Sex-related differences in aggressive and emotional behavior in mice with the conditional inactivation of limbic Npy1r

Anxiety- and depression-related disorders are frequently associated with deficits in social behavior, including excessive aggression and violence, which may arise from disruptions in the neural circuits regulating emotions and social interactions. Sex differences play a crucial role in modulating emotional and social behaviors, particularly aggression and anxiety. Neuropeptide Y (NPY) and its Y1 receptor (Y1R) are involved in regulating various physiological functions, including emotional behavior and stress response. We previously demonstrated that conditional knockout of Npy1r gene in the forebrain excitatory neurons (Npy1rrfb mutant mice) increased anxiety-like behavior and hypothalamus-pituitary-adrenocortical axis reactivity and decreased body weight growth in a sex-dependent manner. In the present study we investigated how the depletion of the Npy1r gene in limbic areas might affect male and female mice by using a test battery aimed at assessing anxiety-like, social and aggressive behavior as well as response to novelty. Our results showed reduced exploratory behavior and increased anxiety in response to a novel environment in Npy1rrfb mice, with females exhibiting more pronounced effects. In contrast, only Npy1rrfb males showed reduced neophobia and increased impulsivity in response to a novel palatable food. Moreover, reduced limbic Npy1r expression decreased territorial aggression and increased defensive behaviors only in males. These findings reveal that limbic Y1R modulates anxiety, social interaction, and aggression in a sex-dependent manner. Moreover, they uncover a novel role for Y1R in regulating intermale aggression and suggest sex-specific links between NPY-Y1R signaling and the modulation of motivational and emotional responses.