E-mail: achen at scintillon dot org
A major goal of my research is to link the molecular, anatomical and function distinctions of neuronal subpopulations in the nervous system with specific behaviors. Recent studies from others have uncovered neural circuits in the motor cortex, brainstem, and spinal cord that mediate skilled limb movements and locomotion, but the contribution of the cerebellar nuclei (CN) and identifiable neuronal subpopulations within CN to skilled movement and locomotion has not yet been examined. We discovered the ability of the Urocortin 3 (Ucn3)-Cre mouse line to label, monitor, and manipulate a subset of neurons in the interposed anterior (IntA) nucleus of the CN (IntUcn3). We mapped the nucleocortical and extra-cerebellar targets of IntUcn3 neurons, and showed that the ablation and optogenetic stimulation of IntUcn3 neurons disrupts the accuracy of forelimb skilled reaching reminiscent of hypermetria and perturbs kinematics of locomotor movement. These findings describe a highly specialized subpopulation of glutamatergic neurons in the cerebellar IntA nucleus that modulates both rhythmic and discrete movements (Low et al., 2018), and raise the possibility that in addition to CN neurons involved in updating of motor output through the thalamus and cortical centers, there are additional neuronal subpopulations in the Int nucleus required for motor refinement through descending pathways (Thanawalla et al., 2020).
In a newly developed project that explores the ability of distinct cerebellar output pathways to influence behaviors beyond motor control, we explore a fundamental neurobiological and ethological question: how does the brain constrain meal sizes to prevent overeating? To identify brain regions that limit feeding behavior, we used a “reverse-translational” approach and screened for dysregulated neural responses to food cues and eating in humans with compulsive hyperphagia [Prader-Willi Syndrome (PWS)]. Our fMRI analysis identified a striking hotspot of neural dysregulation within the deep cerebellum of PWS individuals. To explore this functional significance, we found that activation of mouse deep cerebellar neurons dramatically decreased food intake by terminating meals earlier and reducing meal size. Topographical and transcriptomic analysis revealed an anatomically- and molecularly-distinct cerebellar neuron population that selectively reduces meal size. Activity in these neurons promoted satiation by engaging downstream mesolimbic reward, but not hypothalamic, pathways. Taken together, we have uncovered a previously unknown but evolutionarily conserved neural node that puts a “brake” on food intake (Low et al., 2021). Importantly, the cerebellum as a regulator of food intake is not currently considered as a part of the neural network of feeding behavior, and we aim to provide a roadmap for future exploration of how the cerebellum interacts with other feeding centers.
- Low, A.Y.T., Goldstein, N., Gaunt, J., Huang, K.P., Zainolabidin, N., Yip, A.K.K., Carty, J., Choi, J., Ho, H.S.T., Lenherr, C., Balter, N., Miller, A., Azim, E., Sessions, O., Ch’ng, T.H., Bruce, A., Martin, L., Halko, M., Brady, R., Holsen, L., Alhadeff, A., Chen, A.I.*, Betley, J.N.* (2021). Reverse-translational identification of a cerebellar satiation network. Nature 600, 269-273. *corresponding authors news and views
- Thanawalla, A.R., Chen, A.I.*, Azim, E*. (2020). The cerebellar nuclei and dexterous limb movements. Neuroscience 450, 168-183. *corresponding authors
- Kamath, S., Chen, A.I. (2019). Myocyte enhancer factor 2c regulates dendritic complexity and connectivity of cerebellar Purkinje cells. Molecular Neurobiology 56, 4102-19.
- Low, A.Y.T., Thanawalla, A.R., Yip, A.K.K., Kim, J., Wong, K.L.L., Tantra, M., Augustine, G.J., Chen, A.I. (2018). Precision of discrete and rhythmic forelimb movements requires a distinct neuronal subpopulation in the interposed anterior nucleus. Cell Reports 22, 2322-33.
- Tantra, M., Guo, L., Kim, J., Zainolabidin, N., Augustine, G.J., Eulenburg, V., Chen, A.I. (2018). Conditional deletion of Cadherin-13 perturbs Golgi cells and disrupts cognitive and social behaviors. Genes, Brain and Behavior 15, e12466.
- Zainolabidin, N., Kamath, S.P., Thanawalla, A.R., Chen, A.I. (2017). Distinct activities of Tfap2A and Tfap2B in the specification of GABAergic interneurons in the developing cerebellum. Frontiers in Molecular Neuroscience 10, 281.