Fetal Alcohol Exposure and Cerebrovascular Development

Overview

Critical role of mitochondria in regulating cerebral artery function is well documented, and there is no doubt that mitochondrial is one of the major sensors for alcohol as shown in liver and neurons. In our recent pioneered work, we documented persistent up-regulation of fetal cerebral artery mitochondrial proteome in response to alcohol exposure during mid-pregnancy. However, systematic studies on cerebral artery mitochondria alterations in response to prenatal alcohol exposure remain to be performed and the role of alcohol targeting of fetal cerebral artery mitochondria remains to be established. To overcome these obstacles in the field, we propose to complete three related Aims to test the following central hypothesis: persistent alterations in fetal cerebral artery mitochondrial function critically contribute to developmental delay following fetal alcohol exposure. Aim 1. We will optimize a high-speed PAT system for 3D high-resolution brain imaging of rodents. Aim 2. We will develop advanced software for improved PAT 3D image reconstruction and analysis. Aim 3. We will trace cerebrovascular morphological and functional changes following fetal alcohol exposure into adulthood, with the focus on fetal cerebral vessel density, artery diameter and mitochondrial function. This Aim is intended to utilize technology that is being developed under Aims 1-2. However, if Aims 1-2 become unsuccessful, Aim 3 still can be achieved (albeit at lower level of resolution). Thus, all three aims can be achieved independent of each other. In the course of the study, we will utilize a high-speed PAT for cerebral artery diameter and vessel density monitoring in vivo, fluorescence imaging for assessment of gross mitochondrial function, live-cell metabolic assay platform Seahorse XFe96 Extracellular Flux Analyzer for in-depth analysis of cellular bioenergetics in cerebral arteries ex vivo, and selective pharmacology to complete proposed work. Upon completion, our project will render an indispensable tool that can be ultimately adapted to high-resolution imaging of fetal cerebral circulation in humans for early detection of prenatal alcohol exposure-driven alterations in fetal cerebrovascular system. Moreover, longitudinal characterization of fetal cerebral artery development following prenatal alcohol exposure in our work will provide a “road-map” for understanding of fetal alcohol spectrum disorder-characteristic development with regards to cerebral circulation. Last but not least, our focus on fetal cerebral artery mitochondria will set a new milestone in our understanding of fetal alcohol spectrum disorder.