GLP-1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

J. Patrick Card, Aaron L. Johnson, Ida J. Llewellyn-Smith, Huiyuan Zheng, Rishi Anand, Daniel I. Brierley, Stefan Trapp, Linda Rinaman

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Abstract

Glutamatergic neurons that express pre-proglucagon (PPG) and are immunopositive (+) for glucagon-like peptide-1 (i.e., GLP-1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP-1 neurons give rise to an extensive central network in which GLP-1 receptor (GLP-1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP-1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP-1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin-releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP-1+ axonal varicosities. Surprisingly, GLP-1+ appositions were also observed on dendrites of PPG/GLP-1+ neurons in both species, and electron microscopy in rats revealed that GLP-1+ boutons form asymmetric synaptic contacts with GLP-1+ dendrites. However, RNAscope confirmed that rat GLP-1 neurons do not express GLP-1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP-1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co-express GLP-1R. Collectively, these data suggest that GLP-1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local “feed-forward” synaptic network among GLP-1 neurons that apparently does not use GLP-1R signaling. This local GLP-1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP-1 neural populations that shape behavioral and physiological responses to internal and external challenges.

Original languageEnglish
Pages (from-to)2149-2164
Number of pages16
JournalJournal of Comparative Neurology
Volume526
Issue number14
DOIs
Publication statusPublished - 1 Oct 2018

Bibliographical note

© 2018 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Keywords

  • GABA
  • glutamate
  • local circuit network
  • noradrenergic
  • NTS
  • preproglucagon
  • prolactin-releasing peptide
  • RRID: AB_2314562
  • RRID: AB_300798
  • RRID: AB_518978
  • synapse

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