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dc.contributor.advisorSpringer, Michael
dc.contributor.authorTyssowski, Kelsey M.
dc.date.accessioned2019-12-12T09:23:36Z
dc.date.created2019-05
dc.date.issued2019-04-29
dc.date.submitted2019
dc.identifier.citationTyssowski, Kelsey M. 2019. Different Neuronal Activity Patterns Induce Different Gene Expression Programs. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029792*
dc.description.abstractNeurons 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.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectneuronal activity-regulated genes
dc.subjectMAPK
dc.subjectRNA sequencing
dc.subjectenhancers
dc.subjectneuronal activity patterns
dc.titleDifferent Neuronal Activity Patterns Induce Different Gene Expression Programs
dc.typeThesis or Dissertation
dash.depositing.authorTyssowski, Kelsey M.
dc.date.available2019-12-12T09:23:36Z
thesis.degree.date2019
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberCepko, Constance
dc.contributor.committeeMemberAnthony, Todd
dc.contributor.committeeMemberMedzhitov, Ruslan
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dc.identifier.orcid0000-0002-5324-4872
dash.author.emailktyssowski@gmail.com


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