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

• Published in: Journal of comparative neurology (1911) Vol. 526; no. 14; pp. 2149 - 2164
• Main Authors: Card, J. Patrick, Johnson, Aaron L., Llewellyn‐Smith, Ida J., Zheng, Huiyuan, Anand, Rishi, Brierley, Daniel I., Trapp, Stefan, Rinaman, Linda
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2018; Wiley Subscription Services, Inc
• Subjects: Animals; Brain slice preparation; Calcium imaging; Confocal microscopy; Dendrites; Electron microscopy; Female; Food intake; GABA; Glucagon; Glucagon-Like Peptide 1 - physiology; Glucagon-Like Peptide-1 Receptor - biosynthesis; Glucagon-Like Peptide-1 Receptor - genetics; glutamate; Glutamate Decarboxylase; Glutamatergic transmission; local circuit network; Male; Mice; Mice, Transgenic; Microscopy; mRNA; Nerve Net - cytology; Nerve Net - physiology; Neurons; noradrenergic; Norepinephrine; NTS; preproglucagon; Presynapse; Proglucagon - metabolism; Prolactin; Prolactin-Releasing Hormone - metabolism; prolactin‐releasing peptide; Rats; Rats, Sprague-Dawley; Reinforcement; Reticular formation; Rodents; RRID: AB_2314562; RRID: AB_300798; RRID: AB_518978; Signal Transduction - physiology; Solitary Nucleus - cytology; Solitary Nucleus - physiology; Solitary Nucleus - ultrastructure; Solitary tract nucleus; synapse; Synapses - physiology; Synapses - ultrastructure; RRID: AB_518978; noradrenergic; preproglucagon; RRID: AB_2314562; GABA; prolactin-releasing peptide; synapse; NTS; RRID: AB_300798; local circuit network; glutamate
• ISSN: 0021-9967; 1096-9861
• DOI: 10.1002/cne.24482

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. Confocal imaging of dual immunfluorescent labeling for prolactin‐releasing peptide (PrRP; magenta) and glucagon‐like peptide‐1 (GLP‐1; green) within the rat caudal nucleus of the solitary tract. This study reveals that GLP‐1+ axon terminals contact both PrRP and GLP‐1 neurons, but only PrRP neurons express mRNA for GLP‐1 receptor.