Reverse-translational identification of a cerebellar satiation network

Aloysius Y. T. Low, Nitsan Goldstein, Jessica R. Gaunt, Kuei-Pin Huang, Norliyana Zainolabidin, Alaric K. K. Yip, Jamie R. E. Carty, Ju Y. Choi, Alekso M. Miller, Helen S. T. Ho, Clara Lenherr, Nicholas Baltar, Eiman Azim, October M. Sessions, Toh Hean Ch’ng, Amanda S. Bruce, Laura E. Martin, Mark A. Halko, Roscoe O. Brady, Laura M. Holsen, Amber L. Alhadeff, Albert I. Chen () and J. Nicholas Betley ()
Additional contact information
Aloysius Y. T. Low: University of Pennsylvania
Nitsan Goldstein: University of Pennsylvania
Jessica R. Gaunt: Nanyang Technological University
Kuei-Pin Huang: Monell Chemical Senses Center
Norliyana Zainolabidin: School of Biological Sciences, Nanyang Technological University
Alaric K. K. Yip: Nanyang Technological University
Jamie R. E. Carty: University of Pennsylvania
Ju Y. Choi: University of Pennsylvania
Alekso M. Miller: University of Pennsylvania
Helen S. T. Ho: School of Biological Sciences, Nanyang Technological University
Clara Lenherr: University of Pennsylvania
Nicholas Baltar: Molecular Neurobiology Laboratory, Salk Institute
Eiman Azim: Molecular Neurobiology Laboratory, Salk Institute
October M. Sessions: National University of Singapore
Toh Hean Ch’ng: Nanyang Technological University
Amanda S. Bruce: University of Kansas Medical Center
Laura E. Martin: University of Kansas Medical Center
Mark A. Halko: Schizophrenia and Bipolar Disorder Research Program, McLean Hospital
Roscoe O. Brady: Harvard Medical School
Laura M. Holsen: Harvard Medical School
Amber L. Alhadeff: Monell Chemical Senses Center
Albert I. Chen: Center for Aging Research, Scintillon Institute
J. Nicholas Betley: University of Pennsylvania

Nature, 2021, vol. 600, issue 7888, 269-273

Abstract: Abstract The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1–3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a ‘bedside-to-bench’ approach for the identification of neural circuits that influence behaviour.

Date: 2021
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DOI: 10.1038/s41586-021-04143-5

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