<EM>​</EM>CIRCADIAN-DEPENDENT ALTERATIONS IN SOCIAL AND THREAT-RELATED BEHAVIORS IN <EM >GRM</EM>5 KNOCK-OUT MICE REVEALED BY ECO-HAB PROFILING

Adult mice lacking the metabotropic glutamate receptor 5 gene (Grm5-/-) display a neurobehavioral phenotype reflecting disrupted glutamatergic modulation of cortico-limbic circuits, including increased anxiety-like behavior, impairments in hippocampus- and amygdala-dependent tasks, such as fear conditioning, and a paradoxical increase in social interaction. Traditional task-specific assays, however, provide limited insight into the temporal and integrated nature of these behaviors. Using the Eco-HAB (Ecological Home-cage Analysis Behavior) system, which enables mice to express spontaneous behaviors in a semi-naturalistic environment, we reassessed Grm5-/- mice alongside heterozygous and wild-type littermates. Grm5-/- mice exhibited circadian-phase–dependent exploratory activity, preserved during the dark phase but markedly reduced during the light phase. Social behavior was characterized by decreased time spent solitary during the light phase and reduced chasing. These changes occurred without gross locomotor deficits, indicating selective disruption of anxiety-, social-, and threat-related behaviors rather than generalized hypoactivity. Heterozygous mice displayed intermediate phenotypes. This systems-level approach shifts phenotyping from isolated endpoint assays to integrated, longitudinal behavioral profiling, confirming core aspects of the Grm5-/- phenotype while enhancing mechanistic interpretation and translational relevance.