Extracellular Space Barrier Dysfunction Disrupts Interstitial Fluid Drainage and Is Associated with Memory Heterogeneity in Cognitive Aging

Abnormal cognitive aging is characterized by memory decline beyond normal age-related physiological changes. Nevertheless, the intrinsic mechanisms driving individual memory heterogeneity during aging remain poorly elucidated. Given the critical roles of brain interstitial fluid (ISF) dynamics and extracellular space (ECS) transport in maintaining neural homeostasis, the present study aimed to explore whether ECS compartmentalization and ISF drainage disturbance contribute to interindividual variations in memory performance during aging. Aged rats were stratified according to their memory performance. A multi-modal strategy combining behavioral assessment, microdialysis, metabolomics, and electrophysiological recording was applied to detect structural and functional deficits in ECS barrier integrity and ISF drainage, with the assistance of MRI-based tracer imaging, fluorescence imaging, and ultrastructural observation. The results demonstrated that memory-impaired aged rats exhibited region-specific neurotransmitter imbalance in the caudate nucleus and thalamus, which was closely associated with age-related ECS barrier dysfunction. Such barrier dysfunction induced ISF drainage disturbance, thereby reducing local neurotransmitter concentrations in the caudate nucleus and impairing thalamocortical oscillations during non-rapid eye movement sleep, and ultimately disturbing memory consolidation. Further tracer imaging and electron microscopy examinations confirmed that compromised myelin integrity in the internal capsule served as the structural basis for age-related ISF drainage disturbance. Collectively, these findings reveal that ISF drainage disturbance induced by age-related ECS barrier alterations acts as a non-degenerative mechanism underlying memory heterogeneity in cognitive aging. This work highlights ECS compartment integrity as a promising biomarker and therapeutic target for intervening age-related cognitive decline.