Project Summary/Abstract Neuronal plasticity is fundamental for cognitive and behavioral processes. Emerging evidence has shed light on the role of oligodendrocytes in regulating activity-dependent plasticity. Although primarily recognized for their role in forming myelin, mature oligodendrocytes also perform additional metabolic functions that facilitate energy- efficient and rapid saltatory conduction in white matter tracts across neuronal circuits. Although it is established that myelin plasticity can influence neurophysiology and behavior, a comprehensive understanding of the molecular mechanisms by which mature oligodendrocytes regulate hippocampal function remain elusive. Recent reports have identified the presence of distinct mature oligodendroglial subtypes within the hippocampus that differ in their transcriptomic profiles, topographical distribution, and myelination characteristics, and it is likely that these mature oligodendroglial subclasses also exhibit differences in cell-type-specific and spatial molecular signatures during long-term memory storage. Our preliminary findings provide evidence of rapid changes in transcriptomic signatures in mature myelinating oligodendrocytes within the first hour after spatial learning, likely reflecting myelin-independent aspects of mature oligodendroglial function. The rapid and dynamic changes observed in the transcriptomic landscape, coupled with the diversity in mature oligodendroglial cell types, necessitate a thorough molecular investigation to fully comprehend the role of these cells in hippocampal function. This proposal aims to elucidate the molecular signatures of mature oligodendroglial subtypes at single- cell and spatial resolution during memory consolidation and investigate the functional consequences of manipulating mature oligodendroglial gene expression on activity-dependent oligodendroglial plasticity underlying hippocampal memory consolidation. The research will be conducted in two aims. In Specifi