Different Neuronal Activity Patterns Induce Different Gene Expression Programs

Abstract

Neurons induce hundreds of activity-regulated genes (ARGs) in response to extracellular stimuli, suggesting that a vast number of different stimuli could each be coupled to a distinct ARG expression profile. Such coupling could explain how neurons induce different types of plasticity in response to different stimuli. In this dissertation, I focus on one aspect of extracellular stimuli: its temporal pattern. Few studies have compared ARG induction between different neuronal activity patterns, especially on a genomic scale. Using RNA-sequencing, I show—both in cultured cortical neurons and in the mouse visual cortex—that neurons stimulated for different durations induce different ARGs. Specifically, brief activity selectively induces a small subset of ARGs that corresponds to the first of three temporal waves of ARGs induced by sustained activity. I formally demonstrate that I can use this differential ARG induction to infer neurons’ activity duration history. I then apply this inference to single-cell RNA-sequencing data from individual neurons in stimulated cortex, demonstrating the potential for pattern-dependent ARG expression to be used as a tool for inferring neuronal stimulation histories. I further show that the first-wave genes induced by brief activity uniquely require MAPK/ERK signaling for their induction. MAPK/ERK signaling likely regulates first-wave genes by promoting eRNA production but not histone acetylation at the enhancers near first-wave genes. These mechanistic findings provide a molecular handle for testing the role of first-wave genes in plasticity. Furthermore, they demonstrate that the same mechanisms that establish the multi-wave temporal structure of gene induction also enable different gene sets to be induced by different durations of stimulation.