Investigation of cerebellar control of striatal dopamine activity and food intake in PWS

Funding Summary

These researchers have demonstrated that activation of a distinct class of cerebellar neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. In this proposal, we will characterize this novel cerebellar satiation network and evaluate whether this network is disrupted in PWS mouse models and explore how manipulating dopamine activity can alleviate diet-induced obesity in PWS mouse models.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

Individuals with Prader-Willi Syndrome (PWS) display an insatiable appetite that may lead to morbid obesity. Therapeutics that target known food intake-inhibitory mechanisms in the brain have not been successful at promoting lasting management of food intake in PWS individuals, which raises the possibility that other brain regions should be considered for the development of more effective treatments for PWS. Previous PWS imaging studies have identified disrupted activities in the midbrain reward system, but how changes in dopamine signaling might lead to hyperphagia is not clear. We have recently identified a distinct class of neurons in the cerebellum that are activated by food intake, and demonstrated that activation of these cerebellar neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. We discovered that activity of these cerebellar neurons reduces dopamine response to additional food, likely curbing the urge to eat by reducing the reward value of additional food. In this proposal, we will characterize this novel cerebellar satiation network and evaluate whether this network is disrupted in PWS mouse models and explore how manipulating dopamine activity can alleviate diet-induced obesity in PWS mouse models. This proposal will test these hypotheses through two aims. In Aim 1, we will examine the influence of cerebellar-mediated changes in dopamine levels in specific reward processing brain regions in PWS mouse models. These experiments will allow us to examine how cerebellar activity influences the response to food and nutrients. In Aim 2, we will assess how diet-induced obesity impacts cerebellar-mediated changes in dopamine activity in PWS mouse models. By defining this newly identified brain pathway with the ability to robustly suppress food intake, how cerebellar activity controls dopamine function, and how this pathway might be disrupted in PWS, this work will reveal mechanisms that regulate food reward processing with added translational value of guiding the development of non-invasive cerebellar stimulation and cell-type specific pharmacological manipulation for PWS.