Enhancing motor recovery after stroke through psychedelic-induced neuromodulation.

Post-stroke rehabilitation primarily relies on physiotherapy, yet functional gains plateau in many survivors. Classical “psychoplastogens” such as Psilocybin and N,N-dimethyltryptamine (DMT) are high-affinity 5-HT2A agonists, promoting dendritic spine density and synaptogenesis and therefore support reorganisation after ischemic insults. In a mouse model, we will systematically test whether psychedelics can support functional recovery after stroke in combination with rehabilitation training. Prior to ischemia, mice will be habituated and trained in all behavior tests for 14 days. Using a photothrombotic stroke model (PT), a 7-Tesla MRI will be used to measure lesion volume and localization 24 hours after ischemia. Beginning on post-stroke day 1, mice will receive either psilocybin (1-2mg/kg BW) or DMT (5mg/kg BW) twice (day 1 and 5) or receive DMT (1mg/kg BW) in a low-dose scheme daily for 28 days. A fourth group will be injected with a vehicle solution (0,9% saline). Motor function will be quantified and tested in a weekly interval with a multi-level kinematic battery: Staircase, irregular ladder rung, treadmill. Resting state fMRI will be acquired 28 days after the ischemic event. At the end of the experiment, brains will be prepared, immunostained for c-FOS and imaged with a lightsheet and confocal microscopes. Using different published pipelines, we will perform Allen-atlas registration and automated cell segmentation for unbiased brain-wide activity mapping. Post-ischemic T2-lesion volume, stable vital parameters and achievement of acceptable baseline kinematics will determine inclusion. A vital component of filling the gap between acute lysis or thrombectomy and long-term focused physiotherapy is to investigate whether psychedelics can restore motor function in the post-acute phase of ischemic insults.