Prediction error neurons in mouse cortex are molecularly targetable cell types

ABSTRACT Predictive processing postulates the existence of prediction error neurons in cortex. Functionally, both negative and positive prediction error neurons have been identified in layer 2/3 of visual cortex, but whether they correspond to transcriptionally defined subpopulations is unclear. Here we used the activity-dependent, photoconvertible marker CaMPARI2 to tag neurons in layer 2/3 of visual cortex during stimuli and behaviors designed to trigger prediction errors. We performed single-cell RNA-sequencing on these populations and found that previously annotated Adamts2 and Rrad layer 2/3 cell types were enriched when photolabeling for negative or positive prediction error responses respectively. Finally, we validated these results functionally by designing artificial promoters for use in AAV vectors to express genetically encoded calcium indicators. Thus, positive and negative prediction error responses mapped onto transcriptionally distinct cell types in layer 2/3 that can be targeted using AAV vectors.