scholarly journals Central neurogenetic signatures of the visuomotor integration system

2020 ◽  
Vol 117 (12) ◽  
pp. 6836-6843 ◽  
Author(s):  
Elisenda Bueichekú ◽  
Maite Aznárez-Sanado ◽  
Ibai Diez ◽  
Federico d’Oleire Uquillas ◽  
Laura Ortiz-Terán ◽  
...  
Keyword(s):  
Human Brain ◽  
Neural Development ◽  
Fragile X ◽  
Autism Spectrum ◽  
Brain Atlas ◽  
Functional Impairments ◽  
Visuomotor Integration ◽  
Human Cortex ◽  
Genetic Expression ◽  
Brain Transcriptome

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader–Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes—TBR1, SCN1A, MAGEL2, and CACNB4—to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

scholarly journals The role of CPEB family proteins in the nervous system function in the norm and pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kozlov ◽  
Yulii V. Shidlovskii ◽  
Rudolf Gilmutdinov ◽  
Paul Schedl ◽  
Mariya Zhukova
Keyword(s):  
Nervous System ◽  
Gene Regulation ◽  
Neural Development ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mrna Transport ◽  
Ribonucleoprotein Complexes ◽  
Posttranscriptional Gene Regulation ◽  
Nervous System Function ◽  
Functional Features

AbstractPosttranscriptional gene regulation includes mRNA transport, localization, translation, and regulation of mRNA stability. CPEB (cytoplasmic polyadenylation element binding) family proteins bind to specific sites within the 3′-untranslated region and mediate poly- and deadenylation of transcripts, activating or repressing protein synthesis. As part of ribonucleoprotein complexes, the CPEB proteins participate in mRNA transport and localization to different sub-cellular compartments. The CPEB proteins are evolutionarily conserved and have similar functions in vertebrates and invertebrates. In the nervous system, the CPEB proteins are involved in cell division, neural development, learning, and memory. Here we consider the functional features of these proteins in the nervous system of phylogenetically distant organisms: Drosophila, a well-studied model, and mammals. Disruption of the CPEB proteins functioning is associated with various pathologies, such as autism spectrum disorder and brain cancer. At the same time, CPEB gene regulation can provide for a recovery of the brain function in patients with fragile X syndrome and Huntington's disease, making the CPEB genes promising targets for gene therapy.

scholarly journals Do Fragile X Syndrome and Other Intellectual Disorders Converge at Aberrant Pre-mRNA Splicing?

2021 ◽  
Vol 12 ◽  
Author(s):  
Sneha Shah ◽  
Joel D. Richter
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Protein Product ◽  
Aberrant Splicing ◽  
Brain Transcriptome ◽  
Post Mortem Brain ◽  
Spectrum Disorders ◽  
General Translation

Fragile X Syndrome is a neuro-developmental disorder caused by the silencing of the FMR1 gene, resulting in the loss of its protein product, FMRP. FMRP binds mRNA and represses general translation in the brain. Transcriptome analysis of the Fmr1-deficient mouse hippocampus reveals widespread dysregulation of alternative splicing of pre-mRNAs. Many of these aberrant splicing changes coincide with those found in post-mortem brain tissue from individuals with autism spectrum disorders (ASDs) as well as in mouse models of intellectual disability such as PTEN hamartoma syndrome (PHTS) and Rett Syndrome (RTT). These splicing changes could result from chromatin modifications (e.g., in FXS, RTT) and/or splicing factor alterations (e.g., PTEN, autism). Based on the identities of the RNAs that are mis-spliced in these disorders, it may be that they are at least partly responsible for some shared pathophysiological conditions. The convergence of splicing aberrations among these autism spectrum disorders might be crucial to understanding their underlying cognitive impairments.

scholarly journals Genes involved in cholesterol cascades are linked to brain connectivity in one third of autistic patients

2020 ◽  
Author(s):  
Javier Rasero ◽  
Antonio Jimenez-Marin ◽  
Ibai Diez ◽  
Mazahir T. Hasan ◽  
Jesus M. Cortes
Keyword(s):  
Human Brain ◽  
Large Scale ◽  
Functional Neuroimaging ◽  
Brain Connectivity ◽  
Autism Spectrum ◽  
The Other ◽  
Brain Atlas ◽  
Consensus Clustering ◽  
Major Drawback ◽  
Large Populations

AbstractThe large heterogeneity in the symptomatology and severity of autism spectrum disorder (ASD) is a major drawback for the design of effective therapies. Beyond behavioral phenotypes, subtype stratification strategies that can be applied to large populations are needed, these combining different neurobiological characteristics and based on the large-scale organization of the human brain, as well as neurogenetic fingerprints. Here, we make use of ABIDE, the largest publicly available database of functional neuroimaging in ASD, to which we have applied rigorous data harmonization between the different scanning institutions in order to employ analyses based on consensus clustering and to evaluate the patterns of brain connectivity. As a result, we identified three subtypes of ASD, the first of which was characterized by a mixture of hyper- and hypo-connectivity, stronger network segregation and weaker integration, and it represented approximately 13% of all patients. The second subtype was associated with 31% of the patients, and it was characterized by hyperconnectivity but no topological differences with respect to the group of typically developing controls. The third was the most numerous subtype, assigned to 52% of all patients, and it was characterized by hypoconnectivity, decreased network segregation and increased integration. We also defined a neurobiological signature for each of these subtypes, detailing the connectivity and structures most specific to each subtype. Strikingly, at the behavioral level, none of the neuropsychological scores used in the diagnosis of ASD is capable of differentiating any of the subtypes from the other two. Finally, we use the Allen Human Brain Atlas of gene transcription brain maps to show that subtype 2 has an extraordinary enrichment in biological processes related to the synthesis, regulation and transport of cholesterol and other lipoproteins, one of the mechanisms previously attributed to ASD. We also show that this lipid-susceptible ASD subtype could be represented by the dysfunctionality of the network, unlike the other two subtypes that have more structural alterations in the connectome. Thus, our study provide compelling support for prospects of cholesterol-related therapies in this subset of autistic individuals.

Searching for convergent pathways in autism spectrum disorders: insights from human brain transcriptome studies

2016 ◽  
Vol 73 (23) ◽  
pp. 4517-4530 ◽  
Author(s):  
Akira Gokoolparsadh ◽  
Gavin J. Sutton ◽  
Alexiy Charamko ◽  
Nicole F. Oldham Green ◽  
Christopher J. Pardy ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Human Brain ◽  
Autism Spectrum ◽  
Brain Transcriptome ◽  
Spectrum Disorders

Attention Deficit Hyperactivity Disorder in Autism Spectrum Disorder

2020 ◽  
pp. 158-176
Author(s):  
Karen Bearss ◽  
Aaron J. Kaat
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Autism Spectrum ◽  
Developmental Trajectory ◽  
Spectrum Disorder ◽  
Adhd Symptoms ◽  
Functional Impairments ◽  
Hyperactivity Disorder ◽  
Delayed Recognition

This chapter will review the available evidence on individuals with co-occurring diagnoses of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). This chapter contends that children diagnosed with both disorders (ASD+ADHD) are a subset of the ASD population that is at risk for delayed recognition of their ASD diagnosis, poor treatment response, and poorer functional outcomes compared to those with ASD without ADHD. Specifically, the chapter highlights the best estimates of the prevalence of the comorbidity, the developmental trajectory of people with co-occurring ASD and ADHD, how ADHD symptoms change across development, overlapping genetic and neurobiological risk factors, psychometrics of ADHD diagnostic instruments in an ASD population, neuropsychological and functional impairments associated with co-occurring ASD and ADHD, and the current state of evidence-based treatment for both ASD and ADHD symptoms. Finally, the chapter discusses fruitful avenues of research for improving understanding of this high-risk comorbidity so that mechanism-to-treatment pathways for ADHD in children with ASD can be better developed.

scholarly journals Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dwaipayan Adhya ◽  
George Chennell ◽  
James A. Crowe ◽  
Eva P. Valencia-Alarcón ◽  
James Seyforth ◽  
...  
Keyword(s):  
High Resolution ◽  
Human Brain ◽  
Light Sheet ◽  
Autism Spectrum ◽  
Model Systems ◽  
Large Field ◽  
Autism Spectrum Conditions ◽  
Patient Specific ◽  
Airy Beam

Abstract Background The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points. Results Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified, in vitro tissues, in both speed and resolution when compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes. Conclusion We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and cleared in vitro human brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. This process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes in vitro.

scholarly journals Local Protein Translation and RNA Processing of Synaptic Proteins in Autism Spectrum Disorder

2021 ◽  
Vol 22 (6) ◽  
pp. 2811
Author(s):  
Yuyoung Joo ◽  
David R. Benavides
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Synaptic Proteins ◽  
Local Translation ◽  
Translation Control

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition associated with impairments in social interaction, communication and repetitive behaviors. While the underlying disease mechanisms remain to be fully elucidated, dysfunction of neuronal plasticity and local translation control have emerged as key points of interest. Translation of mRNAs for critical synaptic proteins are negatively regulated by Fragile X mental retardation protein (FMRP), which is lost in the most common single-gene disorder associated with ASD. Numerous studies have shown that mRNA transport, RNA metabolism, and translation of synaptic proteins are important for neuronal health, synaptic plasticity, and learning and memory. Accordingly, dysfunction of these mechanisms may contribute to the abnormal brain function observed in individuals with autism spectrum disorder (ASD). In this review, we summarize recent studies about local translation and mRNA processing of synaptic proteins and discuss how perturbations of these processes may be related to the pathophysiology of ASD.

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

scholarly journals Role of Exclusive Breastfeeding in Conferring Protection in Children At-Risk for Autism Spectrum Disorder: Results from a Sibling Case–control Study

2018 ◽  
Vol 09 (01) ◽  
pp. 132-136 ◽  
Author(s):  
Harshini Manohar ◽  
Madhavapuri Pravallika ◽  
Preeti Kandasamy ◽  
Venkatesh Chandrasekaran ◽  
Ravi Philip Rajkumar
Keyword(s):  
Neural Development ◽  
Exclusive Breastfeeding ◽  
Feeding Practices ◽  
Autism Spectrum ◽  
Gut Microflora ◽  
Typically Developing ◽  
Lower Odds ◽  
Children With Asd ◽  
Typically Developing Siblings

ABSTRACTBackground: Gut microflora influences neural development through complex mechanisms. Feeding practices, especially breastfeeding influence gut microbiome and thereby play a pivotal role in immune and neural development. Current understandings of the role of healthy distal gut microflora in the development of immune and neural systems provide insights into immunological mechanisms as one of the possible etiologies in autism spectrum disorder (ASD). Studies have shown that optimal breastfeeding is associated with lower odds of being at-risk for ASD and children with ASD are suboptimally breastfed. Methods: The feeding practices of children with ASD (n = 30) was compared to their typically developing siblings as matched controls (n = 30). Information regarding feeding practices was collected from mothers through a semi-structured questionnaire. Results: About 43.3% of children with ASD received exclusive breastfeeding, whereas 76.7% of their typically developing siblings were exclusively breastfed. Exclusive breastfeeding was associated with lower odds for ASD (odds ratio [OR] = 0.166; 95% confidence interval [CI] = 0.025–0.65), while early introduction of top feeds was associated with higher odds (OR = 6; 95% CI = 1.33–55.19). Difficulties in breastfeeding were attributed to child-related factors in 13.2% of the children. Conclusion: Children with ASD are suboptimally breastfed compared to their typically developing siblings. Exclusive breastfeeding may confer protection in vulnerable children. Further studies on larger prospective sample are required to establish the association.

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