Optogenetic Stimulation Effects On Cortico-thalamic Circuit Plasticity After Stroke

Introduction: Post-stroke optogenetic stimulation in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Recent brain imaging data indicate that iM1-stimulated stroke mice restore activation of the ipsilesional cortico-thalamic tract. To determine whether iM1 stimulation enhanced post-stroke plasticity in the cortico-thalamic tract, we investigate the expression of plasticity markers in the ipsilesional thalamus (iTH). We selectively stimulate the cortico-thalamic circuit to investigate its influences on plasticity changes and functional outcome. Methods: C57BL6 male mice (6-7 weeks old) were injected and implanted in iM1 with AAV1-CaMKIIa-hChR2 virus and optical fiber for iM1 stimulation. Another set of mice were injected with AAV1-CaMKIIa-hChR2 virus in iM1 with an optical fiber implanted in ipsilesional thalamus (iTH) to selectively stimulate the cortico-thalamic circuit. Six weeks after virus injection, mice underwent transient middle cerebral artery occlusion (tMCAo, 30min), followed by optogenetic stimulations from PD5-14. Functional recovery was evaluated by rotating beam tests at pre-stroke and post-stroke days (PD) 4, 7 and 14. Brain sections were immunostained with plasticity marker synaptophysin and imaged for co-localization with ChR2. Thalamic tissues were processed with western blot for plasticity markers. Results: iM1-stimulated mice (Stim group) exhibited significant functional recovery at post-stroke day14 on the rotating beam test, when compared to non-stimulated mice (NoStim group) (p<0.05). GAP43, an axonal growth marker, was significantly higher in iTH of iM1-stimulated mice (p<0.05). Moreover, we detected higher co-localization of ChR2 + /Synaptophysin + terminals in iTH of iM1-stimulated mice (p<0.05). Robust ChR2 is detected in the iM1-iTH motor cortico-thalamic circuit and selective stimulation of this cortico-thalamic circuit is sufficient to improve recovery (p<0.05). Conclusion: Our results show that cortico-thalamic circuit plays a key role in functional recovery after stroke. Ongoing studies investigates the transcriptome and plasticity changes in the cortico-thalamic circuit circuit.