Effects of Alcohol Exposure during Developmental Phases on Brain Functional Connectivity

Abstract

Fetal alcohol spectrum disorders (FASD) is one of the most common causes of mental disability in the world. There is growing evidence that developmental alcohol exposure can cause reduced cognitive flexibility and alter multisensory processing, suggesting impairments in fronto-striatal and multisensory integrative cortical areas. The central hypothesis is that developmental alcohol exposure leads to impaired connectivity within these areas, and will result in reorganization of the large-scale brain network. We tested this hypothesis with two animal models that are known to exhibit abnormities in cognitive flexibility and sensory processing: (1) a rat FASD model with alcohol exposure from gestational day 6 to 20, similar to human gestation from the first to the late second trimester; (2) a ferret FASD model with alcohol exposure from postnatal day 10 to 30, similar to the third trimester of gestation in humans. These two models mimic alcohol exposure during early and late fetal stage humans. Our study revealed reduced resting-state functional connectivity within fronto-striatal circuit and a visual-tactile circuit in young adult animals with alcohol exposure during early fetal stage. Although alcohol exposure during late fetal stage did not alter the resting-state functional connectivity within fronto-striatal circuit, an increased functional connectivity within the visual-tactile circuit was detected in juvenile animals. Graph theoretical analysis was used to assess the alteration in brain network properties after alcohol exposure during early or late fetal stage. A reduction of large-scale brain network small-worldness was observed following alcohol exposure during early fetal stage. No significant group difference was observed following alcohol exposure during late fetal stage. In conclusion, the results supported the central hypothesis that developmental alcohol exposure alters resting-state functional connectivity within fronto-striatal circuit and visual-tactile circuit and may eventually alter the organization of large-scale brain networks. The timing of alcohol exposure plays an important role in the outcomes and should be taken into consideration in future research, the usage of diagnostic biomarkers and the application of intervention approaches.