Sex Differences on Social and Anxiety-Related Responses in Low-Density Lipoprotein Receptor Knockout Mice

Familial hypercholesterolemia, caused by mutations in the low-density lipoprotein receptor (LDLr), is associated with cognitive and affective disturbances. However, sex differences in the impact of LDLr deficiency on anxiety and social behaviors remain poorly characterized. Male and female LDLr⁻/⁻ and wild-type (WT) C57BL/6 mice (4-5 months old) underwent a battery of behavioral tests assessing locomotion, anxiety-like behavior (open field, elevated plus maze, marble-burying test), and sociability (social interaction and three-chamber test). Serum cholesterol levels and catechol-O-methyltransferase (COMT) levels in the prefrontal cortex (PFC) and amygdala (AMY) were subsequently analyzed by Western blotting. Both male and female LDLr⁻/⁻ mice displayed marked hypercholesterolemia relative to WT controls. Female LDLr⁻/⁻ mice exhibited hyperlocomotion and reduced anxiety-like behavior in multiple tasks. Both sexes demonstrated increased sociability, although with test- and sex-dependent variations. Neurochemical analysis revealed a selective reduction of COMT in the PFC of LDLr⁻/⁻ females, suggesting sex-specific dopaminergic modulation underlying the behavioral phenotypes. LDLr deficiency induced sex-dependent changes in locomotor, anxiety-related, and social behaviors, accompanied by altered COMT expression in corticolimbic regions. These findings reveal an association between LDL receptors, dopaminergic regulation, and socio-emotional behaviors, emphasizing the relevance of social characterization in the neurobehavioral assessment of dyslipidemia.