Systematic Profiling and Functional Characterization of Alternative Splicing in C. elegans Olfactory Learning

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.