Animal models for investigating post-stroke cognitive impairment: A neurovascular trafficking perspective

Post-stroke cognitive impairment (PSCI) is a major cause of long-term disability after ischemic stroke, yet its mechanisms remain incompletely explained by infarct volume, lesion location, or conventional vascular risk factors alone. Animal models are indispensable for clarifying how ischemic injury evolves into delayed cognitive dysfunction and for determining which mechanisms are experimentally tractable, reproducible, and translationally relevant. This review examines PSCI from a neurovascular trafficking perspective, focusing on how laboratory animal models can be used to investigate secretory pathway stress, endolysosomal dysfunction, autophagy-lysosomal flux, extracellular vesicle signaling, blood-brain barrier disruption, glial reactivity, myelin debris clearance, white matter injury, and cognition-relevant behavioral phenotypes. Rodent models of transient or permanent middle cerebral artery occlusion, photothrombotic stroke, embolic stroke, chronic cerebral hypoperfusion, bilateral carotid artery stenosis, and subcortical white-matter injury each reproduce selected components of the human PSCI spectrum. No single model fully captures the temporal, vascular, cellular, and cognitive complexity of human PSCI; therefore, model selection should be driven by the mechanistic question, disease phase, vascular pathology, cellular compartment, cognitive domain, and welfare burden under investigation. The central argument is not that neurovascular trafficking failure is already a proven causal pathway, but that well-designed animal studies can test, refine, or falsify this hypothesis. Future studies should integrate model validity, translational rigor, and welfare refinement through longitudinal cognitive testing, multimodal imaging, cell-specific molecular profiling, extracellular vesicle phenotyping, intervention-based validation, randomization, blinding, sample-size justification, humane endpoints, perioperative care, and transparent reporting.