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Title: Neural activation to loss and reward among alcohol naive adolescents who later initiate alcohol use
Award ID(s):
1922598
NSF-PAR ID:
10293698
Author(s) / Creator(s):
; ; ; ; ; ;
Date Published:
Journal Name:
Developmental Cognitive Neuroscience
Volume:
50
Issue:
C
ISSN:
1878-9293
Page Range / eLocation ID:
100978
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Abstract Background

    Fetal alcohol syndrome (FAS) due to gestational alcohol exposure represents one of the most common causes of nonheritable lifelong disability worldwide. In vitro and in vivo models have successfully recapitulated multiple facets of the disorder, including morphological and behavioral deficits, but far less is understood regarding the molecular and genetic mechanisms underlying FAS.

    Methods

    In this study, we utilized an in vitro human pluripotent stem cell‐based (hPSC) model of corticogenesis to probe the effects of early, chronic intermittent alcohol exposure on the transcriptome of first trimester‐equivalent cortical neurons.

    Results

    We used RNA sequencing of developing hPSC‐derived neurons treated for 50 days with 50 mM ethanol and identified a relatively small number of biological pathways significantly altered by alcohol exposure. These included cell‐type specification, axon guidance, synaptic function, and regional patterning, with a notable upregulation of WNT signaling‐associated transcripts observed in alcohol‐exposed cultures relative to alcohol‐naïve controls. Importantly, this effect paralleled a shift in gene expression of transcripts associated with regional patterning, such that caudal forebrain‐related transcripts were upregulated at the expense of more anterior ones. Results from H9 embryonic stem cells were largely replicated in an induced pluripotent stem cell line (IMR90‐4), indicating that these patterning alterations are not cell line‐specific.

    Conclusions

    We found that a major effect of chronic intermittent alcohol on the developing cerebral cortex is an overall imbalance in regionalization, with enrichment of gene expression related to the production of posterodorsal progenitors and a diminution of anteroventral progenitors. This finding parallels behavioral and morphological phenotypes observed in animal models of high‐dose prenatal alcohol exposure, as well as patients with FAS.

     
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