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 January 2, 2020; First 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 1

Photostimulation of aBNST GABAergic axons in the arcuate nucleus suppresses feeding.

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Photostimulation of aBNST GABAergic axons in the arcuate nucleus suppres...
(A) Diagram illustrating injections of the aBNST (red) with ChR2-mCherry. (B) Mosaic images (n = 35) of aBNST (enlarged inset on the right) and arcuate nucleus (C) from Vgat-Cre mice with ChR2-mCherry AAV injected into the aBNST. Scale bars: 200 μm (low-magnification images) and 20 μm (high-magnification images). (D) Diagram of Vgat-Cre mice crossed with Pomc-GFP or Npy-hrGFP mice with ChR2-mCherry in the aBNST. (E) Photostimulated synaptic currents from an arcuate NPY neuron in the absence (black) and presence (red) of 20 μM bicuculline (n = 10). (F) Synaptic currents in arcuate POMC (n = 9 neurons from 3 mice) and NPY (n = 10 neurons from 3 mice) neurons. Data represent the mean ± SEM. *P < 0.05 [unpaired t test, t (17) = 2.15, P = 0.046]. (G) Voltage traces (expanded below) from a NPY neuron during photostimulation of aBNST axons (n = 10). Vm, membrane potential. (H) Action potential frequency in NPY neurons (n = 10 neurons from 3 mice) before (baseline) and during photostimulation of aBNST axons. Data represent the mean ± SEM. **P < 0.01, by paired t test, t (9) = 3.33, P = 0.009. (I) Diagram illustrating injection of the aBNST with ChR2-mCherry and optical fiber implantation into the arcuate nucleus. (J) Cumulative food intake in fasted Vgat-Cre mice during (shaded area) and after photostimulation of ChR2-mCherry–expressing axons from the aBNST. Food intake was measured in mice without (red) and with (blue) photostimulation. Data represent the mean ± SEM. n = 25 mice. Two-way repeated-measures ANOVA [interaction: f (6,288) = 9.58, P < 0.0001; stimulation: f (1,48) = 3.68, P = 0.06]. *P < 0.05 and **P < 0.01, by Sidak’s post hoc test. (K) Food intake at 4 hours from nonstimulated and stimulated mice. Data represent the mean ± SEM. n = 25 mice. *P < 0.05, by paired t test, t (24) = 2.46, P = 0.021. 3V, third ventricle; a.c., anterior commissure.