Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections

Abstract

AbstractObjectiveAlthough glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP-1R) and their downstream projections on food intake and determine the relationship with feeding regulation.MethodsUsing chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP-1Rneurons affected food intake inGlp1r-ires-Cremice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP-1Rneurons to the lateral hypothalamic area (LHA) in regulating food intake.ResultsChemogenetic inhibition of dLSGLP-1Rneurons increases food intake. LHA is a major downstream target of dLSGLP-1Rneurons. The dLSGLP-1R→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP-1R→LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP-1R→LHA projection terminals in the LHA rapidly suppressed feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP-1R→LHA GABA release.ConclusionsTogether, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.HighlightsChemogenetic inhibition of dLSGLP-1Rneurons boosts food intake in micedLSGLP-1Rneuron activation does not alter feeding, likely by collateral inhibitiondLSGLP-1Rneurons project to LHA and release GABAActivation of dLSGLP-1R→LHA axonal terminals suppresses food intakeGLP-1R agonism enhances dLSGLP-1R→LHA GABA release via a presynaptic mechanism