Dataset Information

Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

ABSTRACT: Prenatal alcohol exposure (PAE) is associated with reduced overall brain volume. Although this has been reported consistently across studies, the status of cortical thickness after PAE is more variable. The cortex is asymmetric in typical controls, but it is unclear whether the left and right counter parts of the cortical gray matter are unevenly influenced in postpartum brain development after PAE. Brain MRI was acquired in a newly recruited sample of 157 participants (PAE: N?=?78, 5.5-18.9 years, 40 females and controls: N?=?79, 5.8-18.5 years, 44 females) across four Canadian sites in the NeuroDevNet project. The PAE group had other confounds such as psychiatric co-morbidity, different living environment, and so on, not present in the control group. In agreement with previous studies, the volumes of all brain structures were reduced in PAE compared to controls, including gray and white matter of cerebrum and cerebellum, and all deep gray matter including the hippocampus, amygdala, thalamus, caudate, putamen, and pallidum. The PAE group showed reductions in global and regional cortical thickness, while the pattern and degree of cortical thickness asymmetry were preserved in PAE participants with the greatest rightward asymmetry in the lateral parietal lobe and the greatest leftward asymmetry in the lateral frontal cortex. This persistent asymmetry reflects that the homologous left and right cortical regions followed typical relative developmental patterns in the PAE group despite being thinner bilaterally than controls. Hum Brain Mapp 39:72-88, 2018. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Zhou D

PROVIDER: S-EPMC6866315 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

Zhou Dongming D Rasmussen Carmen C Pei Jacqueline J Andrew Gail G Reynolds James N JN Beaulieu Christian C

Human brain mapping 20170928 1

Prenatal alcohol exposure (PAE) is associated with reduced overall brain volume. Although this has been reported consistently across studies, the status of cortical thickness after PAE is more variable. The cortex is asymmetric in typical controls, but it is unclear whether the left and right counter parts of the cortical gray matter are unevenly influenced in postpartum brain development after PAE. Brain MRI was acquired in a newly recruited sample of 157 participants (PAE: N = 78, 5.5-18.9 yea ...[more]

PMID: 28960637

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Project description:Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50?mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

Project description:Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.

Dataset Information

Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

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Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

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