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

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.

Psychedelic 5-HT2Areceptor agonism: neuronal signatures and altered neurovascular coupling

“…Slow trends in channel-specific light levels were temporally detrended with a 5 th order polynomial fit [68, 70–73, 89–91, 95, 96]. The images were spatially smoothed using a Gaussian filter (5×5 pixel kernel, standard deviation of 1.2 pixels).…”

“…Measures of resting-state functional connectivity (RSFC) were calculated using zero lag correlation for all pixel pairs within our field of view, as in previous reports [68, 70, 89, 91, 96]. Briefly, spontaneous activity was filtered over infraslow and delta bands.…”

“…Head-fixed acclimation was performed for 45 minutes a day for a week before experiments began, as previously published [72, 89–91]. All drugs were prepared on the day of experimentation.…”

Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling.

“…One hour before surgery, mice were given buprenorphine-SR (1.0 mg/kg subcutaneous) and three days to recover before beginning handling and acclimation. Head-fixed acclimation was performed for 45 minutes a day for a week before experiments began, as previously published [52,67]. All drugs were prepared on the day of experimentation.…”

Connecting the lines after a stroke

“…To develop enhanced approaches, scientists need to first have a better understanding of how stimulation impacts the circuitry which connects the brain hemispheres. Now, in eLife, Adam Bauer and colleagues at Washington University in St. Louis and Lund University – including Annie Bice as first author – report new findings that suggest stimulating cortical areas contralateral to the regions affected by a stroke inhibits recovery ( Bice et al, 2022 ).…”