Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item CORTICAL AND STRIATAL MECHANISMS OF VALUE-BASED DECISION-MAKING AND THEIR DISRUPTION IN ADDICTION(2022) Hadfield, Heather; Roesch, Matthew R; Neuroscience and Cognitive Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)For decisions both great and small, the brain utilizes an extensive network that integrates value assessment, reward prediction, and motivation to quickly and efficiently select the most beneficial option while minimizing aversive consequences for ourselves. Numerous psychiatric conditions, in particular drug addiction, can disrupt this network and impair decision-making behavior. It is therefore important to understand the neural underpinnings of decision-making and how neural activity and its associated behavior are disrupted by drugs of abuse. My dissertation will expand on current studies of this circuitry by examining epigenetic and neurophysiological mechanisms of value-based decision-making within two regions of the brain. In my final aim, I explore a new behavioral assay that may be used to study these and other regions relevant for value-based decision-making in the context of another complex behavior.In my first aim, I have recorded from single neurons in the rat dorsal lateral striatum (DLS) after overexpressing histone deacetylase 5 (HDAC5), an epigenetic enzyme implicated in incubation of craving, in the dorsal striatum (DS). In my second aim I used pharmacological lesion and single-neuron recording combined with cocaine self-administration techniques to study anterior insula, a region well-known for combining internal and external experience but largely under-studied in the context of higher cognitive processes. These studies were conducted while rats performed an odor-guided decision-making task in which the value of rewards were manipulated by either the delay to or the size of the reward across a series of trial blocks. I have found overexpression of HDAC5 in DS promoted inflexible, faster, and automatic behavior in the decision-making task while increasing DLS’s response to reward cues- similar to previous studies examining DLS activity and behavior after cocaine self-administration. In my studies of insula, I found recording from this region novel, global signals of reward value that seemed to reflect the overall structure of the behavioral task. Following cocaine-exposure, these signals were diminished while immediate rewards were over-represented on a trial-by-trial basis, leading to steeper discounting of delayed rewards. Additional studies lesioning this region promoted faster reaction times and increased goal-directed behavior. Together, these results provide insights into how drugs of abuse may impair behavioral flexibility and the tracking of long-term changes in reward from multiple mechanisms. However, it is still unknown how these changes in value assessment give rise to complex impairments of behavior. As a first step to addressing this issue, I used a new task to examine how chronic drug use- which disrupts both neural signals in the corticostriatal circuit and epigenetic enzymes- also impairs the complex ability to delay gratification. This final study replicated well-established findings of drug-induced reversal-learning impairment, but surprisingly did not alter decision-making. This collection of work demonstrates the complexity with which drug exposure alters neural circuitry and value-based decision-making, and additionally shows the importance of utilizing complex behavioral assays to explore the relationship between brain and behavior.Item Chromatin Control of Papillomavirus Infection(2020) Porter, Samuel Stephen; McBride, Alison A; Molecular and Cell Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The genomes of papillomaviruses are packaged into chromatin throughout the entire viral lifecycle. A peculiar feature of papillomaviruses genome organization is that the viral DNA is associated with host histones even inside the virion particle. However, little is known about the nature of the epigenome within papillomavirions, or its biological impact on early infection. Here, we use three approaches to study the epigenome of papillomavirions. Papillomaviruses can be assembled in packaging cells by expression of the capsid proteins in the presence of the viral genome. We have optimized and manipulated this process to generate viruses with replicated and genetically modified virion DNA and have used these “quasivirions” to evaluate early infection of primary human keratinocytes. We have also profiled the histone modifications on chromatin extracted from native virions isolated from human and bovine warts. We find that, compared to host cells, the viral chromatin is enriched in histone modifications associated with transcriptionally active chromatin (including histone acetylation), and depleted in those associated with transcriptional repression. To examine the biological role of histone acetylation in the early virus lifecycle, we produced HPV quasivirions with highly acetylated chromatin by assembling the virions in cells treated with histone deacetylase inhibitors. We show that acetylation of viral chromatin results in a reduction of early viral transcription in primary keratinocytes indicating that the histone modifications on virion chromatin do influence the early stages of infection. Collectively, these studies demonstrate that histone modifications on virion chromatin are important for the HPV infectious cycle.Item Epigenetics of Neurodegeneration: Quantification of Histone Deacetylase Isoforms and Post-translational Modifications of Histones in Alzheimer’s Disease(2015) Anderson, Kyle; Fenselau, Catherine; Turko, Illarion V; Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Histone post-translational modifications have been implicated in many biological functions and diseases and serve an important role in epigenetic regulation of gene expression. Aberrant modulations in histone post-translational have been suggested to occur in the brain as part of Alzheimer’s disease (AD) pathology, consistent with the epigenetic blockade of neurodegeneration. This dissertation details the development and optimization of unique protein standards for quantification, called quantification concatamers, for the absolute quantification of histone deacetylase isoforms in human frontal cortex with AD, human neural retina with AD and age-related macular degeneration, and whole brain hemisphere of a 5XFAD mouse model of AD. Histone deacetylases are enzymes responsible for the deacetylation of histones, which can directly regulate transcription, and have been implicated in AD pathology. In addition to measuring isoforms of histone-modifying enzymes, measurements of post-translational modifications on histones were also obtained for whole hemispheres of brain from 5XFAD mice and frontal cortex from human donors affected with AD. For the changes in post-translational modifications observed, structural mechanisms were proposed to explain alterations in the DNA-histone affinity in the nucleosome, which can modulate gene expression. Measurements and structural mechanisms were consistent with the global decrease in gene expression observed in AD, which supports the data. This body of work aims to better elucidate the epigenetic pathology of AD and to aid in identification of histone-modifying enzymes involved in AD pathology for drug targets and treatment options. Currently, there are no treatments that prevent, delay, or ameliorate AD, stressing the crucial importance of AD pathology research and the promise of epigenetics as the solution.