Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition
- University of Illinois at Chicago, United States
- University of Colorado Anschutz Medical Campus, United States
Abstract
Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS109862)
- Amynah A Pradhan
National Institute on Drug Abuse (DA040688)
- Amynah A Pradhan
National Center for Complementary and Integrative Health (AT009169)
- Mark M Rasenick
Center for Integrated Healthcare, U.S. Department of Veterans Affairs (BX00149)
- Mark M Rasenick
Amgen Foundation
- Amynah A Pradhan
Center for Clinical and Translational Science, University of Illinois at Chicago
- Amynah A Pradhan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#18-250) of the University of Illinois at Chicago.
Copyright
© 2021, Bertels et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,427
- views
-
- 362
- downloads
-
- 23
- 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)
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition
eLife 10:e63076.
https://doi.org/10.7554/eLife.63076
Further reading
-
- Neuroscience
Categorical sensory representations are critical for many behaviors, including speech perception. In the auditory system, categorical information is thought to arise hierarchically, becoming increasingly prominent in higher-order cortical regions. The neural mechanisms that support this robust and flexible computation remain poorly understood. Here, we studied sound representations in the ferret primary and non-primary auditory cortex while animals engaged in a challenging sound discrimination task. Population-level decoding of simultaneously recorded single neurons revealed that task engagement caused categorical sound representations to emerge in non-primary auditory cortex. In primary auditory cortex, task engagement caused a general enhancement of sound decoding that was not specific to task-relevant categories. These findings are consistent with mixed selectivity models of neural disentanglement, in which early sensory regions build an overcomplete representation of the world and allow neurons in downstream brain regions to flexibly and selectively read out behaviorally relevant, categorical information.
-
- Neuroscience
- Stem Cells and Regenerative Medicine
Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.
