RT Journal Article
SR Electronic
T1 Glucose-sensing in AgRP neurons integrates homeostatic energy state with dopamine signalling in the striatum
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.22.436393
DO 10.1101/2021.03.22.436393
A1 Alex Reichenbach
A1 Rachel E Clarke
A1 Romana Stark
A1 Sarah Haas Lockie
A1 Mathieu Mequinion
A1 Felicia Reed
A1 Sasha Rawlinson
A1 Harry Dempsey
A1 Tara Sepehrizadeh
A1 Michael DeVeer
A1 Astrid C Munder
A1 Juan Nunez-Iglesias
A1 David C. Spanswick
A1 Randall Mynatt
A1 Alexxai V. Kravitz
A1 Christopher V. Dayas
A1 Robyn Brown
A1 Zane B. Andrews
YR 2021
UL http://biorxiv.org/content/early/2021/03/23/2021.03.22.436393.abstract
AB 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.