1. Neuroscience
Download icon

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

Research Article
  • Cited 0
  • Views 830
  • Annotations
Cite this article as: eLife 2021;10:e63076 doi: 10.7554/eLife.63076

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

  1. Zachariah Bertels

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Harinder Singh

    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0160-1575
  3. Isaac Dripps

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kendra Siegersma

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alycia F Tipton

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Wiktor D Witkowski

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zoie Sheets

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Pal Shah

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Catherine Conway

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Elizaveta Mangutov

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mei Ao

    Physiology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Valentina Petukhova

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Bhargava Karumudi

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Pavel A Petukhov

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Serapio M Baca

    Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Mark M Rasenick

    Physiology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Amynah A Pradhan

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    For correspondence
    Pradhan4@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9691-2976

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.

Reviewing Editor

  1. Allan Basbaum, University of California San Francisco, United States

Publication history

  1. Received: September 14, 2020
  2. Accepted: April 12, 2021
  3. Accepted Manuscript published: April 15, 2021 (version 1)

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

  • 830
    Page views
  • 157
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    Romy Frömer et al.
    Research Article Updated

    Influential theories emphasize the importance of predictions in learning: we learn from feedback to the extent that it is surprising, and thus conveys new information. Here, we explore the hypothesis that surprise depends not only on comparing current events to past experience, but also on online evaluation of performance via internal monitoring. Specifically, we propose that people leverage insights from response-based performance monitoring – outcome predictions and confidence – to control learning from feedback. In line with predictions from a Bayesian inference model, we find that people who are better at calibrating their confidence to the precision of their outcome predictions learn more quickly. Further in line with our proposal, EEG signatures of feedback processing are sensitive to the accuracy of, and confidence in, post-response outcome predictions. Taken together, our results suggest that online predictions and confidence serve to calibrate neural error signals to improve the efficiency of learning.

    1. Neuroscience
    Jonas Hansen Kymre et al.
    Research Article

    The pheromone system of heliothine moths is an optimal model for studying principles underlying higher-order olfactory processing. In Helicoverpa armigera, three male-specific glomeruli receive input about three female-produced signals, the primary pheromone component, serving as an attractant, and two minor constituents, serving a dual function, i.e. attraction versus inhibition of attraction. From the antennal-lobe glomeruli, the information is conveyed to higher olfactory centers, including the lateral protocerebrum, via three main paths – of which the medial tract is the most prominent. In this study, we traced physiologically identified medial-tract projection neurons from each of the three male‑specific glomeruli with the aim of mapping their terminal branches in the lateral protocerebrum. Our data suggest that the neurons’ wide-spread projections are organized according to behavioral significance, including a spatial separation of signals representing attraction versus inhibition – however, with a unique capacity of switching behavioral consequence based on the amount of the minor components.