May 14, 2024

Defining the link between the cerebellum, dopamine and obesity.

The dramatic increase in obesity presents a major public health concern with significant medical, societal, and workplace productivity consequences. Although it is well appreciated that energy balance is seeded in the brain, pharmacological treatments targeting the central nervous system are often insufficient to maintain reduced body weight or have unwanted side effects. Thus, there is an urgent need to identify and evaluate understudied neural networks that regulate food intake to identify novel targets for the regulation of body weight.

Scintillon Institute Associate Professor Albert Chen has received a grant from the NIH/NIDDK to study feeding behavior and the cerebellum, an understudied and underappreciated brain region recently identified to have a potent influence on food intake. In collaboration with Associate Professor J. Nicholas Betley (University of Pennsylvania), this project will examine how the cerebellum interacts with midbrain dopaminergic reward centers and test the hypothesis that this cerebellar network is disrupted during obesity. The cerebellum is capable of influencing dopamine levels throughout the brain, and midbrain dopamine neurons are critical regulators of feeding behavior. The Chen and Betley labs have previously demonstrated that the cerebellum modulates dopamine levels in the striatum to control food intake (Low et al., 2021 Nature), and cerebellar neural and striatal dopamine activities respond to food cues, ingestion and gastric infusion of nutrients (Figure below). Thus, this proposed study seeks to structurally and functionally link the cerebellar-striatal circuits and feeding behavior. Additionally, because obesity can change neural activity in the brain, this proposed study also aims to understand how the cerebellum contributes to changes in dopamine signaling before, during, and after weight gain.

This research is significant because the cerebellum has been targeted by deep brain modulation for the treatment of a number of neurological disorders. The accessibility of the cerebellum to non-invasive neuromodulation motivates the urgency to form a deeper understanding of the cerebellar networks that control food intake, as this may rapidly facilitate therapeutic approaches for the treatment of obesity and overeating.

Previous single nuclei RNA-sequencing analysis by the Chen and Betley labs has found that neurons in the deep cerebellar nuclei (DCN) activated by food intake selectively express the gene secreted phosphoprotein 1 (Spp1) (Low et al., 2021). This provides an exciting opportunity to explore two key questions: 1) are there different transcriptional classifiers for cerebellar neurons with distinct functions and discrete brain targets? 2) are there transcriptional changes in Spp1-positive cerebellar neurons following diet induced obesity? Molecular analysis of hunger-linked neural circuits by others have revealed that obesity and high-fat diet dramatically changes transcriptional programs in hunger-activated neurons. Identifying molecular differences in the cerebellum in sated and hunger states could facilitate the identification of novel pharmacological targets for the reduction in food intake and obesity.

This research is supported by the NIH/NIDDK R01DK134857-01A1.