Adolescent experiences remodel hippocampal glycerophospholipid metabolism associated with adult memory

Adolescent experiences profoundly shape brain development and cognition. Environmental enrichment (EE) and social isolation (SI) represent opposing forms of stimulation and deprivation, yet the metabolic mechanisms connecting these conditions to cognitive outcomes remain poorly defined. In this study, we investigated how EE and SI during adolescence (PND 21-49) influence hippocampal metabolism and cognition in adult C57BL/6 mice. Behaviorally, SI impaired working and recognition memory, as reflected by reduced spontaneous alternation in the Y-maze and diminished novelty discrimination in the novel location and novel object recognition tasks. In contrast, EE mice showed preserved performance across these cognitive domains. Untargeted hippocampal metabolomics revealed clear group separation and showed that differential metabolites were overrepresented in glycerophospholipid-related classes. Consistently, KEGG pathway enrichment repeatedly highlighted glycerophospholipid metabolism along with membrane-associated signaling pathways. Correlation and network analyses further identified a tightly interconnected phospholipid module as a principal axis of between-group divergence, involving coordinated shifts across phosphatidylcholines, phosphatidylethanolamines, and lysophospholipids. To provide signaling-level support, we examined key components of the ERK-cPLA2 axis along with a synaptic protein marker in the hippocampus. SI mice exhibited reduced p-ERK/ERK ratios, elevated p-cPLA2 /cPLA2, and decreased PSD-95 expression, whereas EE mice showed higher p-ERK/ERK and a modest increase in p-cPLA2 /cPLA2 relative to SE controls. Together, these findings suggest that adolescent social experiences shape enduring hippocampal phospholipid turnover states that are coupled to plasticity-related signaling, providing a molecular and metabolic framework for experience-associated differences in memory.