TY - JOUR T1 - Glucose-sensing in AgRP neurons integrates homeostatic energy state with dopamine signalling in the striatum JF - bioRxiv DO - 10.1101/2021.03.22.436393 SP - 2021.03.22.436393 AU - Alex Reichenbach AU - Rachel E Clarke AU - Romana Stark AU - Sarah Haas Lockie AU - Mathieu Mequinion AU - Felicia Reed AU - Sasha Rawlinson AU - Harry Dempsey AU - Tara Sepehrizadeh AU - Michael DeVeer AU - Astrid C Munder AU - Juan Nunez-Iglesias AU - David C. Spanswick AU - Randall Mynatt AU - Alexxai V. Kravitz AU - Christopher V. Dayas AU - Robyn Brown AU - Zane B. Andrews Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/23/2021.03.22.436393.abstract N2 - Hunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods by acting on the midbrain dopaminergic system. Here, we identify a novel molecular mechanism through which hunger-sensing AgRP neurons detect low energy availability and modulate dopamine release to increase motivation for food reward.We tested the hypothesis that carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, in AgRP neurons is necessary to sense low energy states and regulate motivation for food rewards by modulating accumbal or striatal dopamine release. In support of this, electrophysiological studies show that AgRP neurons require Crat for appropriate glucose-sensing. Intact glucose-sensing in AgRP neurons controls post-ingestive dopamine accumulation in the dorsal striatum. Fibre photometry experiments, using the dopamine sensor GRABDA, revealed that impaired glucose-sensing, in mice lacking Crat in AgRP neurons, reduces dopamine release in the nucleus accumbens to palatable food consumption and during operant responding, particularly in the fasted state. Finally, the reduced dopamine release in the nucleus accumbens of mice lacking Crat in AgRP neurons affects sucrose preference and motivated operant responding for sucrose rewards. Notably, these effects are potentiated in the hungry state and therefore highlight that glucose-sensing by Crat in AgRP neurons is required for the appropriate integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum. These studies offer a novel molecular target to control the overconsumption of palatable foods in a population of hunger-sensing AgRP neurons.Competing Interest StatementThe authors have declared no competing interest. ER -