Different Neuronal Activity Patterns Induce Different Gene Expression Programs
Citation
Tyssowski, Kelsey M. 2019. Different Neuronal Activity Patterns Induce Different Gene Expression Programs. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.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.
Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:42029792
Collections
- FAS Theses and Dissertations [5858]
Contact administrator regarding this item (to report mistakes or request changes)