PSYCHEDELIC MODULATION OF FUNCTIONAL NETWORK REORGANIZATION AND MOTOR RECOVERY AFTER FOCAL CORTICAL STROKE

Stroke-induced network disruption critically limits functional recovery, yet therapeutic strategies promoting long-term circuit reorganization remain rare. Psychedelic compounds such as psilocybin and N,N-dimethyltryptamine (DMT) have recently emerged as potent neuromodulators, but their impact on post-stroke brain reorganization is largely unknown. Here, we investigate whether psychedelic treatment enhances functional network remodeling and motor recovery following focal ischemic injury. Focal cortical stroke was induced in adult mice using photothrombosis. Lesion extent was assessed by T2-weighted MRI one day post-stroke and animals were assigned to a vehicle control group, a single-dose psilocybin group (administered 24 h post-stroke), a single-dose DMT group, or a repeated low-dose DMT group receiving treatment every second day during recovery. Animals underwent daily motor training in a skilled staircase reaching task throughout the recovery period. Motor performance was longitudinally assessed using weekly kinematic recordings during the ladder rung walking task, video-based staircase reaching, and treadmill locomotion. On day 27 post-stroke, functional MRI was performed to evaluate large-scale network connectivity. At day 28, immediately prior to perfusion, animals completed a final motor task to engage stroke-relevant circuits and brains were collected for histological analysis. Activity-dependent neuronal recruitment was quantified using brain-wide c-Fos mapping, enabling correlation of task-induced activation patterns with fMRI-derived functional connectivity and behavioral outcomes.
This multimodal approach integrates structural lesion assessment, functional network dynamics, detailed motor behavior, and cellular-level activity mapping within the same animals. Our findings aim to provide mechanistic insight into how psychedelic compounds influence post-stroke network plasticity and functional recovery.