Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke

  1. Annie R Bice
  2. Qingli Xiao
  3. Justin Kong
  4. Ping Yan
  5. Zachary Pollack Rosenthal
  6. Andrew W Kraft
  7. Karen P Smith
  8. Tadeusz Wieloch
  9. Jin-Moo Lee
  10. Joseph P Culver
  11. Adam Q Bauer  Is a corresponding author
  1. Washington University in St. Louis, United States
  2. Washington University School of Medicine, United States
  3. Lund University, Sweden

Abstract

Understanding circuit-level manipulations that affect the brain's capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging (OISI) to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for therapeutic intervention after focal ischemia.

Data availability

Data reported in Figures 1, 6, 7 are publicly available:Fig. 1: https://figshare.com/articles/dataset/Cylinder_Rearing_Scores/19773487Fig. 6: https://figshare.com/articles/dataset/Neuroimaging_Data_Pre_Post_Stroke_for_26-03-2021-RA-eLife-68852/19773244Fig. 7: https://figshare.com/articles/dataset/RT-PCR_Data/19773364Data reported in Figures 2, 3, 4, 5 are unavailable due to technical issues with storage hard drives.Analysis code is available at https://github.com/BauerLabCodebase

Article and author information

Author details

  1. Annie R Bice

    Department of Radiology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Qingli Xiao

    Department of Neurology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Justin Kong

    Department of Biology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ping Yan

    Department of Neurology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zachary Pollack Rosenthal

    Department of Neurology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8787-0858
  6. Andrew W Kraft

    Department of Neurology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5168-3986
  7. Karen P Smith

    Department of Neurology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Tadeusz Wieloch

    Department of Clinical Sciences, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Jin-Moo Lee

    Department of Neurology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joseph P Culver

    Department of Radiology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Adam Q Bauer

    Department of Radiology, Washington University in St. Louis, Saint Louis, United States
    For correspondence
    aqbauer@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8364-3209

Funding

National Institutes of Health (R01NS102870)

  • Adam Q Bauer

National Institutes of Health (F31NS103275)

  • Zachary Pollack Rosenthal

McDonnell Center for Systems Neuroscience

  • Adam Q Bauer

The Alborada Trust

  • Tadeusz Wieloch

The Wachtmeister Foundation

  • Tadeusz Wieloch

Swedish Research Council

  • Tadeusz Wieloch

National Institutes of Health (K25NS083754)

  • Adam Q Bauer

National Institutes of Health (R37NS110699)

  • Jin-Moo Lee

National Institutes of Health (R01NS084028)

  • Jin-Moo Lee

National Institutes of Health (R01NS094692)

  • Jin-Moo Lee

National Institutes of Health (R01NS078223)

  • Joseph P Culver

National Institutes of Health (P01NS080675)

  • Joseph P Culver

National Institutes of Health (R01NS099429)

  • Joseph P Culver

National Institutes of Health (F31NS089135)

  • Andrew W Kraft

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures described below were approved by theWashington University Animal Studies Committee in compliance with theAmerican Association for Accreditation of Laboratory Animal Care guidelines (Protocol #20-0022)

Reviewing Editor

  1. Mackenzie W Mathis, EPFL, Switzerland

Publication history

  1. Received: March 27, 2021
  2. Accepted: June 14, 2022
  3. Accepted Manuscript published: June 20, 2022 (version 1)

Copyright

© 2022, Bice 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.

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  1. Annie R Bice
  2. Qingli Xiao
  3. Justin Kong
  4. Ping Yan
  5. Zachary Pollack Rosenthal
  6. Andrew W Kraft
  7. Karen P Smith
  8. Tadeusz Wieloch
  9. Jin-Moo Lee
  10. Joseph P Culver
  11. Adam Q Bauer
(2022)
Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
eLife 11:e68852.
https://doi.org/10.7554/eLife.68852

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