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)
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.
Metrics
-
- 1,399
- views
-
- 324
- downloads
-
- 22
- 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)
Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
eLife 11:e68852.
https://doi.org/10.7554/eLife.68852
Further reading
-
- Neuroscience
- Physics of Living Systems
Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.
-
- Neuroscience
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
