Neuropeptide Y is crucial for nutritional state-dependent regulation of maternal behavior.

Lactation is indispensable for the survival of mammalian pups. However, any excess of energy expenditure for lactation over energy intake threatens the mother's survival. Here, we report that an orexigenic molecule, neuropeptide Y (NPY), mediates nutritional state-dependent regulation of maternal behavior. After 9h of fasting, dams showed a dramatic decrease in the expression of maternal behavior. Intracerebroventricular or direct dorsal raphe nucleus (DRN) injection of NPY inhibited the expression of maternal behavior in non-fasted dams. In contrast, injection of the NPY Y1 receptor antagonist BIBP-3226 into the DRN, in which the expression of the Y1 receptor was confirmed in serotonergic (5-HT) and GABAergic interneurons, recovered the expression of maternal behavior in fasted dams. When the pups were presented, the increase in the number of c-Fos-positive GABAergic, but not serotonergic, neurons was smaller in fasted than in non-fasted dams. These results suggest that NPY may inhibit pup-induced activation of GABAergic neurons via the Y1 receptor. Injection of a 5-HT1A agonist, GABAA receptor antagonist, or GABAB receptor antagonist into the DRN induced incomplete maternal behavior in non-fasted dams. In contrast, each of a 5-HT2A receptor agonist or a GABAB receptor agonist, but not a GABAA receptor agonist, recovered separate components of maternal behavior in fasted dams. These results suggest that NPY inhibits both 5-HT neuronal activity and its modulation via the GABA receptor in the DRN, resulting in the suppression of maternal behavior under food-restricted conditions.