Conditional inactivation of Neuropeptide Y Y1 receptors unravels the role of Y1 and Y5 receptors coexpressing neurons in anxiety

Neuropeptide Y (NPY) is widely distributed in the central nervous system, where it is involved in the regulation of several biological functions, including emotionality and stress reactions, energy balance, and cognition. In the brain, NPY interacts with a family of G-protein???coupled receptors that includes the Y1 (Y1R), Y5 (Y5R), and Y2 receptors. Pharmacologic and genetic studies suggest that NPY induces anxiolytic effects via activation of the Y1Rs in amygdala, hippocampus, and locus coeruleus. The Y5Rs and Y1Rs have overlapping function in regulating anxiety. The genes Npy1r and Npy5r are located on the same chromosome in humans and rodents, displaying an opposite transcriptional orientation and a partly overlapping gene structure. In rodents, the Y1R and Y5R are colocalized in several forebrain regions, including the basolateral amygdala (BLA) and hippocampal neurons. We hypothesized that the coordinated expression of the Y1R and Y5R might be required for the regulation of anxiety, spatial learning, and memory. In agreement, pharmacologic studies indicated that NPY induces anxiolytic effects via activation of the Y5R in the BLA. We generated conditional knockout mice in which the inactivation of Npy1r was induced in Y5R-expressing neurons of adolescent mice (Npy1r Y5R-/-). We achieved this by combining the gene targeted floxed Npy1r alleles and the inducible Cre recombinase transgene (Cre) that is transcriptionally controlled by a bacterial artificial chromosome-encoded Npy5r promoter???driven tetracycline suppressible transactivator (tTA)