Human in vitro models for understanding mechanisms of autism spectrum disorder.

Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled

The Future of Our Children

Christopher Greeley and Robert Sanborn\u27s introduction to Volume 7, Issue 2: The Critical Years: Research and Progress in Early Education and Early Brain Development

Environmental Effects On Drosophila Brain Development And Learning

Brain development and behavior are sensitive to a variety of environmental influences including social interactions and physicochemical stressors. Sensory input in situ is a mosaic of both enrichment and stress, yet little is known about how multiple environmental factors interact to affect brain anatomical structures, circuits and cognitive function. In this study, we addressed these issues by testing the individual and combined effects of sub-adult thermal stress, larval density and early-adult living spatial enrichment on brain anatomy and olfactory associative learning in adult Drosophila melanogaster. In response to heat stress, the mushroom bodies (MBs) were the most volumetrically impaired among all of the brain structures, an effect highly correlated with reduced odor learning performance. However, MBs were not sensitive to either larval culture density or early-adult living conditions. Extreme larval crowding reduced the volume of the antennal lobes, optic lobes and central complex. Neither larval crowding nor early-adult spatial enrichment affected olfactory learning. These results illustrate that various brain structures react differently to environmental inputs, and that MB development and learning are highly sensitive to certain stressors (pre-adult hyperthermia) and resistant to others (larval crowding). © 2018. Published by The Company of Biologists Ltd

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain

Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration

Environmental and genetic influences on neurocognitive development: the importance of multiple methodologies and time-dependent intervention

Genetic mutations and environmental factors dynamically influence gene expression and developmental trajectories at the neural, cognitive, and behavioral levels. The examples in this article cover different periods of neurocognitive development—early childhood, adolescence, and adulthood—and focus on studies in which researchers have used a variety of methodologies to illustrate the early effects of socioeconomic status and stress on brain function, as well as how allelic differences explain why some individuals respond to intervention and others do not. These studies highlight how similar behaviors can be driven by different underlying neural processes and show how a neurocomputational model of early development can account for neurodevelopmental syndromes, such as autism spectrum disorders, with novel implications for intervention. Finally, these studies illustrate the importance of the timing of environmental and genetic factors on development, consistent with our view that phenotypes are emergent, not predetermined