Krashes, MJ, Shah, BP, Madara, JC, Olson, DP, Strochlic, DE, Garfield, AS, Vong, L, Pei, H, Watabe-Uchida, M, Uchida, N, Liberles, SD and Lowell, BB (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. pp. 238-242.

Abstract

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated. 2014 Macmillan Publishers Limited. All rights reserved

Item Type:	Article
Additional Information:	NIBR author: Olson, DP institute: NIBR- address only contributor address: (Krashes, Shah, Madara, Olson, Garfield, Vong, Lowell) Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States (Strochlic, Liberles) Department of Cell Biology, Harvard Medical School, Boston, MA 02115, United States (Strochlic, Uchida, Liberles, Lowell) Program in Neuroscience, Harvard Medical School, Boston, MA 02115, United States (Garfield) Center for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom (Olson, Pei) Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, MI 48105, United States (Watabe-Uchida, Uchida) Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, United States (Krashes) Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States (Krashes) National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States (Shah) Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, MA 02139, United States (Vong) Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, United States
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22663