DOI
https://doi.org/10.25772/9PFE-5825
Author ORCID Identifier
0000-0003-1455-0065
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Pamela E Knapp
Abstract
HIV-associated neurocognitive disorders remain pervasive even with increased efficacy/use of antiretroviral therapies. Opioid use/abuse among HIV+ individuals is documented to exacerbate deficits. White matter (WM) alterations (myelin pallor, volume/structural) detected by diffusion tensor imaging, are common observations in HIV+ individuals. Using transgenic mice expressing HIV-1 Tat, we examined effects of 2-6 weeks of Tat/morphine exposure on WM using genomic/biochemical methods. RNA sequencing of striatal tissue after 2-weeks revealed robust changes in mRNAs associated with oligodendrocyte populations/myelin integrity, including Transferrin, Ndrg1, and myelin regulatory factor (Myrf/Mrf), an oligodendrocyte-specific transcription factor involved in differentiation/maturation. Immunoblots conducted after 6-weeks exposure in 3 brain regions (striatum, corpus callosum, and pre-frontal cortex) revealed regionally varied effects of Tat/morphine on Myrf, and myelin basic protein (MBP) levels, whose transcription is partially regulated by Myrf. Responses included individual and interactive effects. Although baseline and post-treatment levels of Myrf and MBP differed regionally, MBP levels within striatum and pre-frontal cortex were compatible with respective Myrf changes. Additionally, Myrf regulatory protein Fbxw7 was altered at 6-weeks. Purified oligodendrocyte-precursor cell (OPC) cultures were treated with Tat, morphine, and naloxone to assess direct affects. Tat/morphine had no direct effects on expression of target genes (Myrf, Mbp, Fbxw7, Hes5). Significant naloxone effects (decrease) were observed on Hes5, Mbp, and Pdyn. Treatment with specific opioid receptor antagonists identified strong affects through kappa/delta opioid receptor antagonism. Together this establishes novel targets Fbxw7, Myrf, notch signaling (Hes5). Culture results suggest Tat/morphine effects are mediated indirectly through stimulation of endogenous opioid signaling.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-5-2023