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

Abstract

ObjectiveAlthough 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-1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP-1R neurons to the lateral hypothalamic area (LHA) in regulating food intake. ResultsChemogenetic inhibition of dLSGLP-1R neurons increases food intake. LHA is a major downstream target of dLSGLP-1R neurons. 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. HighlightsO_LIChemogenetic inhibition of dLSGLP-1R neurons boosts food intake in mice C_LIO_LIdLSGLP-1R neuron activation does not alter feeding, likely by collateral inhibition C_LIO_LIdLSGLP-1R neurons project to LHA and release GABA C_LIO_LIActivation of dLSGLP-1R [->]LHA axonal terminals suppresses food intake C_LIO_LIGLP-1R agonism enhances dLSGLP-1R [->]LHA GABA release via a presynaptic mechanism C_LI