Scientists found that a brain chemical called PACAP, made by specific neurons, talks to kisspeptin cells that control fertility. Removing PACAP from those neurons in female mice delayed puberty and messed up their ability to reproduce, while males were unaffected. This suggests PACAP helps link nutrition signals to reproductive hormones in females.

Pituitary adenylate cyclase activating polypeptide (PACAP, <i>Adcyap1</i>) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMV^PACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with <i>Adcyap1</i>^fl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction in female mice.