PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse
Rachel A Ross,
Silvia Leon,
Joseph C Madara,
Danielle Schafer,
Chrysanthi Fergani,
Caroline A Maguire,
Anne MJ Verstegen,
Emily Brengle,
Dong Kong,
Allan E Herbison,
Ursula B Kaiser,
Bradford B Lowell,
Victor M Navarro
Affiliations
Rachel A Ross
Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, United States; Department of Psychiatry, Massachusetts General Hospital, Massachusetts, United States; Harvard Medical School, Massachusetts, United States; McLean Hospital, Boston, United States
Silvia Leon
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States
Joseph C Madara
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
Danielle Schafer
Centre for Neuroendocrinology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand
Chrysanthi Fergani
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States
Caroline A Maguire
Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States
Anne MJ Verstegen
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
Emily Brengle
Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
Dong Kong
Department of Neuroscience, Tufts University School of Medicine, Massachusetts, United States; Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, United States
Centre for Neuroendocrinology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand
Ursula B Kaiser
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States
Bradford B Lowell
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
Harvard Medical School, Massachusetts, United States; Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, United States
Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) 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 (PMVPACAP) 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 Adcyap1fl/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.
