Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia
Sasha Rawlinson
Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia
Felicia Reed
Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia
Tara Sepehrizadeh
Monash Biomedical Imaging Facility, Monash University, Clayton, Australia
Michael DeVeer
Monash Biomedical Imaging Facility, Monash University, Clayton, Australia
Astrid C Munder
Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia; Florey Institute of Neuroscience & Mental Health, Parkville, Australia
Juan Nunez-Iglesias
Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
David C Spanswick
Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia; Warwick Medical School, University of Warwick, Coventry, United Kingdom
Randall Mynatt
Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge,, United States
Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University in St Louis, St Louis, United States
Christopher V Dayas
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
Robyn Brown
Florey Institute of Neuroscience & Mental Health, Parkville, Australia; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia
Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgRP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.
