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

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) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation.

METHODS

Using chemogenetic manipulations, we assessed how activation or inhibition of dLS 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 →LHA projections in regulating food intake.

RESULTS

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