Paraventricular Thalamic Control of Food Intake and Reward: Role of Glucagon-Like Peptide-1 Receptor Signaling

Paraventricular thalamic nucleus (PVT) neurons receive hindbrain and hypothalamic inputs, and project to forebrain sites involved in reward and motivation function. The role of PVT in energy balance and reward control is however understudied. Given that PVT neurons express glucagon-like peptide-1 receptors (GLP-1R), which are critical to feeding and body weight control, we tested the hypothesis that PVT GLP-1R signaling contributes to food intake and reward inhibition. To assess the hypothesis, behavioral tests including chow and high-fat diet intake, meal patterns, conditioned place preference for high-fat food, cue-induced reinstatement of sucrose-seeking, and motivation to work for sucrose were employed following intra-PVT delivery of either GLP-1R agonist, exendin-4 (Ex4), or GLP-1R antagonist, exendin-9-39 (Ex9). Anatomical and electrophysiological experiments were conducted to examine the neural connections and cellular mechanisms of GLP-1R signaling on PVT-to-nucleus accumbens (NAc) projecting neurons. PVT GLP-1R agonism reduced food intake, food-motivation, and food-seeking, while blocking endogenous PVT GLP-1R signaling increased meal size and food intake. PVT neurons receive GLP-1 innervation from nucleus tractus solitarius preproglucagon neurons that were activated by food intake; these GLP-1 fibers formed close appositions to putative GLP-1R-expressing PVT cells that project to the NAc. Electrophysiological recordings of PVT-to-NAc neurons revealed that GLP-1R activation reduced their excitability, mediated in part via suppression of excitatory synaptic drive. Collectively, these behavioral, electrophysiological and anatomical data illuminate a novel function for PVT GLP-1R signaling in food intake control and suggest a role for the PVT-to-NAc pathway in mediating the effects of PVT GLP-1R activation.