Early-Life Psychological Stress Impairs Spatial Learning and Memory in Rats by Altering the Hippocampal Proteome

Early-life stress has been linked to anxiety, pessimism, and cognitive decline, all of which can have detrimental effects on individuals. One critical structure impacted by early-life stress is the hippocampus, which plays a vital role in regulating learning and memory functions. This study aims to elucidate the molecular mechanisms through which early-life psychological stress (ELPS) affects the learning and memory capabilities of the hippocampus in rats. In this study, ELPS model was applied on juvenile rats for 14 days. To evaluate the spatial learning and memory abilities of rats, the Morris Water Maze (MWM) test was adopted in this study. This study employed two-dimensional gel electrophoresis (2DE) and ultrahigh-performance liquid chromatographic-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) techniques to reveal the proteomic map of the rat hippocampus. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and direct protein-protein interaction (PPI) network construction were performed to identify the biological pathways associated with the differentially expressed proteins (DEPs). ELPS treatment induced age-dependent spatial cognitive deficits. In juvenile rats, ELPS caused mild impairments in spatial learning, as reflected by increased escape latency during specific training days, but did not affect spatial memory. In contrast, adult rats exhibited significant and robust impairments in both spatial learning and spatial memory, with longer escape latency across training days, fewer platform crossings, and reduced time and distance in the target quadrant. These findings demonstrate that ELPS-induced cognitive dysfunction is far more pronounced in adult animals, representing persistent and progressive spatial learning and memory deficits. After therapy, 71 proteins were found in the hippocampal region, including 10 DEPs across the juvenile and adult groups post-treatment. Subsequent pathway analysis indicated the involvement of 4 DEPs in various pathways, including Biosynthesis of amino acids, Prion disease, HIF-1 signaling pathway, Distal axon, Alzheimer disease, and Necroptosis pathways. Our study revealed significant proteomic changes in the hippocampus of rats as they transitioned from juveniles to adults, including 10 consistently differentially expressed proteins. These proteomic alterations correspond to the age-dependent spatial cognitive deficits induced by ELPS-mild spatial learning impairment in juveniles and more pronounced deficits in both spatial learning and memory in adults-collectively supporting the lasting effects of ELPS on spatial cognitive function.