Bates, S. G.; Harris, N.; Sengupta, P.

Long-term neuronal plasticity is driven by activity-regulated gene (ARG) expression programs that encode stimulus features in a neuron type-specific manner 1-6. ARG programs are typically characterized by rapid induction of immediate early genes (IEGs) without requiring new protein synthesis, followed by induction of secondary response genes regulated by IEG-encoded transcription factors 2,5,7-14. However, the molecular mechanisms that pattern these programs in specific neuron types in vivo in response to physiological stimuli remain unclear. We previously showed that temperature regulates an ARG program in the C. elegans AFD thermosensory neuron pair to drive behavioral plasticity 3,15,16. Here, by profiling AFD following temperature upshifts of varying durations, we show that ARGs in this neuron exhibit distinct temporal trajectories. Notably, rapidly induced genes do not include known IEGs but are enriched for molecules implicated in signal transduction and navigation. Both rapid and delayed ARG expression require the CMK-1 CaMKI kinase and CRH-1/CREB transcription factor, with CRH-1 acting at both early and late stages. We further define a temporal regulatory cascade in which CREB-dependent induction of the RCAN-1 calcineurin regulator acts in parallel with the MEF-2 MEF2/MADS domain transcription factor to repress expression of a delayed ARG at early timepoints. Subsequent downregulation of RCAN-1 likely enables CRH-1-dependent ARG expression at later stages. Our results demonstrate that in addition to classical gene-activating transcriptional cascades, ARG-controlled repressive mechanisms also operate to precisely shape the dynamics of an ARG cascade in a sensory neuron type in vivo, and suggest that distinct cell type-specific regulatory pathways may operate across neuron types to drive ARG expression programs.