Myelin and Brain Plasticity: How Neural Activity Shapes White Matter

The brain’s capacity to learn and adapt relies not only on changes at synapses but also on activity-driven remodeling of the cells that insulate nerve fibers.

For decades, neuroscientists have emphasized synaptic plasticity — the selective strengthening or weakening of connections between neurons — as the foundation of learning and adaptation. New research from Stanford University School of Medicine adds an important complement to that view: neuronal activity can directly influence the cells that create myelin, the insulating sheath around axons, and this myelin remodeling contributes to brain plasticity.

Michelle Monje, MD, PhD, assistant professor of neurology and neurological sciences, explains that “myelin plasticity” provides a mechanism by which experience and practice can reshape information flow across brain circuits. The research team documents how increased neural firing stimulates the proliferation and maturation of oligodendrocyte precursor cells and triggers adaptive changes in the thickness of myelin sheaths within active pathways.

Myelinated axons comprise the brain’s white matter: the extensive tracts that connect separate areas responsible for processing information. Monje likens white matter to a city’s road network — highways and arterial routes that determine how quickly and efficiently signals travel across the brain. By selectively reinforcing insulation where activity is highest, the brain can optimize traffic flow across its networks.

In the study, researchers used an approach that allowed them to stimulate specific neurons without causing the tissue damage that confounds many previous experiments. They employed optogenetics, a method that makes targeted neurons responsive to light by expressing light-sensitive ion channels. Shining light at precise wavelengths on those neurons triggers firing without the need to insert electrodes directly into the tissue.

Using mice engineered to express light-sensitive channels in motor-related brain regions, the team switched neuronal activity on and off with light and observed corresponding responses from oligodendrocyte lineage cells. Direct stimulation promoted proliferation of oligodendrocyte precursor cells and their differentiation into myelin-producing oligodendrocytes. At the same time, the myelin sheaths surrounding active axons became thicker, improving conduction efficiency along those circuits.

These findings provide the strongest evidence to date that neuronal activity can causally drive myelination and myelin remodeling in an intact brain. Previous studies had shown correlations between experience and myelin dynamics or had suggested activity-myelination relationships in cultured cells, but they could not demonstrate a direct causal link in vivo without injury-induced confounds.

Understanding the molecular signals that translate neural firing into oligodendrocyte proliferation and adaptive myelination is an important next step. Uncovering those pathways could open therapeutic avenues to promote myelin repair in disorders where myelin is damaged, such as multiple sclerosis, certain leukodystrophies, and spinal cord injury. Conversely, disruptions in the regulation of myelination may contribute to diseases in which these processes go awry.

Monje highlights diffuse intrinsic pontine glioma (DIPG), a devastating pediatric brain tumor that typically appears in children aged five to nine, as one condition where myelination-related mechanisms may be implicated. In DIPG, normal developmental changes in myelination and cell growth become dysregulated, contributing to uncontrolled growth of certain brain cells.

The research team included lead authors Erin Gibson, PhD (postdoctoral scholar) and David Purger (graduate student), with Michelle Monje serving as senior author. Additional Stanford co-authors were Hannes Vogel, MD; Ben Barres, MD, PhD; J. Bradley Zuchero, PhD; Christopher Mount; Grant Lin; Lauren Wood; Gregor Bieri; Andrea Goldstein; Sarah Miller; and Ingrid Inema, among others.

Funding for the project came from a range of sources, including the National Institutes of Health, the California Institute for Regenerative Medicine, several foundations dedicated to childhood cancer and neurological disease research, institutional training programs and scholarships, and other philanthropic support. These funding streams helped support experiments, personnel and the optogenetic tools required to probe activity-dependent myelination in vivo.

Contact: Christopher Vaughan, Stanford University (Stanford University communication office)

Source: Stanford University press release reporting on research published in Science Express titled “Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain.” Authors include Erin M. Gibson, David Purger, Christopher W. Mount, Andrea K. Goldstein, Grant L. Lin, Lauren S. Wood, Ingrid Inema, Sarah E. Miller, Gregor Bieri, J. Bradley Zuchero, Ben A. Barres, Pamelyn J. Woo, Hannes Vogel, and Michelle Monje. Published online April 10, 2014; doi:10.1126/science.1252304.