an-appetitive-spatial-working-memory-task-for-mice-semi-automated-8

An Appetitive Spatial Working Memory Task for Mice in a Semi-Automated 8-Arm Radial Maze, Reducing Fearful Memory Association in the Maze

This method paper details a protocol to test spatial working memory in mice using a semi-automated radial 8-arm maze (RAM). The RAM is a partially ...

University College London

Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.

Oligodendrocyte dynamics dictate cognitive performance outcomes of working memory training in mice.

Chromatin remodeling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival, and maintenance. We asked whether CRCs also control the proliferation of OL precursors (OPs)-focusing on the INO80 complex, which is known to regulate the proliferation of a variety of other cell types during development and disease. CRISPR/Cas9-mediated inactivation of Ino80 in vitro, or Cre-mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80-deficient mice, but correlated RNAseq and ATAC-seq uncovered no general correlation between gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following the loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.

Article	Year
Oligodendrocyte dynamics dictate cognitive performance outcomes of working memory training in mice. Nature communications\| PubMed ID: 37838794	2023
The INO80 Chromatin Remodeling Complex Regulates Histone H2A.Z Mobility and the G1-S Transition in Oligodendrocyte Precursors. Glia\| PubMed ID: 40017313	2025

Stuart G. Nayar

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