Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

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 hypothesized 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 minutes 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.

Identification of a stress-sensitive anorexigenic neurocircuit from medial prefrontal cortex to lateral hypothalamus

“…Further evidence to support this comes from the reduced time spent rearing in the open field after mPFC-LH inhibition, since rearing behavior is normally expressed within a novel environment to survey for potential danger or threat (30). Food consumption, but not food presentation, approach, or wooden dowel chewing reduced mPFC-LH activity and surprisingly, the magnitude of the fall was not related to metabolic state, palatability or food consumed, as has been observed with hunger-sensing AgRP neurons (48,49). Altered mPFC activity has been observed in response to palatable food consumption in models of binge eating (50), suggesting that this circuit may play an important role regulating emotional state in the absence of homeostatic need.…”

Food-induced dopamine signaling in AgRP neurons promotes feeding

“…This also brings up an interesting potential feedforward mechanism in which intra-hypothalamic DA can regulate the metabolic state-dependent ARC AgRP/NPY neuron-mediated mesolimbic responses. 29 , 49 , 50 Therefore, this node represents a significant integration point for DA neurotransmission in energy homeostasis.…”

Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

“…Data from the Ca 2+ -dependent 465 nm channel were then linearly scaled using the fitted decay of the isosbestic channel, correcting for any photobleaching which occurred during the recordings (Meng et al, 2018). The resulting vector was converted to a ΔF/F trace as previously described (Evans et al, 2022), and each trace was normalized as a z-score (Reichenbach et al, 2022). Z-scored ΔF/F traces were analyzed for area under the curve, peak frequency, and maximum fluorescence.…”