Elucidating learning-induced molecular signatures in hippocampal mature oligodendrocytes at single-cell and spatial resolution: Implications for hippocampal function - 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 Specific Aim 1, we will identify learning-induced molecular signatures in mature oligodendrocyte subtypes using cutting-edge single-cell multiomics and high-plex in situ approaches. In Specific Aim 2, we will develop in vivo strategies of gene manipulation specifically targeting mature myelinating oligodendrocytes. We will then examine functional signatures of activity-dependent oligodendroglial plasticity in vivo, by quantifying myelination changes after learning and utilizing fiber-photometry to investigate the dynamics of calcium and glucose in mature myelinating oligodendrocytes during spatial learning. The expected outcomes of this exploratory/developmental R21 proposal will provide unprecedented insights into the functional heterogeneity of mature oligodendrocytes during memory consolidation, laying the groundwork for future research to investigate the mechanistic relationship between transcriptomic changes that underlie learning-dependent oligodendroglial plasticity and hippocampal memory consolidation. These findings will significantly advance our understanding of long-term memory and offer novel avenues for therapeutic interventions for cognitive impairments associated with neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.
