Extrahypothalamic GABAergic nociceptin-expressing neurons regulate AgRP neuron activity to control feeding behavior.

Mark A Smith,Sanjay Khadayate,Elaine E Irvine,Dominic J Withers,Hanns Ulrich Zeilhofer,Pedro Caldas Custodio De Campos Silva,Paulius Viskaitis,Agharul I Choudhury,Justyna A Glegola

doi:10.1172/jci130340

Abstract

Arcuate nucleus agouti–related peptide (AgRP) neurons play a central role in feeding and are under complex regulation by both homeostatic hormonal and nutrient signals and hypothalamic neuronal pathways. Feeding may also be influenced by environmental cues, sensory inputs, and other behaviors, implying the involvement of higher brain regions. However, whether such pathways modulate feeding through direct synaptic control of AgRP neuron activity is unknown. Here, we show that nociceptin-expressing neurons in the anterior bed nuclei of the stria terminalis (aBNST) make direct GABAergic inputs onto AgRP neurons. We found that activation of these neurons inhibited AgRP neurons and feeding. The activity of these neurons increased upon food availability, and their ablation resulted in obesity. Furthermore, these neurons received afferent inputs from a range of upstream brain regions as well as hypothalamic nuclei. Therefore, aBNST GABAergic nociceptin neurons may act as a gateway to feeding behavior by connecting AgRP neurons to both homeostatic and nonhomeostatic neuronal inputs.

Highlights

Feeding requires the integration of multiple neuronal networks to elicit appropriate behavioral and metabolic responses [1,2,3]
The control of feeding by agouti–related peptide (AgRP)/NPY neuron activity is sensitive to many homeostatic influences, and the nature of the hormonal and nutrient signals and hypothalamic neurocircuitry underlying such regulation has been well explored
We targeted the anterior bed nuclei of the stria terminalis (aBNST) for several reasons: (a) it receives inputs from a diverse array of brain regions that may be involved in feeding [16, 20, 21]; (b) it sends axonal projections to the arcuate nucleus, and retrograde mapping of AgRP neurons indicates a connection to the bed nuclei of the stria terminalis (BNST) [15, 16]; and (c) lesioning studies, local pharmacological manipulation of the BNST, and optogenetic control of the aBNST alter body weight and feeding [18,19,20]

Summary

Introduction

Feeding requires the integration of multiple neuronal networks to elicit appropriate behavioral and metabolic responses [1,2,3] These networks are sensitive to a range of modulatory inputs including nutrients and hormones, the reward value of food, environmental cues, and the internal emotional state [1,2,3]. We show that anterior BNST (aBNST) neurons coexpressing GABA and the opioid-like peptide nociceptin (a) inhibited arcuate AgRP/NPY neurons via GABAergic transmission to suppress food intake independent of changes in anxiety; (b) showed increases in endogenous activity at the initiation of feeding, which was temporally consistent with the reduction in AgRP/ NPY activity; (c) regulated body weight; and (d) received afferent inputs from a range of upstream brain regions. These studies identify aBNST GABAergic nociceptin neurons as a previously unrecognized extrahypothalamic neuron population that regulates food intake and body weight via AgRP/NPY neurons by acting as a potential feeding gateway to link both homeostatic and nonhomeostatic inputs

Results

Discussion

Findings

Methods