Results To evaluate successful learning, we tested for a linear increase in participants’ ability to enhance fMRI activity/connectivity voluntarily across visits. Participants in the SMA-activity NF group were the only group that showed a linear increase across visits. We also evaluated participants’ capacity to upregulate their brain activity after the end oBackground. White matter atrophy and myelin abnormalities appear to be significant features in Huntington disease (HD). Although white matter atrophy appears very early in the disease course, the molecular factors that underline myelination deficits in HD are poorly understood.
Aim We hypothesize that intrinsic mutant huntingtin (mHTT)-mediated effects in oligodendroglia contribute to myelin deficits and behavioural manifestations in HD.
Method To test this hypothesis, we crossed the BACHD mouse model of HD, which expresses full-length human mHTT and mimics many of the behavioural and neuropathological features of the human condition, to NG2-Cre mice in order to silence mHTT specifically in oligodendroglia. Electron microscopy was used to analyze myelin fibers of the corpus callosum (CC) at 1 and 12 months of age and a battery of behavioral tests was performed to evaluate motor and psychiatric-like phenotypes in mice. To gain insights into the molecular mechanisms underlying the oligodendrocyte dysfunction observed in HD mice, we performed RNA-seq analysis on the CC of mice at 1 month of age.
Results We show that selective removal of mHTT from oligodendroglia rescues the deficits in thickness and compactness of myelin sheaths and improves certain aspects of behavioural dysfunction in the HD mice. Our results also implicate aberrant PRC2 activity in the myelination deficits in HD.
Conclusions Our findings suggest that epigenetic mechanisms are involved in the intrinsic oligodendroglia dysfunction in HD and contribute to myelin abnormalities and certain behavioural manifestations of the disease. training in the absence of explicit feedback (transfer effects). The SMA-activity NF group was again the only group that showed successful upregulation.
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