All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

Adam R Wende

Jane B Allendorfer

Marcas Bamman

Rita Cowell

Lawrence Ver Hoef

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Temporal lobe epilepsy (TLE) is a neurological disease marked by recurring unprovoked seizures originating from temporal lobe structures and is frequently associated with cognitive deficits. Exercise holds promise as a therapeutic approach to alleviate seizures and cognitive impairments in TLE. However, the exact cellular and molecular mechanisms by which exercise influences pathways related to seizure activity and cognition in the context of TLE still need to be understood. Neuronal network formation relies on the regulation of gene expression, which can lead to either an increase or a decrease in the production of essential proteins involved in neuronal signaling. Genes are actively regulated through epigenetic mechanisms such as DNA methylation (DNAme), histone modifications, and noncoding RNAs, impacting transcription to form neuronal networks. Using a rodent model of TLE induced by kainic acid (KA), this dissertation investigated the role of DNAme and single-cell transcriptomics in the context of TLE and improved cognition in response to aerobic exercise. A 4-week aerobic exercise intervention resulted in an exercise-specific decrease in serum Brain-Derived Neurotrophic Factor (BDNF) levels and increases in serum Interleukin-6 (IL-6) levels. Measuring the two primary forms of DNAme, 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC), aerobic exercise resulted in altered whole blood bulk DNAme 5-hmC levels in TLE. Notably, in response to aerobic exercise, there was a decrease in 5-hmC levels in the epileptic hippocampal area CA3, particularly in neurons. Ten-eleven translocation proteins (TET) are dioxygenases that oxidize 5-mC into 5-hmC; mainly, TET1 expression is a potential mediator for these changes. Furthermore, the aerobic exercise intervention improved cognitive performance in TLE measured by contextual fear conditioning. Notably, the single-nuclei RNA sequencing (snRNA-seq) transcriptomic analysis in TLE revealed that most differential gene expression (DGE) was limited to excitatory neurons and microglia. However, the 4-week exercise intervention impacted different DGEs, mostly in excitatory neurons. Ultimately, this research seeks to bridge the gap between the cellular and molecular aspects of TLE, specifically as it relates to improved cognition in response to aerobic exercise for therapeutic strategies that can enhance the quality of life for individuals affected by this disease.

Available for download on Thursday, June 27, 2024

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