Combined Optogenetic Stimulation and Training Boost Recovery and Cortical Plasticity After Stroke

Background: An ischemic event is followed by extensive changes in cortical excitability involving both hemispheres. Plasticity in the injured hemisphere plays a crucial role in post-stroke motor recovery and it is a primary target for rehabilitation therapy. Though stimulation of the ipsilesional motor cortex, especially when paired with motor training, facilitates plasticity and functional restoration, the mechanisms underneath the reshaping of cortical functionality are widely unknown. Methods: Here we designed a rehabilitation protocol that combines a neuro-plasticizing intervention to motor training. In detail, we applied an optogenetic approach to stimulate peri-infarct spared neurons expressing Channelrhodopsin 2 in combination with daily motor training on a robotic device. Findings: Combined rehabilitative treatment promoted a generalized recovery in forelimb function occurring significantly earlier than single treatments. Furthermore, the longitudinal spatio-temporal analysis of calcium dynamic shows that functional recovery is associated with the rescue of the essential features of cortical activation profiles during motor training execution. The increased expression of GAP43 in the cells of the peri-infarct cortex projecting to the contralesional hemisphere indicates the support of plasticizing factors in the recovery process. Interpretation: The present work, by exploiting cutting-edge optical tools, suggests that only a combined rehabilitation protocol can counteract the imbalance between hemispheres caused by stroke, developing a novel equilibrium that promotes a fast and generalized recovery after stroke. Funding Statement: This project has received funding from the H2020 EXCELLENT SCIENCE - European Research Council (ERC) under grant agreement 692943 BrainBIT. In addition, it was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreements 785907 (HBP SGA2), and 654148 (Laserlab-Europe). Part of this work was performed within the framework of the Proof of Concept Studies for the ESFRI research infrastructure project EuroBioImaging at the PCS facility LENS. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures involving mice were performed in accordance with the regulations of the Italian Ministry of Health authorization n. 871/2018.