Changes in white matter in mice resulting from low-frequency brain stimulation.
Journal: 2018/September - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Abstract:
Recent reports have begun to elucidate mechanisms by which learning and experience produce white matter changes in the brain. We previously reported changes in white matter surrounding the anterior cingulate cortex in humans after 2-4 weeks of meditation training. We further found that low-frequency optogenetic stimulation of the anterior cingulate in mice increased time spent in the light in a light/dark box paradigm, suggesting decreased anxiety similar to what is observed following meditation training. Here, we investigated the impact of this stimulation at the cellular level. We found that laser stimulation in the range of 1-8 Hz results in changes to subcortical white matter projection fibers in the corpus callosum. Specifically, stimulation resulted in increased oligodendrocyte proliferation, accompanied by a decrease in the g-ratio within the corpus callosum underlying the anterior cingulate cortex. These results suggest that low-frequency stimulation can result in activity-dependent remodeling of myelin, giving rise to enhanced connectivity and altered behavior.
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Proc Natl Acad Sci U S A 115(27): E6339-E6346

Changes in white matter in mice resulting from low-frequency brain stimulation

Department of Biology, University of Oregon, Eugene, OR, 97403;
Institute of Neuroscience, University of Oregon, Eugene, OR, 97403;
Department of Psychology, University of Oregon, Eugene, OR, 97403
To whom correspondence should be addressed. Email: ude.nogerou@rensopm.
Contributed by Michael I. Posner, May 15, 2018 (sent for review February 6, 2018; reviewed by Richard J. Davidson and Ben Emery)

Author contributions: D.M.P., A.P.W., M.K.R., M.I.P., and C.M.N. designed research; D.M.P. and A.P.W. performed research; D.M.P. analyzed data; and D.M.P., M.K.R., M.I.P., and C.M.N. wrote the paper.

Reviewers: R.J.D., University of Wisconsin–Madison; and B.E., Oregon Health & Science University.

Contributed by Michael I. Posner, May 15, 2018 (sent for review February 6, 2018; reviewed by Richard J. Davidson and Ben Emery)
Published under the PNAS license.

Significance

Meditation has been shown to modify brain connections. However, the cellular mechanisms by which this occurs are not known. We hypothesized that changes in white matter found following meditation may be due to increased rhythmicity observed in frontal areas in the cortex. The current study in mice tested this directly by rhythmically stimulating cells in the frontal midline. We found that such stimulation caused an increase in connectivity due to changes in the axons in the corpus callosum, which transmit impulses to and from the frontal midline. This work provides a plausible but not proven mechanism through which a mental activity such as meditation can improve brain connectivity.

Keywords: anterior cingulate cortex, electron microscopy, meditation, mouse, myelination
Significance

Abstract

Recent reports have begun to elucidate mechanisms by which learning and experience produce white matter changes in the brain. We previously reported changes in white matter surrounding the anterior cingulate cortex in humans after 2–4 weeks of meditation training. We further found that low-frequency optogenetic stimulation of the anterior cingulate in mice increased time spent in the light in a light/dark box paradigm, suggesting decreased anxiety similar to what is observed following meditation training. Here, we investigated the impact of this stimulation at the cellular level. We found that laser stimulation in the range of 1–8 Hz results in changes to subcortical white matter projection fibers in the corpus callosum. Specifically, stimulation resulted in increased oligodendrocyte proliferation, accompanied by a decrease in the g-ratio within the corpus callosum underlying the anterior cingulate cortex. These results suggest that low-frequency stimulation can result in activity-dependent remodeling of myelin, giving rise to enhanced connectivity and altered behavior.

Abstract

A variety of training methods have shown white matter change in humans using diffusion tensor imaging (DTI) (1, 2). These include training in working memory, juggling, and meditation (2, 3). Our human studies reported that 2–4 wk (30 min per day) of integrated body mind training (IBMT) resulted in white matter changes as measured by DTI around the anterior cingulate cortex (ACC) compared with a control group practicing relaxation (4, 5). IBMT, a form of mindfulness meditation, is associated with improvements in memory and attention and reductions in self-reported levels of negative affect (6).

We hypothesized (7) that the white matter changes might be due to increases in midfrontal theta oscillations (4–8 Hz) found in our study (8) and other research (9). Moreover, human studies have provided evidence that increases in theta current density are correlated with increased metabolism in the ACC (10). When the ACC receives theta stimulation that is in phase with stimulation of a lateral frontal area, there is an improvement in measures of executive function (11). Based on these findings, we wanted to explore the potential causal relationships between increased midfrontal theta and white matter change.

Depending on factors such as age and brain region, a given fraction of axons within white matter tracts are insulated by myelin. Myelination is thought to be critical for cognition because it is an effective mechanism for optimizing conduction velocity and coordinating spike-timing between distant brain regions (reviewed in refs. 1214). It has been shown that adult-born oligodendrocytes contribute to remodeling of myelin and their activity can be modulated by both intrinsic and extrinsic factors (2). Specifically, studies in animal models show that proliferation, differentiation, and synthesis of myelin by oligodendrocyte progenitor cells (OPCs) are regulated by neural activity in both the developing and adult brain (13, 1519). These results demonstrate that neuronal activity is sensed by oligodendrocytes and instructs the selective myelination of an active circuit.

There is mounting evidence from studies in rodents that natural experience can modulate myelination by oligodendrocytes in the adult, allowing the potential for improvement of neural circuit function. Learning a new skill can increase white matter and oligodendrocyte proliferation in regions of the brain engaged by the learned task (2022). Conversely, social isolation can result in decreased myelination and impaired cognitive function (19, 23, 24). Furthermore, it has been shown that visual deprivation not only shortens the length of myelin internodes, but also results in reduced nerve conduction velocity in the optic nerve (25).

In an effort to elucidate the mechanisms involved in the regulation of myelination, a recent study using optogenetic stimulation of layer 5 pyramidal cells in the mouse motor cortex reported an increase in oligodendrocyte proliferation and differentiation within both the motor cortex and the subcortical projections of the corpus callosum (16). These changes were associated with myelin remodeling and improved behavioral performance. Another study (26) used an implanted electrode array to examine the effect of stimulation frequency (5, 25, or 300 Hz) on OPC proliferation and differentiation in the corpus callosum and effects were dependent upon the stimulation paradigm: 5-Hz stimulation showed the greatest effect on the differentiation of OPCs, whereas 25- and 300-Hz stimulation had the greatest effects on proliferation.

We previously reported the behavioral effects of rhythmic stimulation or suppression of ACC activity in mice (27). Using light-activated channels [both Channelrhodopsin-2 (ChR2) and Archaerhodopsin (Arch)], we drove periodic activation or inhibition of fast-spiking inhibitory interneurons at three different frequencies (1, 8, and 40 Hz) to increase or decrease the activity of ACC output neurons. We reported that mice receiving 1- and 8-Hz stimulation, which rhythmically increased ACC spike output, exhibited greater exploratory activity in the light area of a light/dark box compared with controls or mice receiving rhythmic suppression of cortical activity. Increased exploration in the light area of the light/dark box correlates inversely with anxiety (28). Therefore, our behavioral data were consistent with the reductions in anxiety reported by practitioners of IBMT (6) and interpreted as favoring the hypothesis that low-frequency stimulation could induce at least some of the behavioral benefits of meditation.

In the present study, using tissue obtained from the mice in our previous report (27), we sought to describe the effects of this stimulation paradigm at both the cellular and ultrastructural level. We hypothesized that low-frequency stimulation of the ACC in the theta range (4–8 Hz) could stimulate the proliferation and/or differentiation of oligodendrocytes and increase myelination as measured by electron microscopy (EM). Specifically, we focused on the genu of the corpus callosum because of its proximity to the site of laser stimulation and because it is one of the major tracts through which axons from the ACC project to the rest of the mammalian brain. Neurons sending projections through the corpus callosum relay sensory, motor, and other cognitive information between the two hemispheres. Furthermore, in our previous study (5) we found significant increases in fractional anisotropy (FA) in the body and genu of the corpus callosum following IBMT training.

First, we analyzed the effects of rhythmic stimulation and suppression on oligodendrocyte proliferation and differentiation. Subsequently, we used EM to assess changes in myelination and axon diameter following 1- and 8-Hz stimulation, the frequencies previously found to most effectively reduce anxiety-related behavior.

Acknowledgments

We thank Prof. Yiyuan Tang (Texas Tech University) and Prof. Gary Lynch (University of California, Irvine) for their consultations on this work. We gratefully acknowledge the use of the electron microscopy facility at the Center for Advanced Materials Characterization in Oregon. This research was funded by Office of Naval Research Grants N00014-15-1-2148 and N00014-17-1-2824 (to the University of Oregon).

Acknowledgments

Footnotes

The authors declare no conflict of interest.

Footnotes

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