Experiences critically shape brain development and cognitive trajectories across the lifespan. Environmental conditions during sensitive developmental windows, particularly the juvenile and adolescent periods, can profoundly influence neural plasticity, emotional regulation, and learning ability (Fuhrmann et al., 2015; Larsen and Luna, 2018). In rodent models, two contrasting paradigms widely used to interrogate the impact of environmental influences are social isolation (SI) and environmental enrichment (EE). SI deprives animals of social interaction and sensory stimulation, mimicking adverse childhood conditions, whereas EE enhances cognitive, physical, and social engagement through increased environmental complexity (Nithianantharajah and Hannan, 2006). These paradigms provide valuable frameworks for understanding how environmental adversity or stimulation influences adult cognition.

Accumulating evidence shows that EE, by increasing social and sensorimotor complexity, promotes experience-dependent plasticity and improves learning and memory, partly through enhanced neurogenesis, dendritic remodeling, and synaptic density (Colditz et al., 2024; Kempermann, 2019; Nithianantharajah and Hannan, 2006; Ohline and Abraham, 2019; Shobe et al., 2025; Zhang et al., 2021a). In contrast, SI impairs multiple cognitive domains, especially working and recognition memory, in both humans and animal models. Epidemiological findings during the COVID-19 pandemic linked increased isolation to accelerated memory decline in older adults (Allé and Berntsen, 2021; Mosen et al., 2022). Consistently, rodent studies, including those from our group, have found that post-weaning SI induces to robust deficits in hippocampal-dependent memory (Almeida-Santos et al., 2019; Shang et al., 2024; Zhang et al., 2021b). Notably, adolescent SI also elevates anxiety-like behavior and alters novelty-driven exploration, which may confound interpretation of recognition tasks if reduced investigation of novel stimuli reflects neophobia rather than memory impairment (Lander et al., 2017; Lodha et al., 2023). These findings highlight the importance of integrating behavioral and biological measures to characterize enduring brain-state changes following adolescent experience.

The hippocampus, a key structure for declarative and spatial memory, is highly sensitive to environmental modulation (Albadawi, 2025). Both SI and EE induce long-lasting molecular and cellular changes within this region. For instance, EE upregulates neurotrophic signaling and genes associated with synaptic remodeling (Keloglan Musuroglu et al., 2022), while SI triggers stress responses via activation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to impaired neural plasticity and reduced cognitive flexibility (Xiong et al., 2023). However, despite extensive characterization of transcriptional and cellular consequences, the metabolic pathways through which these experiences shape hippocampal function remain incompletely understood. Advances in metabolomics now allow comprehensive profiling of small-molecule metabolites that reflect cellular and systemic physiology (Ivanisevic and Siuzdak, 2015). The hippocampal metabolome dynamically responds to environmental and behavioral stimuli, serving as a biochemical signature of neural activity and plasticity. Previous studies indicate that SI disrupts amino acid and taurine metabolism associated with stress responses (Elhussiny et al., 2022). In contrast, EE modulates brain lipid metabolism, particularly glycerophospholipid and sterol pathways. It alters phosphatidylcholine and phosphatidylethanolamine species, consistent with membrane and synaptic remodeling (Borgmeyer et al., 2021), and it influences cholesterol and related sterol pathways that support membrane organization and synaptic function (Xu et al., 2023). These findings highlight metabolism as a potential mechanistic link between environmental experience and cognition; however, metabolic comparisons between SI and EE conditions remain limited.

In this study, we examined how SI and EE influence hippocampal metabolism and cognitive performance in mice. By integrating behavioral assessment with untargeted liquid chromatography–mass spectrometry (LC-MS) metabolomics, we mapped metabolic alterations associated with adolescent experiences. These results elucidate how environmental conditions modulate hippocampal metabolism, offering mechanistic insight into the effects of experience on cognitive function and resilience.