NPY-Y1 coexpressed with NPY-Y5 receptors modulate anxiety but not mild social stress response in mice

The Y1 and Y5 receptors for neuropeptide Y have overlapping functions in regulating anxiety. We previously demonstrated that conditional removal of the Y1 receptor in the Y5 receptor expressing neurons in juvenile Npy1r^Y5R-/- mice leads to higher anxiety but no changes in hypothalamus-pituitary-adrenocortical axis activity, under basal conditions or after acute restraint stress. In the present study, we used the same conditional system to analyze the specific contribution of limbic neurons coexpressing Y1 and Y5 receptors on the emotional and neuroendocrine responses to social chronic stress, using different housing conditions (isolation vs. group-housing) as a model. We demonstrated that control Npy1r^2lox male mice housed in groups show increased anxiety and hypothalamus-pituitary-adrenocortical axis activity compared with Npy1r^2lox mice isolated for six weeks immediately after weaning. Conversely, Npy1r^Y5R-/- conditional mutants display an anxious-like behavior but no changes in hypothalamus-pituitary-adrenocortical axis activity as compared with their control littermates, independently of housing conditions. These results suggest that group housing constitutes a mild social stress for our B6129S mouse strain and they confirm that the conditional inactivation of Y1 receptors specifically in Y5 receptor containing neurons increases stress-related anxiety without affecting endocrine stress responses. Conditional inactivation of Y1 receptors in Y5 receptor containing neurons increases anxiety without affecting endocrine stress responses.