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

Abstract

Objective: Although 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; dLS ^GLP-1R ) and their downstream projections on food intake and determine the relationship with feeding regulation.

Methods: Using chemogenetic manipulations, we assessed how activation or inhibition of dLS ^GLP-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 dLS ^GLP-1R neurons to the lateral hypothalamic area (LHA) in regulating food intake.

Results: Chemogenetic inhibition of dLS ^GLP-1R neurons increases food intake. LHA is a major downstream target of dLS ^GLP-1R neurons. The dLS ^GLP-1R →LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLS ^GLP-1R →LHA projections modestly decreases food intake, optogenetic stimulation of the dLS ^GLP-1R →LHA projection terminals in the LHA rapidly suppressed feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLS ^GLP-1R →LHA GABA release.

Conclusions: Together, 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.

Highlights: Chemogenetic inhibition of dLS ^GLP-1R neurons boosts food intake in mice dLS ^GLP-1R neuron activation does not alter feeding, likely by collateral inhibition dLS ^GLP-1R neurons project to LHA and release GABA Activation of dLS ^GLP-1R →LHA axonal terminals suppresses food intake GLP-1R agonism enhances dLS ^GLP-1R →LHA GABA release via a presynaptic mechanism.