Rossi, M. A. | Search bioRxiv

bioRxiv2024

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

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

neuroscience↗

bioRxiv2021

An endogenous opioid circuit determines state-dependent appetitive behavior

Mu-opioid peptide receptor (MOPR) stimulation alters respiration, analgesia, and reward behavior, and can induce addiction and drug overdose. Despite its evident importance, the endogenous mechanisms for MOPR regulation of appetitive behavior have remained unknown. Here we report that endogenous MOPR regulation of appetitive behavior in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine appetitive behavioral state while select enkephalin-containing NAc ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of endogenous MOPR ligand. Selective modulation of NAc enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent appetitive behavior and suggest alternative mechanisms for opiate modulation of reward.

neuroscience↗