Abstract

Alternative splicing (AS) is prevalent in neuronal gene expression. However, its function in learning has not been systematically characterized. Here, by profiling pan-neuronal translatome changes during a C. elegans learning paradigm, we show that AS remodels expression of neuronal genes with critical function in learning at the genome-wide scale. Intriguingly, AS operates on a functionally distinct gene set from those showing transcript abundance changes, serving as a separate regulatory layer in response to experience. Specifically, a neuronally enriched worm ortholog of a mitochondrial DNA helicase twnk-1 displays significant learning-associated AS changes, with both isoform types acting in a pair of sensory neurons to regulate learning with distinct functions. AS of twnk-1 modulates a cell-nonautonomous signal from neuronal mitochondria to peripheral tissues to regulate physiological states critical for learning. These results establish AS as a systematic regulator of learning and mechanistically reveal how AS shapes physiological states to facilitate learning.