PROJECT SUMMARY During development, oligodendrocyte precursor cells (OPCs) widely dispersed into surrounding areas of gray matter (neuronal cell bodies) or white matter (axon fiber tracts). As development proceeds into postnatal stages, OPCs readily differentiate to give rise to oligodendrocytes, which are responsible for insulating neuronal axons with myelin sheath. Interestingly, many OPCs remain undifferentiated into adult stages where they have been shown to play an important role in adaptive myelination, a neuronal activity driven, experience-mediated process that is essential for various forms of learning and memory. Previous studies show that OPCs are vulnerable to the effects of developmental alcohol exposure, resulting in a decrease or delay in differentiation and myelination of major white matter tracts in the brain. It is possible that these myelination deficits, especially in brain regions critical for learning and memory, may directly contribute to the neurodevelopmental and behavioral abnormalities observed in individuals with fetal alcohol spectrum disorders (FASDs). However, how developmental alcohol exposure impacts the gene expression and function of OPCs and oligodendrocytes, and their roles in myelin plasticity during learning and memory remains to be elucidated. To bridge this gap in knowledge, this component aims to pursue the following specific aims in a third trimester equivalent mouse model of alcohol exposure (TTAE) in which oligodendrogenesis and myelination are compromised in the brain. Specific Aim 1. To determine the effects of developmental alcohol exposure on transcriptional programs essential for differentiation of OPCs into oligodendrocytes in gray matter and white matter in the brain. Specific Aim 2. To determine the impact of developmental alcohol exposure on activity-dependent, experience- mediated myelin plasticity in early adulthood. We anticipate that the completion of these aims will provide important clinical implications regarding strategies to pharmacologically stimulate the myelination capacity of OPCs and oligodendrocytes to reverse the myelination deficits seen in those affected by FASD.