Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 recep- tors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To un- cover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1r rfb ). Npy1r rfb mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1r rfb mutants also had a hyperactive hypothalamic–pituitary– adrenocortical axis, as indicated by higher peripheral corticoste- rone and higher density of NPY immunoreactive fibers and corti- cotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fos- tering experiments, we determined that differences in phenotype between Npy1r rfb and Npy1r 2lox mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis.