An Excitatory Paraventricular Nucleus to AgRP Neuron Circuit That Drives Hunger

Nature. 2014 Mar 13;507(7491):238-42. doi: 10.1038/nature12956. Epub 2014 Feb 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / deficiency
  • Agouti-Related Protein / metabolism*
  • Animals
  • Appetite / drug effects
  • Appetite / physiology
  • Arcuate Nucleus of Hypothalamus / cytology
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Brain Mapping
  • Cell Tracking
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Dependovirus / genetics
  • Eating / drug effects
  • Eating / physiology
  • Female
  • Food Deprivation
  • Hunger / drug effects
  • Hunger / physiology*
  • Integrases / metabolism
  • Male
  • Mice
  • Neural Pathways / drug effects
  • Neural Pathways / physiology*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / physiology*
  • Peptide Fragments / deficiency
  • Peptide Fragments / metabolism
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism
  • Rabies virus / genetics
  • Satiety Response / physiology
  • Thyrotropin-Releasing Hormone / metabolism

Substances

  • Agouti-Related Protein
  • Peptide Fragments
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Thyrotropin-Releasing Hormone
  • Cre recombinase
  • Integrases
  • Clozapine
  • clozapine N-oxide