In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
- National Institute of Neurological Disorders and Stroke, United States
- University of Pittsburgh, United States
- National Institute of Mental Health, United States
- Vertex Phamaceuticals Inc, United States
- Cedars-Sinai Medical Center, United States
Abstract
Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In 6 animals followed with multisequence 7-tesla MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in 4 of 6 marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.
Data availability
All of the 6 marmosets' serial in vivo MRI images, including all the sequences used for analysis and figure generation, were uploaded in an easily accessible format (NIFTI). The file names are titled with the corresponding animal # used in the manuscript, as well as the date of MRI acquisition. All the Iba1 and PLP immunohistochemistry stains have been uploaded as well.
Article and author information
Author details
Funding
National Institutes of Health (Intramural Research Program)
- Nathanael J Lee
Adelson Family Foundation
- Maxime Donadieu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jeannie Chin, Baylor College of Medicine, United States
Ethics
Animal experimentation: The study was performed under the guideline and in accordance with the National Institutes of Health IACUC. Specifically, the neuroethics committee of the National Institutes of Neurological Diseases and Stroke formally went through our manuscript prior to submission on salient topics including minimization of pain, justification of number of animals and the sex ratio, dosing of methylprednisone based on available human data. All procedures were performed under anesthesia to minimize discomfort and pain. Animals were housed in pairs or triplets to maximize social interactions and well-being. The institutional IACUC protocol number is #1308.
Version history
- Received: September 10, 2021
- Preprint posted: October 28, 2021 (view preprint)
- Accepted: April 12, 2023
- Accepted Manuscript published: April 21, 2023 (version 1)
- Version of Record published: May 10, 2023 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 1,097
- views
-
- 165
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
eLife 12:e73786.
https://doi.org/10.7554/eLife.73786
Further reading
-
- Neuroscience
Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.
-
- Neuroscience
Acetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.
