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Title:Quantifying effects of aging across structures of the mouse auditory system, with in-vitro brain slice preparations
Author(s):Stebbings, Kevin A.
Director of Research:Llano, Daniel A
Doctoral Committee Chair(s):Llano, Daniel A
Doctoral Committee Member(s):Rhodes, Justin S; Wickesberg, Robert E; Woods, Jeffrey A
Department / Program:Neuroscience Program
Discipline:Neuroscience
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):aging
auditory
mitochondria
hippocampus
redox
imaging
Abstract:Aging is a process fundamentally different from those studied by most scientists. Whereas in the course of most scientific inquiry, engineers or scientists attempt to create order or elucidate how its complexity arises, aging is the study of precisely the opposite. How order decays, how and with what efficacy it resists the decay, where its decay deviates from chaos and stochasticity; these are the core questions of aging. In the following work, I look at the intersection of aging, the auditory system, and metabolism. The first section of this work deals with aging in the auditory system, the most salient and defining feature of which is hearing loss. Although hearing loss may be primary, hearing requires central brain structures, not just the ear. These central structures are themselves sensitive to the process of aging and their attempts to compensate for peripheral loss combined with their own changes are not always successful in maintaining proper hearing. Our work attempts to disentangle the effects of hearing loss and age on a specific brain region, the auditory cortex, by using a brain slice preparation which partially isolates it from the potential influences of other auditory structures. We show through a combination of electrical activation, flavoprotein imaging, and redox imaging, that the levels of inhibition and rate-level functions are altered in the auditory cortex with age and that these differences were not likely due to differences in brain slice health. We also found that the primary driver of this effect was chronological age rather than hearing. The second study examines a highly conspicuous effect of an increase in redox potential in particular regions of the hippocampus in old animals which was noticed quite by accident in the first study and which ultimately prevented blinding by age group. We quantify this effect and show its specificity not only between brain areas, but to certain regions of the hippocampus. We then look at the association between it and other metrics that may be related to aging such as hearing ability, cortical thickness, and body weight to see if these other metrics, which may incorporate some level of information relating to internal health status, can predict redox status in the brain. We found that in old animals with lower body weights, the redox potential in their hippocampi is elevated beyond their chronological age. In our final study, we again treated the redox potential in the hippocampus as a marker of aging in the brain and used it to test if increased mitochondrial dysfunction would accelerate brain aging. The mitochondrial theory of aging has been a predominating model for decades and hypothesizes a common metabolic cause to all aging processes. The PolG mouse model was created by earlier investigators to test this hypothesis by generating an increased rate of mitochondrial DNA mutations, resulting in increased and diffuse mitochondrial dysfunction. This model ultimately showed an advanced aging phenotype with many defining features of aging such as hearing, weight, and hair loss and a lifespan approximately half that of normal animals. Since few if any indicators had been examined in the brain of this model, we chose to look at the redox status in the hippocampus as a marker of brain aging to assess whether brain aging in this model was commensurate with body aging. We show that although PolG mice undergo weight loss and splenic enlargement, preceding early death, as previously discovered, their rate and level of brain aging as measured by hippocampal redox status and other indicators of aging, is not accelerated. Along these metrics, PolG mice look exactly like their wild-type counterparts with no evidence at all of advanced aging. These results suggest that different tissues of the body may not have the same sensitivity to increasing mitochondrial DNA mutation load, specifically that the brain may have a lower sensitivity, which may be contrary to a base assumption that most investigators might have. These studies in many ways rediscover the well-known difficulties of studying the various processes of aging, which mostly tend to change together. Nevertheless, all the studies show the powerful effect of simple chronological age across a wide range of variables. The final study shows, however, that it is possible to separate certain processes of aging and specifically test certain hypothesis. Taken with other results in the PolG model of aging, we show that aging processes driven ultimately by increased mitochondrial mutation rates may be differentially reflected in different tissues of the body. Specifically, the brain may, in fact, be less sensitive to mitochondrial dysfunction despite its high rate of metabolism.
Issue Date:2018-08-15
Type:Thesis
URI:http://hdl.handle.net/2142/101833
Rights Information:Copyright 2018 Kevin Stebbings
Date Available in IDEALS:2018-09-27
Date Deposited:2018-08


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