104-OR: State-Dependent Activity in Hindbrain Glucagon-Like Peptide 1—Producing Neurons Regulates Consummatory and Valence Behavior through Functionally Interconnected Hypothalamic and Limbic Circuits

Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (Gcg^NTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of Gcg^NTS neurons to consummatory and valence behavior.

Methods: electrophysiology, in vivo optogenetics, fiber photometry.

Results: Using electrophysiology, we observed that Gcg^NTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, Gcg^NTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, Gcg^NTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of Gcg^NTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of Gcg^NTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of Gcg^NTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that Gcg^NTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between Gcg^NTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala.

Conclusions: Gcg^NTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala.