Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior
Mark A. Smith, … , Hanns Ulrich Zeilhofer, Dominic J. Withers
Mark A. Smith, … , Hanns Ulrich Zeilhofer, Dominic J. Withers
Published September 26, 2019
Citation Information: J Clin Invest. 2020;130(1):126-142. https://doi.org/10.1172/JCI130340.
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Research Article Metabolism Neuroscience

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

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.

Authors

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

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Figure 5

Optogenetic stimulation of aBNST nociceptin fibers in the arcuate nucleus does not induce anxiety-like behavior.

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Optogenetic stimulation of aBNST nociceptin fibers in the arcuate nucleu...
(A) Diagram illustrating the injection of Pnoc-EGFP mice and WT littermate controls with DOGCre, with or without ChR2-mCherry AAVs, into the aBNST and implantation of optical fibers into the arcuate nucleus. (B) Schematic representation of mice tethered to a 470-nm laser and photostimulated (3-second, 10-Hz bursts every 4 seconds) for 30 minutes in a novel open-field arena. (C–E) Percentage of time spent in the center (C) [unpaired t test, t (24) = 0.63, P = 0.53], total distance traveled (D) [unpaired t test, t (24) = 1.20, P = 0.24], and mouse velocity (E) [2-way repeated-measures ANOVA, interaction: f (173,4152) = 1.08, P = 0.241; ChR2 expression: f (1,24) = 1.44, P = 0.241] in the open-field arena for mice expressing (blue, n = 15 mice) or not expressing (red, n = 11 mice) ChR2-mCherry. Data represent the mean ± SEM. (F) Schematic representation of mice tethered to a 470-nm laser and photostimulated (3-second, 10-Hz bursts every 4 seconds) for 10 minutes on a novel elevated zero maze. (G) Percentage of time spent in the anxiogenic open zones [unpaired t test, t (17) = 0.99, P = 0.33] and (H) number of entries into the anxiogenic open zones [unpaired t test, t (17) = 1.74, P = 0.10] for mice expressing (blue, n = 11 mice) or not expressing (red, n = 8 mice) ChR2-mCherry. Data represent the mean ± SEM.