Author ORCID Identifier


Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Dr. Jennifer Wolstenholme


Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant changes to myelination within the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36) and histone 3 lysine 9 (H3K9), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesized that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. H3K9me3 is a repressive histone mark that has been shown to play a significant role in the maturation of oligodendrocytes. We hypothesized that dysregulation of this mark could be associated with myelin deficits seen after adolescent binge ethanol treatment. To investigate this at the molecular level, ethanol (4 g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same prefrontal cortex tissue to determine gene expression changes and identify genes and loci where H3K36me3 or H3K9me3 were disrupted by ethanol. Lastly, we aimed to manipulate levels of brain methylation to determine whether we could prevent changes to histone methylation and therefore, cognitive deficits. While our methionine manipulation experiments were inconclusive, our RNA-sequencing and ChIP-sequencing experiments showed that adolescent binge ethanol disrupted the expression and regulation of synaptic-related genes. These experiments provide preliminary evidence that ethanol-induced changes to H3K36me3 and H3K9me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level. The occurrence of synaptic dysfunction during a critical period of PFC neurodevelopment may underlie the lasting behavioral changes caused by exposure to ethanol during adolescence.


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Available for download on Saturday, April 29, 2028