Extended Data Fig. 13: Proposed role of the cerebellum in feeding control.

The cerebellum is well-positioned to integrate homeostatic satiation signals and is capable of orchestrating adaptive feeding responses by modulating motor, cognitive, affective and endocrine functions^{20,66,67,68,69,70,71,72,73,74,75}. Visual, gustatory and olfactory inputs are all known to activate the cerebellum^76,77,78 which could provide salience update to control appetitive drive. It functions as a comparator of physiological nutrient state (interoception) and post-ingestion nutritional outcome (nutrient feedback) to fine-tune predictive reward signals (reward network)⁷⁹ and ultimately influence meal size (feeding network). While cerebellar output has been shown to influence VTA neuron activity^12,80, our observed changes in DA signalling are tightly associated with decreases in food intake, suggesting a dedicated role of the cerebellum in regulating DA circuits that influence feeding that is distinct from motor⁸⁰ or social¹² behaviours. Based on our mechanistic studies into the changes in the reward system mediated by the cerebellum, it is possible that previously discovered differences between PWS and control subjects arise because of cerebellar alterations^8,81,82. In response to a predicted meal size (predicted nutritional reward outcome) by either food cues or food, cerebellar activity increases dopamine efflux that blunts dopamine transients. Consequently, the reward value of consuming food reduces and meals are terminated. In PWS patients^8,81,82, food-dependent cerebellar activity is absent and thus, dopamine transients remain regardless of amount of food consumed, leading to excessive eating. Conversely, in dopamine-deficient animals, there is a complete absence of drive to eat¹⁴. A better understanding of the mechanisms and circuits underlying cerebellar-mediated behaviours can guide brain stimulation strategies to control food intake recently shown to have the capability of ameliorating symptoms for disorders associated with the cerebellum^83,84,85,86.