SEX-DEPENDENT ALTERATIONS IN HIPPOCAMPAL PROTEIN EXPRESSION INDUCED BY JUVENILE AND ADULT STRESS IN MICE

Stress during sensitive developmental periods can induce neuroplastic changes in brain regions such as the hippocampus, including alterations in protein expression that may increase vulnerability to second stressor during adulthood, precipitating depressive-like symptoms. Additionally, it is known that depression is more common in females (5.1%) than in males (3.6%), suggesting sex-dependent mechanism of stress susceptibility. Consequently, we investigated potential sex differences in stress-induced alterations of hipocampal protein expression profiles. For this reason, male and female C57BL/6J mice were subjected to two stress protocols, the first in the juvenile period and the second in adulthood. Changes in hippocampal protein expression profiles were analyzed in both sexes. The results revealed the magnitude of these changes was consistently greater in females, Specifically, juvenile stress altered the abundance of 7 proteins in males compared with 42 proteins in females. Adult stress modified 19 proteins in males and 53 proteins in females, whereas combined juvenile and adult stress affected 16 proteins in males and 49 proteins in females. Functional profiling of differentially expressed proteins revealed distinct stress- and sex-dependent molecular patterns. In males, stress exposure predominantly affected proteins related to synaptic function, neurotransmission, and cellular stress-response pathways, with specific alterations depending on stress timing. In females, stress induced more extensive proteomic changes involving synaptic organization, structural plasticity, metabolic processes, and glial-related pathways, suggesting a more pronounced molecular adaptation to stress. Overall, stress-induced proteomic alterations were highly dependent on sex and previous stress exposure, with females showing a more pronounced molecular response across all stress conditions.