DECODING SEX-SPECIFIC VULNERABILITY TO ADOLESCENT SOCIAL STRESS THROUGH HOMECAGE BEHAVIOR AND SPATIAL PROTEOMICS

Adolescence represents a critical developmental window marked by extensive brain maturation, synaptic remodeling, and neural circuit refinement. Exposure to social instability and environmental stressors during this period can produce long-lasting effects on emotional and cognitive function. However, only a subset of individuals exposed to adolescent stress develops persistent psychopathology, suggesting that pre-existing biological differences may influence vulnerability or resilience to stress.
Here, we utilize the social instability stress model in adolescent male and female mice to investigate why some individuals develop stress-related behavioral dysregulation later in life, while others remain resilient. For this, we employ a multimodal approach combining classical behavioral phenotyping, continuous homecage monitoring, and spatially resolved single-cell proteomics. This integrative framework enables the identification of behavioral and molecular signatures associated with stress susceptibility and resilience.We demonstrate that stress-susceptible animals exhibit distinct and persistent alterations in homecage behavior during both baseline and challenge conditions.
These findings highlight continuous homecage monitoring as a sensitive tool for detecting early indicators of stress vulnerability and depressive-like phenotypes. Spatial proteomic analyses further reveal cell-type-specific and region-specific molecular differences within the hippocampus that distinguish susceptible from resilient animals. Importantly, these molecular signatures may reflect both stress-induced adaptations and pre-existing biological features that influence individual stress responsiveness.
Together, these findings suggest that adolescent stress interacts with individual biological predispositions to shape behavioral and molecular outcomes. This work advances our understanding of the neurobiological mechanisms underlying stress vulnerability and highlights integrative behavioral and spatial omics approaches as powerful tools for studying psychiatric disease risk.