated with increased behavioral emotionality (r = -0.56; p = 0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r = 0.35, p < 0.05), which also correlated with increased behavioral emotionality (r = -0.44, p < 0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108562DOI Listing
June 2021

Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome.

Hum Mol Genet 2021 May;30(7):575-594

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.

The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddab081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120135PMC
May 2021

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

Mol Psychiatry 2021 Mar 16. Epub 2021 Mar 16.

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

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 a 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 embryonic, early postnatal and adult 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 defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.
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http://dx.doi.org/10.1038/s41380-021-01052-xDOI Listing
March 2021

Multisite Comparison of MRI Defacing Software Across Multiple Cohorts.

Front Psychiatry 2021 24;12:617997. Epub 2021 Feb 24.

Rotman Research Institute, Baycrest Health Sciences Centre, Toronto, ON, Canada.

With improvements to both scan quality and facial recognition software, there is an increased risk of participants being identified by a 3D render of their structural neuroimaging scans, even when all other personal information has been removed. To prevent this, facial features should be removed before data are shared or openly released, but while there are several publicly available software algorithms to do this, there has been no comprehensive review of their accuracy within the general population. To address this, we tested multiple algorithms on 300 scans from three neuroscience research projects, funded in part by the Ontario Brain Institute, to cover a wide range of ages (3-85 years) and multiple patient cohorts. While skull stripping is more thorough at removing identifiable features, we focused mainly on defacing software, as skull stripping also removes potentially useful information, which may be required for future analyses. We tested six publicly available algorithms (afni_refacer, deepdefacer, mri_deface, mridefacer, pydeface, quickshear), with one skull stripper (FreeSurfer) included for comparison. Accuracy was measured through a pass/fail system with two criteria; one, that all facial features had been removed and two, that no brain tissue was removed in the process. A subset of defaced scans were also run through several preprocessing pipelines to ensure that none of the algorithms would alter the resulting outputs. We found that the success rates varied strongly between defacers, with afni_refacer (89%) and pydeface (83%) having the highest rates, overall. In both cases, the primary source of failure came from a single dataset that the defacer appeared to struggle with - the youngest cohort (3-20 years) for afni_refacer and the oldest (44-85 years) for pydeface, demonstrating that defacer performance not only depends on the data provided, but that this effect varies between algorithms. While there were some very minor differences between the preprocessing results for defaced and original scans, none of these were significant and were within the range of variation between using different NIfTI converters, or using raw DICOM files.
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http://dx.doi.org/10.3389/fpsyt.2021.617997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943842PMC
February 2021

Quantitative and Qualitative Sex Modulations in the Brain Anatomy of Autism.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 10. Epub 2021 Mar 10.

Department of Psychiatry, Hospital for Sick Children, Toronto, Ontario, Canada; Neurosciences and Mental Health Program, SickKids Research Institute, Toronto, Ontario, Canada; Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health and Azrieli Adult Neurodevelopmental Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. Electronic address:

Background: Sex-based neurobiological heterogeneity in autism is poorly understood. Research is disproportionately biased to males, leading to an unwarranted presumption that autism neurobiology is the same across sexes. Previous neuroimaging studies using amalgamated multicenter datasets to increase autistic female samples are characterized by large statistical noise.

Methods: We used a better-powered dataset of 1183 scans of 839 individuals-299 (467 scans) autistic males, 74 (102 scans) autistic females, 240 (334 scans) control males, and 226 (280 scans) control females-to test two whole-brain models of overall/global sex modulations on autism neuroanatomy, by summary measures computed across the brain: the local magnitude model, in which the same brain regions/circuitries are involved across sexes but effect sizes are larger in females, indicating quantitative sex modulation; and spatial dissimilarity model, in which the neuroanatomy differs spatially between sexes, indicating qualitative sex modulation. The male and female autism groups were matched on age, IQ, and autism symptoms. Autism brain features were defined by comparisons with same-sex control individuals.

Results: Across five metrics (cortical thickness, surface area, volume, mean absolute curvature, and subcortical volume), we found no evidence supporting the local magnitude model. We found indicators supporting the spatial dissimilarity model on cortical mean absolute curvature and subcortical volume, but not on other metrics.

Conclusions: The overall/global autism neuroanatomy in females and males does not simply differ quantitatively in the same brain regions/circuitries. They may differ qualitatively in spatial involvement in cortical curvature and subcortical volume. The neuroanatomy of autism may be partly sex specific. Sex stratification to inform autism preclinical/clinical research is needed to identify sex-informed neurodevelopmental targets.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.001DOI Listing
March 2021

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Cereb Cortex 2021 Jun;31(7):3338-3352

Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal H4H 1R3, Canada.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.
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http://dx.doi.org/10.1093/cercor/bhab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196259PMC
June 2021

Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Aug 7;110:110297. Epub 2021 Mar 7.

Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Canada; Robarts Research Institute, Western University, London, Canada; Lawson Health Research Institute, London, Canada. Electronic address:

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulnerable due to variation in glutamate receptor densities. We investigated hippocampal anomalies in first-episode psychosis (FEP) in relation to receptor distributions by leveraging 4 sources of data: (1) ultra high-field (7-Tesla) structural neuroimaging, and (2) proton magnetic resonance spectroscopy (1H-MRS) of glutamate from 27 healthy and 41 FEP subjects, (3) gene expression data from the Allen Human Brain Atlas and (4) atlases of the serotonin receptor system. Automated methods delineated the hippocampus to map receptor density across subfields. We used gene expression data to correlate serotonin and glutamate receptor genes across the hippocampus. Measures of individual hippocampal shape-receptor alignment were derived through normative modelling and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). We found reduced hippocampal volumes in FEP, while CA4-dentate gyrus showed greatest reductions. Gene expression indicated 5-HT1A and 5-HT4 to correlate with AMPA and NMDA expression, respectively. Magnitudes of subfield volumetric reduction in FEP correlated most with 5-HT1A (R = 0.64, p = 4.09E-03) and 5-HT4 (R = 0.54, p = 0.02) densities as expected, and replicated using previously published data from two FEP studies. Right-sided 5-HT4-RSMS was correlated with MRS glutamate (R = 0.357, p = 0.048). We demonstrate a putative glutamate-driven hippocampal variability in FEP through a serotonin receptor-density gated mechanism, thus outlining a mechanistic interplay between serotonin and glutamate in determining the hippocampal morphology in schizophrenia.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110297DOI Listing
August 2021

Exposure to maternal high-fat diet induces extensive changes in the brain of adult offspring.

Transl Psychiatry 2021 03 2;11(1):149. Epub 2021 Mar 2.

Division of Endocrinology, The Hospital for Sick Children, Toronto, ON, Canada.

Maternal environmental exposures, such as high-fat diets, diabetes and obesity, can induce long-term effects in offspring. These effects include increased risk of neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), depression and anxiety. The mechanisms underlying these late-life neurologic effects are unknown. In this article, we measured changes in the offspring brain and determined which brain regions are sensitive to maternal metabolic milieu and therefore may mediate NDD risk. We showed that mice exposed to a maternal high-fat diet display extensive brain changes in adulthood despite being switched to a low-fat diet at weaning. Brain regions impacted by early-life diet include the extended amygdalar system, which plays an important role in reward-seeking behaviour. Genes preferentially expressed in these regions have functions related to feeding behaviour, while also being implicated in human NDDs, such as autism. Our data demonstrated that exposure to maternal high-fat diet in early-life leads to brain alterations that persist into adulthood, even after dietary modifications.
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http://dx.doi.org/10.1038/s41398-021-01274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925669PMC
March 2021

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development.

Mol Autism 2021 02 24;12(1):16. Epub 2021 Feb 24.

Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.

Background: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.

Methods: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate.

Results: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice.

Conclusions: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.
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http://dx.doi.org/10.1186/s13229-020-00409-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905672PMC
February 2021

Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.

Cell Rep 2021 Feb;34(8):108780

Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea. Electronic address:

CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.
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http://dx.doi.org/10.1016/j.celrep.2021.108780DOI Listing
February 2021

Cortical Gyrification Morphology in Individuals with ASD and ADHD across the Lifespan: A Systematic Review and Meta-Analysis.

Cereb Cortex 2021 Mar;31(5):2653-2669

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.

Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are common neurodevelopmental disorders (NDDs) that may impact brain maturation. A number of studies have examined cortical gyrification morphology in both NDDs. Here we review and when possible pool their results to better understand the shared and potentially disorder-specific gyrification features. We searched MEDLINE, PsycINFO, and EMBASE databases, and 24 and 10 studies met the criteria to be included in the systematic review and meta-analysis portions, respectively. Meta-analysis of local Gyrification Index (lGI) findings across ASD studies was conducted with SDM software adapted for surface-based morphometry studies. Meta-regressions were used to explore effects of age, sex, and sample size on gyrification differences. There were no significant differences in gyrification across groups. Qualitative synthesis of remaining ASD studies highlighted heterogeneity in findings. Large-scale ADHD studies reported no differences in gyrification between cases and controls suggesting that, similar to ASD, there is currently no evidence of differences in gyrification morphology compared with controls. Larger, longitudinal studies are needed to further clarify the effects of age, sex, and IQ on cortical gyrification in these NDDs.
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http://dx.doi.org/10.1093/cercor/bhaa381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023842PMC
March 2021

Exploring the Neural Structures Underlying the Procedural Memory Network as Predictors of Language Ability in Children and Adolescents With Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Front Hum Neurosci 2020 10;14:587019. Epub 2020 Dec 10.

Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.

: There is significant overlap in the type of structural language impairments exhibited by children with autism spectrum disorder (ASD) and children with attention deficit hyperactivity disorder (ADHD). This similarity suggests that the cognitive impairment(s) contributing to the structural language deficits in ASD and ADHD may be shared. Previous studies have speculated that procedural memory deficits may be the shared cognitive impairment. The procedural deficit hypothesis (PDH) argues that language deficits can be explained by differences in the neural structures underlying the procedural memory network. This hypothesis is based on the premise that the neural structures comprising the procedural network support language learning. In this study, we aimed to test the PDH in children with ASD, ADHD, and typical development (TD). : One hundred and sixty-three participants (ages 10-21): 91 with ASD, 26 with ADHD, and 46 with TD, completed standardized measures of cognitive and language ability as well as structural magnetic resonance imaging. We compared the structural language abilities, the neural structures underlying the procedural memory network, and the relationship between structural language and neural structure across diagnostic groups. : Our analyses revealed that while the structural language abilities differed across ASD, ADHD, and TD groups, the thickness, area, and volume of the structures supporting the procedural memory network were not significantly different between diagnostic groups. Also, several neural structures were associated with structural language abilities across diagnostic groups. Only two of these structures, the inferior frontal gyrus, and the left superior parietal gyrus, are known to be linked to the procedural memory network. : The inferior frontal gyrus and the left superior parietal gyrus, have well-established roles in language learning independent of their role as part of the procedural memory system. Other structures such as the caudate and cerebellum, with critical roles in the procedural memory network, were not associated with structural language abilities across diagnostic groups. It is unclear whether the procedural memory network plays a fundamental role in language learning in ASD, ADHD, and TD.
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http://dx.doi.org/10.3389/fnhum.2020.587019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759764PMC
December 2020

Tracking Inhibitory Control in Youth With ADHD: A Multi-Modal Neuroimaging Approach.

Front Psychiatry 2020 19;11:00831. Epub 2020 Nov 19.

Department of Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.

Background: A decreased ability to inhibit a speeded motor response is a well-studied deficit in Attention Deficit Hyperactivity Disorder (ADHD), and has been proposed as an endophenotype. Inhibitory control has been assessed reliably with the Stop Signal Task (SST) and is associated with prior documented differences in regional brain function using f-MRI. Here, we advance on these findings by examining their structural connectivity and white matter integrity with the goal of identifying a network underlying a core cognitive deficit in ADHD.

Methods: Healthy controls (N=16) and youth diagnosed with ADHD (N=60) were recruited through the Province of Ontario Neurodevelopmental Disorders Network (POND) and the Hospital for Sick Children. An f-MRI activation difference map was co-registered with each participant's white matter imaging data, representing the specific network nodes where ADHD youth diverged significantly from controls while performing the SST. Probabilistic tractography was applied from these nodes, and white matter integrity indices such as fractional anisotropy (FA) within the tracts of interest were contrasted between the groups and correlated with SST output measures, including the measure of inhibitory control, the stop signal reaction time (SSRT).

Results: The tracts that connected the network nodes belonged primarily to the inferior fronto-occipital fasciculus (IFOF) and cingulum. ADHD subjects showed trend differences in FA compared to controls between right inferior frontal gyrus (IFG) and right superior temporal gyrus (P= 0.09), right IFG and right posterior cingulate (P= 0.01), right anterior cingulate to posterior cingulate (p= 0.08), and between left middle temporal gyrus (BA 39) and left posterior cingulate (P=0.02). A trend correlation was found between radial diffusivity within IFG to STG white matter (IFOF) and SSRT.

Conclusions: We identified potential white matter tracts related to deficient inhibitory control, elucidating the brain mechanisms of an important cognitive deficit in ADHD. These findings could be integrated into future endophenotypic biomarker studies, incorporating altogether brain structure, function, and behavior for future studies of ADHD and other psychiatric conditions that exhibit this deficit.
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http://dx.doi.org/10.3389/fpsyt.2020.00831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710692PMC
November 2020

Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos.

J Neurodev Disord 2020 12 16;12(1):40. Epub 2020 Dec 16.

MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.

Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest that children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of intellectual delay or disability, ADHD, or ASD.

Methods: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes (i.e., deficits in social communication and repetitive, restricted behavior). Male and female rat pups were exposed to CPF at 0.1, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4.

Results: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group.

Conclusions: This work generated and characterized a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.
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http://dx.doi.org/10.1186/s11689-020-09342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745485PMC
December 2020

Changing Faces: Dynamic Emotional Face Processing in Autism Spectrum Disorder Across Childhood and Adulthood.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Sep 12. Epub 2020 Sep 12.

Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Ontario, Canada; Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.

Background: Autism spectrum disorder (ASD) is classically associated with poor emotional face processing. Few studies, however, have used more ecological dynamic stimuli. We contrasted functional magnetic resonance imaging measures of dynamic emotional face processing in ASD and typically developing (TD) cohorts across a wide age range to determine if the processing and age-related trajectories differed between participants with and without ASD.

Methods: Functional magnetic resonance imaging data collected from 200 participants (5-42 years old; 107 in ASD cohort, 93 in TD cohort) during the presentation of dynamic emotional faces (neutral-to-happy, neutral-to-angry) and dynamic flowers (closed-to-open) were analyzed. Group differences and group-by-age interactions in the faces versus flowers and between emotion contrasts were investigated.

Results: Differences in activation between dynamic faces and flowers in occipital regions, including the fusiform gyri, were reduced in the ASD group. Contrasting the two emotions, ASD compared with TD participants showed increased engagement of the precentral, postcentral, and superior temporal gyri to happy faces and increased activation to angry faces occipitally. Emotion processing regions, such as insula, temporal pole, and frontal regions, showed increased recruitment with age to happy faces compared with both angry faces and flowers in the TD group, but decreased recruitment with age in the ASD group.

Conclusions: Using dynamic stimuli, we demonstrated that participants with ASD processed faces similarly to nonface stimuli, and age-related atypicalities were more pronounced to happy faces in participants with ASD. We demonstrated emotion-specific atypicalities in a large group of participants with ASD that underscore persistent difficulties from childhood into mid-adulthood.
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http://dx.doi.org/10.1016/j.bpsc.2020.09.006DOI Listing
September 2020

Characterization of mice bearing humanized androgen receptor genes (h/mAr) varying in polymorphism length.

Neuroimage 2021 02 26;226:117594. Epub 2020 Nov 26.

Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Wellcome Centre for Integrative Neuroimaging (WIN), FMRIB, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.

The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al., 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neu- roanatomical changes due to Q tract length are only associated with neurode- velopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmen- tal processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood is not likely to lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mech- anisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117594DOI Listing
February 2021

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.

Mol Psychiatry 2021 02 23;26(2):396-410. Epub 2020 Nov 23.

Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.

Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.
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http://dx.doi.org/10.1038/s41380-020-00952-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850974PMC
February 2021

Beyond diagnosis: Cross-diagnostic features in canonical resting-state networks in children with neurodevelopmental disorders.

Neuroimage Clin 2020 27;28:102476. Epub 2020 Oct 27.

Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.

Children with neurodevelopmental disorders (NDDs) share common behavioural manifestations despite distinct categorical diagnostic criteria. Here, we examined canonical resting-state network connectivity in three diagnostic groups (autism spectrum disorder, attention-deficit/hyperactivity disorder and paediatric obsessive-compulsive disorder) and typically developing controls (TD) in a large single-site sample (N = 407), applying diagnosis-based and dimensional approaches to understand underlying neurobiology across NDDs. Each participant's functional network graphs were computed using five graph metrics. In diagnosis-based comparisons, an analysis of covariance was performed to compare all NDDs to TD, followed by pairwise comparisons between NDDs. In the dimensional approach, participants' functional network graphs were correlated with continuous behavioural measures, and a data-driven k-means clustering analysis was applied to determine if subgroups of participants were seen, without diagnostic information having been included. In the diagnosis-based comparisons, children with NDDs did not differ significantly from the TD group and the NDD categorical groups also did not differ significantly from each other, across all graph metrics. In the dimensional, diagnostic-independent approach, however, subcortical functional connectivity was significantly correlated with participants' general adaptive functioning across all participants. The clustering analysis identified an optimal solution of two clusters, and participants assigned in the same data-driven cluster were highly heterogeneous in diagnosis. Neither cluster exclusively contained a specific diagnostic group, nor did NDDs separate cleanly from TDs. Each participant's distance ratio between the two clusters was significantly correlated with general adaptive functioning, social deficits and attentional problems. Our results suggest the neurobiological similarity and dissimilarity between NDDs need to be investigated beyond DSM/ICD-based, behaviourally-defined diagnostic categories.
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http://dx.doi.org/10.1016/j.nicl.2020.102476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649647PMC
June 2021

Cross-species neuroscience: closing the explanatory gap.

Philos Trans R Soc Lond B Biol Sci 2021 01 16;376(1815):20190633. Epub 2020 Nov 16.

Wellcome Centre for Integrative Neuroimaging, University of Oxford, FMRIB, John Radcliffe Hospital, Oxford OX3 9DU, UK.

Neuroscience has seen substantial development in non-invasive methods available for investigating the living human brain. However, these tools are limited to coarse macroscopic measures of neural activity that aggregate the diverse responses of thousands of cells. To access neural activity at the cellular and circuit level, researchers instead rely on invasive recordings in animals. Recent advances in invasive methods now permit large-scale recording and circuit-level manipulations with exquisite spatio-temporal precision. Yet, there has been limited progress in relating these microcircuit measures to complex cognition and behaviour observed in humans. Contemporary neuroscience thus faces an explanatory gap between macroscopic descriptions of the human brain and microscopic descriptions in animal models. To close the explanatory gap, we propose adopting a cross-species approach. Despite dramatic differences in the size of mammalian brains, this approach is broadly justified by preserved homology. Here, we outline a three-armed approach for effective cross-species investigation that highlights the need to translate different measures of neural activity into a common space. We discuss how a cross-species approach has the potential to transform basic neuroscience while also benefiting neuropsychiatric drug development where clinical translation has, to date, seen minimal success. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.
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http://dx.doi.org/10.1098/rstb.2019.0633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116399PMC
January 2021

Characterizing Inscapes and resting-state in MEG: Effects in typical and atypical development.

Neuroimage 2021 01 2;225:117524. Epub 2020 Nov 2.

Department of Diagnostic Imaging, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada; Department of Medical Imaging, University of Toronto, Toronto, Canada; Department of Psychology, University of Toronto, Toronto, Canada.

Examining the brain at rest is a powerful approach used to understand the intrinsic properties of typical and disordered human brain function, yet task-free paradigms are associated with greater head motion, particularly in young and/or clinical populations such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Inscapes, a non-social and non-verbal movie paradigm, has been introduced to increase attention, thus mitigating head motion, while reducing the task-induced activations found during typical movie watching. Inscapes has not yet been validated for use in magnetoencephalography (MEG), and it has yet to be shown whether its effects are stable in clinical populations. Across typically developing (N = 32) children and adolescents and those with ASD (N = 46) and ADHD (N = 42), we demonstrate that head motion is reduced during Inscapes. Due to the task state evoked by movie paradigms, we also expectedly observed concomitant modulations in local neural activity (oscillatory power) and functional connectivity (phase and envelope coupling) in intrinsic resting-state networks and across the frequency spectra compared to a fixation cross resting-state. Increases in local activity were accompanied by decreases in low-frequency connectivity within and between resting-state networks, primarily the visual network, suggesting that task-state evoked by Inscapes moderates ongoing and spontaneous cortical inhibition that forms the idling intrinsic networks found during a fixation cross resting-state. Importantly, these effects were similar in ASD and ADHD, making Inscapes a well-suited advancement for investigations of resting brain function in young and clinical populations.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117524DOI Listing
January 2021

Emotional face processing across neurodevelopmental disorders: a dynamic faces study in children with autism spectrum disorder, attention deficit hyperactivity disorder and obsessive-compulsive disorder.

Transl Psychiatry 2020 11 2;10(1):375. Epub 2020 Nov 2.

Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada.

Autism spectrum disorder (ASD) is classically associated with poor face processing skills, yet evidence suggests that those with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) also have difficulties understanding emotions. We determined the neural underpinnings of dynamic emotional face processing across these three clinical paediatric groups, including developmental trajectories, compared with typically developing (TD) controls. We studied 279 children, 5-19 years of age but 57 were excluded due to excessive motion in fMRI, leaving 222: 87 ASD, 44 ADHD, 42 OCD and 49 TD. Groups were sex- and age-matched. Dynamic faces (happy, angry) and dynamic flowers were presented in 18 pseudo-randomized blocks while fMRI data were collected with a 3T MRI. Group-by-age interactions and group difference contrasts were analysed for the faces vs. flowers and between happy and angry faces. TD children demonstrated different activity patterns across the four contrasts; these patterns were more limited and distinct for the NDDs. Processing happy and angry faces compared to flowers yielded similar activation in occipital regions in the NDDs compared to TDs. Processing happy compared to angry faces showed an age by group interaction in the superior frontal gyrus, increasing with age for ASD and OCD, decreasing for TDs. Children with ASD, ADHD and OCD differentiated less between dynamic faces and dynamic flowers, with most of the effects seen in the occipital and temporal regions, suggesting that emotional difficulties shared in NDDs may be partly attributed to shared atypical visual information processing.
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http://dx.doi.org/10.1038/s41398-020-01063-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608673PMC
November 2020

The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death.

J Neurosci 2020 11 15;40(45):8652-8668. Epub 2020 Oct 15.

Program for Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown. Here, we report that members of the clustered Protocadherins (cPCDHs) control GABAergic interneuron survival during developmentally-regulated cell death. Conditional deletion of the gene cluster encoding the γ-Protocadherins from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurologic deficits such as seizures. By focusing on the neocortex and the cerebellar cortex, we demonstrate that reductions of inhibitory interneurons result from elevated apoptosis during the critical postnatal period of programmed cell death (PCD). By contrast, cortical interneuron (cIN) populations are not affected by removal of from pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling in mutant interneurons, and is rescued by genetic blockade of the pro-apoptotic factor BAX. Together, these findings identify the PCDHGs as pro-survival transmembrane proteins that select inhibitory interneurons for survival and modulate the extent of PCD. We propose that the PCDHGs contribute to the formation of balanced inhibitory networks by controlling the size of GABAergic interneuron populations in the developing brain. A pivotal step for establishing appropriate excitatory-inhibitory ratios is adjustment of neuronal populations by cell death. In the mouse neocortex, a third of GABAergic interneurons are eliminated by BAX-dependent apoptosis during the first postnatal week. Interneuron cell death is modulated by neural activity and pro-survival pathways but the cell-surface molecules that select interneurons for survival or death are unknown. We demonstrate that members of the cadherin superfamily, the clustered γ-Protocadherins (PCDHGs), regulate the survival of inhibitory interneurons and the balance of cell death. Deletion of the in mice causes inhibitory interneuron loss in the cortex and cerebellum, and leads to motor deficits and seizures. Our findings provide a molecular basis for controlling inhibitory interneuron population size during circuit formation.
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http://dx.doi.org/10.1523/JNEUROSCI.1636-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643289PMC
November 2020

Brain Neurodegeneration in the Chronic Stage of the Survivors from Severe Non-Missile Traumatic Brain Injury: A Voxel-Based Morphometry Within-Group at One versus Nine Years from a Head Injury.

J Neurotrauma 2021 01 3;38(2):283-290. Epub 2020 Nov 3.

Institute of Nanotechnology (NANOTEC), National Research Council, Lecce, Italy.

The long-term time course of neuropathological changes occurring in survivors from severe traumatic brain injury (TBI) remains uncertain. We investigated the brain morphometry and memory performance modifications within the same group of severe non-missile traumatic brain injury patients (nmTBI) after about ∼one year and at ∼ nine years from injury. Brain magnetic resonance imaging (MRI) measurements were performed with voxel-based morphometry (VBM) to determine specific changes in the gray matter (GM) and white matter (WM) and the overall gray matter volume modifications (GMV) and white matter volume modifications (WMV). Contemporarily, memory-tests were also administered. In comparison with healthy control subjects (HC), those with nmTBI showed a significant change and volume reduction in the GM and WM and also in the GMV and WMV after ∼one year; conversely, ∼nine years after injury, neurodegenerative changes spared the GM and GMV, but a prominent loss was detected in WMV and in WM sites, such as the superior longitudinal fasciculi, the body of the corpus callosum, the optic radiation, and the uncinate fasciculus. Memory performance at ∼one year in comparison with ∼nine years was stable with a subtle but significant trend toward recovery. These data demonstrate that patients with nmTBI undergo neurodegenerative processes during the chronic stage affecting mainly the cerebral WM rather than GM. Despite these anatomical brain parenchyma losses, memory performance tends to be stable or even slightly recovered. These results suggest possible correlations between progressive demyelinization and/or neuropsychiatric changes other than memory performance, and support possible treatments to prevent long-term WM degeneration of the examined nmTBI.
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http://dx.doi.org/10.1089/neu.2020.7203DOI Listing
January 2021

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

Transl Psychiatry 2020 08 12;10(1):280. Epub 2020 Aug 12.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.
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http://dx.doi.org/10.1038/s41398-020-00943-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423986PMC
August 2020

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Nat Neurosci 2020 09 13;23(9):1102-1110. Epub 2020 Jul 13.

Departments of Otolaryngology-Head and Neck Surgery, Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.
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http://dx.doi.org/10.1038/s41593-020-0665-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483861PMC
September 2020

Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.

Cell Rep 2020 06;31(13):107838

Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada. Electronic address:

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the suppressive histone mark H3K27me3 is significantly reduced upon the loss of ATRX. We conclude that the ablation of ATRX in excitatory forebrain neurons leads to sexually dimorphic effects on miR-137 expression and on spatial memory, identifying a potential therapeutic target for neurological defects caused by ATRX dysfunction.
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http://dx.doi.org/10.1016/j.celrep.2020.107838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326465PMC
June 2020
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