Systemic metabolic correlates of environmental sensitivity in group-housed mice

Environmental changes significantly impact the social behaviors of animals, yet individuals exhibit substantial variability in their responsiveness, known as environmental sensitivity. Understanding the biological basis of this individual variability is critical for elucidating vulnerability to stress-related and psychiatric disorders. To investigate the organism-wide physiological states linked to environmental sensitivity, we combined continuous, non-invasive RFID-based behavioral tracking with untargeted plasma metabolomics in group-housed mice undergoing spatial and social environmental restructuring. Following the environmental alteration, we observed heterogeneous behavioral shifts across individuals, enabling their operational classification into high-responsiveness mice (HRM) and low-responsiveness mice (LRM). Untargeted metabolomic profiling revealed distinct systemic metabolic signatures associated with these behavioral phenotypes. Specifically, HRM exhibited elevated levels of circulating essential and non-essential amino acids, as well as metabolites linked to one-carbon and energy metabolism. Exploratory co-variation analysis further identified plasma metabolic modules associated with individual behavioral metrics. These findings suggest that individual differences in behavioral adaptation are not solely neural phenomena but are coupled with coordinated, organism-wide metabolic adjustments. This study provides a framework for identifying candidate peripheral metabolic correlates of behavioral responsiveness to environmental and social change.