Subtypes of neurons in the cerebellar cortex

For decades, the cerebellar cortex was viewed as a simple circuit comprised of repeated modules containing only a few basic cell types. However, discoveries made possible by modern molecular and physiological approaches have challenged this traditional view. In particular, single-nucleus RNA sequencing (snRNA-seq) revealed that every major class of cerebellar neuron consists of multiple transcriptionally distinct subtypes. Here, we explore how mapping and functionally characterizing this transcriptomic diversity are fundamentally rewriting our understanding of neural computation in the cerebellum. We focus initially on molecular layer interneurons (MLIs), which exemplify the power of this approach: transcriptomics divides MLIs into distinct subtypes, which were subsequently discovered to perform entirely opposing computational roles, dictating Purkinje cell firing and regulating dendritic calcium signals critical for synaptic plasticity and learning. This same multi-modal "playbook" can now be leveraged to determine how subtypes of granule cells, Golgi cells, Purkinje layer interneurons, Purkinje cells, and unipolar brush cells are specialized to meet distinct computational needs that allow the cerebellum to contribute to a wide range of behaviors. Ultimately, the cellular diversity unmasked in the cerebellum offers a uniquely tractable model for learning the rules by which molecular diversification of cell types equips brain circuits with the computational flexibility needed to drive complex behaviors.