Abstract
Neuronal activity is a potent extrinsic regulator of oligodendrocyte generation and central nervous system myelination. Clinically, repetitive transcranial magnetic stimulation (rTMS) is delivered to noninvasively modulate neuronal activity; however, the ability of rTMS to facilitate adaptive myelination has not been explored. By performing cre‐lox lineage tracing, to follow the fate of oligodendrocyte progenitor cells in the adult mouse brain, we determined that low intensity rTMS (LI‐rTMS), administered as an intermittent theta burst stimulation, but not as a continuous theta burst or 10 Hz stimulation, increased the number of newborn oligodendrocytes in the adult mouse cortex. LI‐rTMS did not alter oligodendrogenesis per se, but instead increased cell survival and enhanced myelination. These data suggest that LI‐rTMS can be used to noninvasively promote myelin addition to the brain, which has potential implications for the treatment of demyelinating diseases such as multiple sclerosis.
Highlights
Myelinating oligodendrocytes are added to the central nervous system (CNS) throughout life, generated from immature, proliferative oligodendrocyte progenitor cells (OPCs), known as NG2-glia
We report that 14 or 28 days of intermittent theta-burst pattern (iTBS) had no effect on the number of new premyelinating or myelinating oligodendrocytes in the corpus callosum (CC), yet 14 days of iTBS still increased the average length of the green fluorescent protein (GFP)+ internodes produced by new myelinating oligodendrocytes added to this region (Figure 6h,i,l))
This study shows that LI-repetitive transcranial magnetic stimulation (rTMS), applied in an iTBS pattern, can increase the number of new oligodendrocytes that are incorporated into the cortex over time (Figure 1 and Figure 4)
Summary
Myelinating oligodendrocytes are added to the central nervous system (CNS) throughout life, generated from immature, proliferative oligodendrocyte progenitor cells (OPCs), known as NG2-glia (reviewed by Pepper, Pitman, Cullen, & Young, 2018). Et al, 2016; Hoppenrath & Funke, 2013; Lenz et al, 2015; Lenz et al, 2016; Vlachos et al, 2012), increasing intracellular calcium levels (Grehl et al, 2015) and promoting the release of growth factors such as brain-derived neurotrophic factor (BDNF) (Castillo-Padilla & Funke, 2016; Makowiecki, Harvey, Sherrard, & Rodger, 2014; Müller, Toschi, Kresse, Post, & Keck, 2000; Zhang, Xing, Wang, Tao, & Cheng, 2015)—all of which are key regulators of oligodendrogenesis and adaptive myelination (Gautier et al, 2015; Hamilton et al, 2017; Pitman & Young, 2016; Wong, Xiao, Kemper, Kilpatrick, & Murray, 2013; Xiao et al, 2010) For these reasons, rTMS has the potential to influence adaptive myelination, and find application in the repair of demyelinated lesions in the CNS of people with multiple sclerosis (MS). We demonstrate that the delivery of low intensity rTMS (LI-rTMS; 120 mT) in an intermittent theta-burst pattern (iTBS), can increase the number of newborn or newly differentiated oligodendrocytes that survive and mature in the cortex, and enhance myelin internode extension by differentiating oligodendrocytes, effectively promoting myelination of the healthy CNS
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