scholarly journals Maternal SSRI treatment during offspring development results in long-term behavioral, cellular, and neuroimaging disruptions

2017 ◽  
Author(s):  
Susan E. Maloney ◽  
Rachel Rahn ◽  
Shyam Akula ◽  
Michael A. Rieger ◽  
Katherine B. McCullough ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Epidemiological Studies ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Repetitive Behaviors ◽  
Intrinsic Signal ◽  
Optical Intrinsic Signal ◽  
Ssri Treatment

SummarySerotonergic dysregulation is implicated in psychiatric disorders, including autism spectrum disorders (ASD). Epidemiological studies suggest selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy may increase ASD risk in offspring, however it is unclear from these studies whether ASD susceptibility is related to the maternal diagnosis or if treatment poses additional risk. Here, we exposed mouse dams to fluoxetine and characterized the offspring to isolate possible effects of SSRI exposure on ASD-relevant behaviors. We demonstrate social communication and interaction deficits and repetitive behaviors, with corresponding dendritic morphology changes in pertinent brain regions. Also, using a novel application of optical intrinsic signal imaging, we show altered stimulus-evoked cortical response and region-specific decreases in functional connectivity. These findings indicate drug exposure alone is sufficient to induce long-term behavioral, cellular, and hemodynamic-response disruptions in offspring, thus contributing to our understanding of ASD pathogenesis, risk and mechanism, as well as the developmental role of serotonin.

Emotion Dysregulation in Autism Spectrum Disorder

2018 ◽  
pp. 282-298
Author(s):  
Emily Neuhaus
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Educational Outcomes ◽  
Emotion Dysregulation ◽  
Research Priorities ◽  
Theoretical Models ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder

Autism spectrum disorder (ASD) is defined by deficits in social communication and interaction, and restricted and repetitive behaviors and interests. Although current diagnostic conceptualizations of ASD do not include emotional difficulties as core deficits, the disorder is associated with emotion dysregulation across the lifespan, with considerable implications for long-term psychological, social, and educational outcomes. The overarching goal of this chapter is to integrate existing knowledge of emotion dysregulation in ASD and identify areas for further investigation. The chapter reviews the prevalence and expressions of emotion dysregulation in ASD, discusses emerging theoretical models that frame emotion dysregulation as an inherent (rather than associated) feature of ASD, presents neurobiological findings and mechanisms related to emotion dysregulation in ASD, and identifies continuing controversies and resulting research priorities.

scholarly journals Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph R. Abraham ◽  
Nicholas Szoko ◽  
John Barnard ◽  
Robert A. Rubin ◽  
Daniela Schlatzer ◽  
...  
Keyword(s):  
Global Analysis ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Acid Oxidation ◽  
Synaptic Membrane ◽  
Label Free ◽  
Proteomic Data ◽  
Control Brain

Abstract Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.

scholarly journals Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

2020 ◽  
Vol 10 (12) ◽  
pp. 951
Author(s):  
Alma Y. Galvez-Contreras ◽  
David Zarate-Lopez ◽  
Ana L. Torres-Chavez ◽  
Oscar Gonzalez-Perez
Keyword(s):  
Autism Spectrum Disorder ◽  
Interpersonal Communication ◽  
Neurodevelopmental Disorder ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Abnormal Development ◽  
Matter Production

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

scholarly journals Spatial Integration of Vascular Changes with Neural Activity in Mouse Cortex

2002 ◽  
Vol 22 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Joseph P. Erinjeri ◽  
Thomas A. Woolsey
Keyword(s):  
Real Time ◽  
Barrel Cortex ◽  
Brain Regions ◽  
Histochemical Staining ◽  
Spatial Integration ◽  
Intrinsic Signals ◽  
Intrinsic Signal ◽  
Cortical Columns ◽  
Optical Intrinsic Signal ◽  
Mouse Cortex

The authors evaluated representations of discretely activated, neighboring brain regions using real-time optical intrinsic signals by transcranial imaging with 540-nm and 610-nm broadband illumination of the mouse barrel cortex. Iron filings were glued to two neighboring whiskers (C2 + D2) that were stimulated magnetically, singly and together. Real-time images were collected, averaged, and analyzed statistically. Postmortem filling of arteries with fluorescent beads was shown in relation to histochemical staining of barrels to accurately relate surface changes to functional cortical columns. Significant optical intrinsic signal changes are related to overlapping distributions of arterioles that feed the two separate areas. Activation of adjacent and interacting cortical columns leads not only to increased magnitude of vascular responses in those columns, but also to wider spatial extent of absorption changes occurring principally in areas of cortex fed by vessels upstream of the active cortex. The localization of changing hemoglobin absorption around upstream blood vessels and their vascular domains suggests that propagated vasodilation of upstream parent vessels is greater when vasodilatory signals from separate areas of active cortex converge on common arterioles that feed them.

scholarly journals Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2024
Author(s):  
Valentina Bieneck ◽  
Anke Bletsch ◽  
Caroline Mann ◽  
Tim Schäfer ◽  
Hanna Seelemeyer ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Individual Differences ◽  
Cortical Thickness ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Developmental Trajectory ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Childhood And Adolescence ◽  
Autism Symptoms

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.

scholarly journals Transcriptional subtyping explains phenotypic variability in genetic subtypes of autism spectrum disorder

2020 ◽  
Vol 32 (4) ◽  
pp. 1353-1361
Author(s):  
Sandy Trinh ◽  
Anne Arnett ◽  
Evangeline Kurtz-Nelson ◽  
Jennifer Beighley ◽  
Marta Picoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Phenotypic Variability ◽  
Expression Patterns ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Phenotypic Heterogeneity ◽  
Spectrum Disorder ◽  
Genetic Subtypes

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication and presence of restricted, repetitive behaviors, and interests. However, individuals with ASD vary significantly in their challenges and abilities in these and other developmental domains. Gene discovery in ASD has accelerated in the past decade, and genetic subtyping has yielded preliminary evidence of utility in parsing phenotypic heterogeneity through genomic subtypes. Recent advances in transcriptomics have provided additional dimensions with which to refine genetic subtyping efforts. In the current study, we investigate phenotypic differences among transcriptional subtypes defined by neurobiological spatiotemporal co-expression patterns. Of the four transcriptional subtypes examined, participants with mutations to genes typically expressed highly in all brain regions prenatally, and those with differential postnatal cerebellar expression relative to other brain regions, showed lower cognitive and adaptive skills, higher severity of social communication deficits, and later acquisition of speech and motor milestones, compared to those with mutations to genes highly expressed during the postnatal period across brain regions. These findings suggest higher-order characterization of genetic subtypes based on neurobiological expression patterns may be a promising approach to parsing phenotypic heterogeneity among those with ASD and related neurodevelopmental disorders.

scholarly journals The Parvalbumin Hypothesis of Autism Spectrum Disorder

2020 ◽  
Vol 14 ◽  
Author(s):  
Federica Filice ◽  
Lucia Janickova ◽  
Thomas Henzi ◽  
Alessandro Bilella ◽  
Beat Schwaller
Keyword(s):  
Autism Spectrum Disorder ◽  
Messenger Rna ◽  
Energy Requirement ◽  
Neurodevelopmental Disorder ◽  
High Energy ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Supporting Evidence

The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

Autism Spectrum Disorders

2013 ◽  
pp. 1022-1033
Author(s):  
Alexander Kolevzon ◽  
A. Ting Wang ◽  
David Grodberg ◽  
Joseph D. Buxbaum
Keyword(s):  
Autism Spectrum Disorders ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Model Systems ◽  
Novel Treatments ◽  
Symptom Domains ◽  
Disease Modifying ◽  
Spectrum Disorders ◽  
Core Symptoms

Autism spectrum disorders (ASD) manifest with deficits in social communication, together with the presence of repetitive behaviors and restricted interests.Behavioral interventions are important first-line treatments in ASD and there is a need for pharmacological treatments that target core symptoms of ASD. Neuroimaging studies implicate specific brain regions and networks in ASD, and there has beensignificant progress in identifying etiological genetic loci for ASD. Gene discovery, coupled with the development of animal model systems, have elucidated the neurobiology of several monogenic forms of ASD. These discoveries have in turn led to important opportunities for developing novel treatments and several clinical trials are underway with potentially disease-modifying medications that target core symptom domains. Although the state of the evidence is preliminary, these studies are the basis for enormous optimism in ASD and underscore how neurobiological approaches are likely to lead to novel therapeutics in ASD.

scholarly journals Multimodal Examination of Structural and Functional Remapping in the Mouse Photothrombotic Stroke Model

2013 ◽  
Vol 33 (5) ◽  
pp. 716-723 ◽  
Author(s):  
Andrew N Clarkson ◽  
Héctor E López-Valdés ◽  
Justine J Overman ◽  
Andrew C Charles ◽  
KC Brennan ◽  
...  
Keyword(s):  
Cortical Reorganization ◽  
Stroke Recovery ◽  
Stroke Model ◽  
Data Set ◽  
Neural Repair ◽  
Reaching Task ◽  
Intrinsic Signal ◽  
Optical Intrinsic Signal ◽  
Photothrombotic Stroke

Recent studies show a limited capacity for neural repair after stroke, which includes remapping of sensorimotor functions and sprouting of new connections. However, physiologic and connectional plasticity of sensory maps during long-term functional recovery in the mouse have not been determined. Using a photothrombotic stroke model, we targeted the motor cortex, which we show results in lasting behavioral deficits on the grid-walking and in the cylinder tasks out to 8 weeks after stroke. Mice recovered performance in a skilled reaching task, showing no deficit from week 2 after stroke. Long-term optical intrinsic signal imaging revealed functional reorganization of sensory cortical maps for both forelimb and hindlimb, with more diffuse sensory physiologic maps. There was a small but significant increase in motor neuron projections within the areas of functional cortical reorganization as assessed using the neuroanatomic tracer biotinylated dextran amine. These findings show that the sensorimotor cortex undergoes remapping of cortical functions and axonal sprouting within the same regions during recovery after stroke. This suggests a linked structural and physiologic plasticity underlying recovery. Combined long-term structural and functional mapping after stroke in the mouse is practical and provides a rich data set for mechanistic analysis of stroke recovery.

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