Inhibited oligodendrogenesis impairs attention and motivation in adult mice regardless of repeated mild traumatic brain injury

Abstract

Introduction The brain’s white matter is responsible for communication across the brain and because attention relies on coordinated communication among distributed brain networks, white matter dysfunction may contribute to attentional impairment. Attention problems are among the most common long-lasting cognitive symptoms of mild traumatic brain injury (mTBI) and as attention is fundamental to many aspects of cognition, the effects of attentional impairment can be broad. mTBI-induced effects on oligodendrocytes and myelin contribute to cognitive deficits following injury and myelin plasticity is a potential mechanism for functional recovery. The aims of this work were to investigate the effects of mTBI and inhibition of oligodendrogenesis on attention in mice, and evaluate the contribution of newly generated oligodendrocytes to behavioral recovery following injury. Methods This study used the Myrf conditional knockout mouse model, in which the Myrf gene, required for oligodendrocyte precursor cell (OPC) differentiation into mature myelinating oligodendrocytes, is deleted from OPCs following tamoxifen injection, thereby halting oligodendrogenesis. Mice were trained on the 5-Choice Serial Reaction Time (5-CSRT) task before receiving tamoxifen followed by three mTBI or sham procedures. Attention was probed on the 5-CSRT task with decreasing stimulus duration at four timepoints following injury out to 12 weeks. Results While no mTBI-induced attentional impairment was observed, OPC-MyrfKO mice showed lower accuracy (β = −4.26%, pBonf = 0.003) across injury groups, timepoints and stimulus durations, and fewer premature trials at the later timepoints (genotype-by-timepoint interaction pBonf = 0.03; β = −4.8%, p = 0.017 at 8 weeks and β = −5.19%, p = 0.027 at 12 weeks), suggesting that active oligodendrogenesis is required for sustained attention and task engagement. Conclusion These results suggest that myelin plasticity in adulthood may contribute to attention and complex task performance. The mouse model of mTBI used did not impact attention as measured by the 5-CSRT task, thus further research is required to elucidate the role of oligodendrogenesis in post-mTBI cognitive recovery.