Date of Award

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Howard S. Fox, M.D., Ph.D.

Abstract

MicroRNAs (miRNAs) are important regulators of gene expression. Many neurological diseases, including traumatic brain injury alter expression of miRNAs in the brain. However, the function of these molecules in the context of TBI is largely unknown. Here we report multiple potential roles for miRNAs in TBI, some of which extend beyond the traditional model of post-transcriptional regulation, highlighting that these RNA molecules may have broader implications for the neurobiology of disease. We found that miR-155 plays an essential role in interferon expression after CCI and that miR-155 contributes to TBI induced anxiety, potentially through regulation of interferons. Expression of miR-155 was identified in neuronal nuclei, suggesting additional roles for miR-155 in the neuronal response to injury that may be outside of traditional gene silencing. Similarly, we found that miR-21 was also expressed in neurons. In addition, miR-21 levels were elevated in extracellular vesicles (EVs). Novel roles have recently been elucidated for miRNAs carried in EVs, including stimulation of toll-like receptor 7/8 (TLR 7/8). We identified 3 differentially expressed EV-associated miRNAs with motifs known to mediate TLR 7/8 binding. This suggests that EV-associated miRNAs may act as damage associated molecular patterns (DAMPs) in TBI. Overall, we have identified multiple potential roles for miRNA in TBI that warrant further study.

In other studies we found that neurotrophic cytokines IL-6 and CNTF could elicit both Stat3 phosphorylation and miR-21 induction in human neurons, providing a possible mechanism for miR-21 induction in many models of neuronal injury. Additionally, we identified disinhibition and hyperactivity as chronic phenotypes of a mouse model of TBI. This finding will allow for future mechanistic studies of TBI induced impulsivity.

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