A repressive regulatory cascade shapes temporal patterning of activity-regulated gene expression in a defined sensory neuron type

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 expression 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 are not fully described. We previously showed that temperature regulates an ARG program in the C. elegans AFD thermosensory neuron pair to drive behavioral plasticity ^3,15,16 . By profiling AFD following temperature upshifts of varying duration, here 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 rapid induction of the RCAN-1 calcineurin regulator acts in parallel with the MEF-2 transcription factor to repress premature expression of a delayed ARG. 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 temporal dynamics of an ARG cascade in a sensory neuron type in vivo , and suggest that distinct cell type-specific regulatory pathways operate to drive ARG expression programs across neuron types.