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

Author:

Bice Annie R1,Xiao Qingli2,Kong Justin3,Yan Ping2,Rosenthal Zachary Pollack4ORCID,Kraft Andrew W2ORCID,Smith Karen P2,Wieloch Tadeusz5,Lee Jin-Moo2,Culver Joseph P1,Bauer Adam Q1ORCID

Affiliation:

1. Department of Radiology, Washington University in St. Louis

2. Department of Neurology, Washington University in St. Louis

3. Department of Biology, Washington University in St. Louis

4. Department of Neurology, Washington University School of Medicine

5. Department of Clinical Sciences, Lund University

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 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 targeted therapeutic interventions after focal ischemia.

Funder

National Institutes of Health

McDonnell Center for Systems Neuroscience

Alborada Trust

The Wachtmeister Foundation

Vetenskapsrådet

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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