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.
To determine if mouse models of PWS recapitulate deficits in cerebellar activity we obtained a novel PWS mouse line (referred to as MADIN mice with deletions of Magel2 and Necdin) from Dr. Francois Muscatelli (Inserm) (Barelle et al., 2025 Journal of Clinical Investigation Insight). Our major goal is to determine if the MADIN PWS model mice (mice with deletions of Magel2 and Necdin) can be used to 1) gain mechanistic insight into how networks that control food intake are dysregulated in PWS and 2) be useful as a preclinical screening tool for therapeutics that regulate the cerebellar – striatal network. Overall, our results suggest that there are alterations in feeding behavior and cerebellar-striatal network activity, however the changes are not reminiscent of human PWS feeding pathology.
We found that both male and female MADIN mice did not exhibit any differences in weight gain when fed with standard lab chow when compared to control wild type mice. However, female MADIN mice on HFD begin to gain more weight than female control wild type mice starting 9 weeks and the weight gain persists until 16 weeks. This increase in weight gain was not observed in male MADIN mice on HFD. Together our behavioral analysis indicates a sex difference in MADIN mice under HFD indicating potentially distinctions in neural mechanisms regulating food intake. We also examined the neural activity of cerebellar neurons in awake behaving male and female MADIN mice. In WT and MADIN mice fed on HFD, we observed differences in the response to high fat diet. We found the neural activity in the lateral nucleus of the DCN of MADIN mice appears less responsive to HFD than in WT control mice. This result potentially indicates hungry WT and MADIN mice on HFD have different cerebellar responses when presented with food after food restriction.
Together, our results indicate a subtle shift in food intake behavior and feeding networks in the MADIN mice. There are sex differences in the feeding behavior of MADIN mice, with female MADIN mice gaining more body weight than control mice when subjected to a high fat diet. Additionally, the neural activity of neurons in the deep cerebellum is perturbed in MADIN mice when presented with high fat diet. Though MADIN mice do not recapitulate hyperphagia observed in PWS, the behavioral and neural activity phenotypes in MADIN mice indicate these mice are useful for learning more about the biology of PWS genes Magel2 and Necdin.