Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
- Washington University in St. Louis, United States
- Washington University School of Medicine, United States
- 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
Zachary Pollack Rosenthal
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
- Mackenzie W Mathis, EPFL, Switzerland
Publication history
- Received: March 27, 2021
- Preprint posted: May 2, 2021 (view preprint)
- Accepted: June 14, 2022
- Accepted Manuscript published: June 20, 2022 (version 1)
- Version of Record published: July 28, 2022 (version 2)
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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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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