Abstract
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 AgPP 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.
Highlights
The motivation to approach and consume food depends on the palatability and caloric density of the available food source, and on the energy state of the organism.For example, when food is abundant many prey species forage within known territories to reduce survival threats [1]
carnitine acetyltransferase (Crat) deletion in Agouti-related peptide (AgRP) neurons is a valid model of impaired metabolic sensing To demonstrate that Crat deletion in AgRP neurons is a reliable model of impaired metabolic sensing, we prepared hypothalamic brain slices from WT and KO mice for electrophysiological characterisation of glucose sensing in AgRP neurons
We show that AgRP neurons require appropriate metabolic sensing of available calories to engage midbrain dopamine circuits and increase food motivation
Summary
The motivation to approach and consume food depends on the palatability and caloric density of the available food source, and on the energy state of the organism.For example, when food is abundant many prey species forage within known territories to reduce survival threats [1]. The motivation to approach and consume food depends on the palatability and caloric density of the available food source, and on the energy state of the organism. When food is scarce, animals are motivated to take greater risks and forage within unfamiliar territories to search for food [2]. The motivation to seek palatable, energy-dense food evolved as a key mechanism for survival and maturation in an environment with limited food resources. Given that heightened motivation for palatable food in an environment of low food availability shaped an evolutionary benefit, it is not surprising that homeostatic feeding circuits can have a profound effect on motivation. With high caloric foods readily available, these circuits may contribute to the overconsumption of highly palatable and calorie dense foods, which is a leading cause for today’s obesity crisis. Human evidence shows that fasting biases reward systems to high caloric foods [3,4]
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