Abstract

Ischemic stroke is a leading cause of death and disability worldwide. Among survivors, one-third live with permanent impairments, and two-thirds experience upper limb dysfunction. Despite advances in acute care, no universally effective rehabilitation strategies are available. Physical exercise improves cardiovascular health and promotes neuroplasticity, acting as a potential preconditioning factor against ischemic injury. While most preclinical studies use extensive lesion models, the effects of physical exercise preconditioning (PEP) on focal stroke and post-stroke motor learning remain underexplored. This study aims to assess the effects of PEP on neurological deficits, motor learning capacities, and plasticity markers, following focal ischemia induced by endothelin-1 in the caudal forelimb area of the primary motor cortex (M1) in rats. Twenty-four Sprague-Dawley male rats were randomized into 4 groups; two of them underwent 4 weeks of voluntary wheel running, and two were sedentary, before sham or stroke surgery, followed by neurological function evaluation, training in a skilled reaching task (SRT), and immunohistochemistry to assess plasticity markers (p-CREB and Arc) in M1. PEP significantly reduced neurological impairment but did not improve motor learning. However, PEP promotes compensatory strategies to solve the task, such as utilizing ipsilesional forelimbs and mitigating motivational deficits. PEP significantly increased p-CREB and Arc expression, suggesting the activation of plasticity-related pathways, despite these markers not correlating with motor learning outcomes. In conclusion, PEP modulated both behavioral and plasticity responses to focal stroke. These findings support exercise as a low-cost, accessible strategy to enhance neuroplasticity, highlighting its role as a foundation for stroke rehabilitation