Rapamycin improves memory and blood pressure stability in asymmetrical cortico–brainstem connectivity following stroke

Emerging reports suggest that patients with ischemic stroke involving the insular cortex (IC), particularly in the right hemisphere, may lead to paradoxical reduction in blood pressure-a condition associated with worse outcomes, including increased mortality and cognitive decline-whereas elevated blood pressure is more commonly observed during the acute phase of stroke. To investigate this lateralized effect and its underlying mechanisms, we established focal ischemic stroke models targeting either the left or right IC in male rats. In this study, we demonstrated that infarction of the right insular cortex results in sustained reductions in systemic blood pressure, changes in blood pressure variability consistent with reduced rostral ventrolateral medulla (RVLM) neurogenic activity, and bilateral impairment of autophagy-related signaling pathways. By contrast, left-sided IC infarction induced no significant changes, indicating a lateralized effect of IC stroke on autonomic regulation. These alterations in the right-sided IC stroke were accompanied by significant memory deficits. Retrograde tracing confirmed direct neuronal projections from the IC to the RVLM, suggesting a cortico-brainstem pathway through which cortical stroke may impair systemic autonomic regulation. Notably, pharmacological activation of autophagy with rapamycin restored RVLM activity, normalized blood pressure, and improved cognitive performance. These findings identify a novel lateralized insula-RVLM autonomic pathway involving autophagy that contributes to post-stroke hypotension and memory impairment, and suggest that modulation of this pathway may offer a therapeutic strategy for stroke patients with autonomic dysfunction beyond the hypotensive presentation.