Transcriptomic mapping uncovers Purkinje neuron plasticity driving learning

Xiaoying Chen, Yanhua Du, Gerard Joey Broussard, Mikhail Kislin, Carla M. Yuede, Shuwei Zhang, Sabine Dietmann, Harrison Gabel, Guoyan Zhao, Samuel S.-H. Wang (), Xiaoqing Zhang () and Azad Bonni ()
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Xiaoying Chen: Washington University School of Medicine
Yanhua Du: Tongji University, School of Medicine
Gerard Joey Broussard: Princeton University
Mikhail Kislin: Princeton University
Carla M. Yuede: Washington University School of Medicine
Shuwei Zhang: Tongji University, School of Medicine
Sabine Dietmann: Washington University School of Medicine
Harrison Gabel: Washington University School of Medicine
Guoyan Zhao: Washington University School of Medicine
Samuel S.-H. Wang: Princeton University
Xiaoqing Zhang: Tongji University, School of Medicine
Azad Bonni: Washington University School of Medicine

Nature, 2022, vol. 605, issue 7911, 722-727

Abstract: Abstract Cellular diversification is critical for specialized functions of the brain including learning and memory1. Single-cell RNA sequencing facilitates transcriptomic profiling of distinct major types of neuron2–4, but the divergence of transcriptomic profiles within a neuronal population and their link to function remain poorly understood. Here we isolate nuclei tagged5 in specific cell types followed by single-nucleus RNA sequencing to profile Purkinje neurons and map their responses to motor activity and learning. We find that two major subpopulations of Purkinje neurons, identified by expression of the genes Aldoc and Plcb4, bear distinct transcriptomic features. Plcb4+, but not Aldoc+, Purkinje neurons exhibit robust plasticity of gene expression in mice subjected to sensorimotor and learning experience. In vivo calcium imaging and optogenetic perturbation reveal that Plcb4+ Purkinje neurons have a crucial role in associative learning. Integrating single-nucleus RNA sequencing datasets with weighted gene co-expression network analysis uncovers a learning gene module that includes components of FGFR2 signalling in Plcb4+ Purkinje neurons. Knockout of Fgfr2 in Plcb4+ Purkinje neurons in mice using CRISPR disrupts motor learning. Our findings define how diversification of Purkinje neurons is linked to their responses in motor learning and provide a foundation for understanding their differential vulnerability to neurological disorders.

Date: 2022
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DOI: 10.1038/s41586-022-04711-3

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