Limbic neuropeptide Y-Y1 receptor expressing neurons are mandatory for anxiolytic-related behaviour and body weight control

Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammal central nervous system where it plays a pivotal role in the regulation of stress response, emotional and feeding behaviour via the activation of the Y1 receptor (Y1R) subtype. Recent clinical data implicate NPY-Y1R in the pathophysiology of human anxiety. Nevertheless, germinal Y1R knockout has little impact on emotional and feeding behaviour in mice. We generated a conditional knockout mouse line (Y1Rfb-/-) in which Y1R function is inactivated postnatally in forebrain by using the doxicycline-controlled Cre/loxP system. Y1RloxP/loxP animals showed the normal widespread brain expression pattern of Y1R whereas in Y1Rfb-/- conditional mutants, Y1R mRNA and Y1R immunoreactivity were selectively decreased in the hippocampus and in the amygdala, but not in the hypothalamic nuclei. Starting at P40, Y1Rfb-/- conditional mutants show a long lasting reduction of body weight which is associated with decreased leptin and glucose plasma levels. Moreover, selective ablation of Y1R in adult mice forebrain increased anxiety-related behaviour in the elevated plus-maze test. There was a significant effect of genotype for percentage of time spent and percentage of entries into the open arms. The anxious phenotype of conditional Y1Rfb-/- mutants was associated with a significant decrease of CRH immunoreactive fibers in the central amygdala. General locomotor activity in the open field protocol as well as spontaneous locomotor activity in cages were similar in both groups. Our data clearly show that deletion of limbic Y1R increases anxious-related behaviour. Furthermore, we provide evidence for a role of limbic Y1R in the control of energy homeostasis that is independent of hypothalamic functions.