Theses and Dissertations at Montana State University (MSU)
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Item Analysis of transport in the brain(Montana State University - Bozeman, College of Engineering, 2021) Ray, Lori Ann; Chairperson, Graduate Committee: Jeffrey Heys; Jeffrey J. Heys was a co-author of the article, 'Fluid flow and mass transport in brain tissue: a literature review' in the journal 'Fluids' which is contained within this dissertation.; Jeffrey J. Iliff and Jeffrey J. Heys were co-authors of the article, 'Analysis of convective and diffusive transport in the brain interstitium' in the journal 'Fluids and barriers of the CNS' which is contained within this dissertation.; Martin Pike, Jeffrey J. Iliff and Jeffrey J. Heys were co-authors of the article, 'Quantification of transport in the whole mouse brain' which is contained within this dissertation.Neurodegeneration is one of the most significant medical challenges facing our time, yet the gap between therapies and understanding of the inner workings of the brain is great. Impairment of waste clearance has been identified as one key underlying factor in the vulnerability of the brain to neurodegeneration, stimulating research towards understanding transport of molecules in the brain. Based on experimental findings, a unique-to-the-brain circulation has been proposed, the glymphatic system, where cerebrospinal fluid surrounding the brain moves into the brain along the periarterial space that surrounds cerebral arteries, flows through the interstitial space between brain cells, where cellular wastes reside, and carries waste out of the brain tissue along perivenous routes. However, current gaps in knowledge about the driving force for fluid flow have generated scientific skepticism, and an independent method for quantifying transport and demonstrating the presence or absence of convection is desirable. In this work, computational transport models are developed and used to analyze published experimental data to determine fundamental transport parameters for different aspects of the glymphatic circulation. Calculated transport parameters are compared to the known diffusivity of tracers through brain tissue to draw conclusions about the presence and significance of bulk flow, or convection. Based on these analyses, transport in the periarterial spaces surrounding major arteries is over 10,000 times faster than diffusion and in brain tissue, containing both periarterial and interstitial space, transport is around 10 times faster than diffusion alone (for characteristic transport lengths around 1 mm). Interstitial velocity is determined to be on the order of 0.01 mm/min, making convection in the interstitial spaces of the brain critical to the transport of large, slow-to-diffuse molecules implicated in neurodegeneration. Convection is demonstrated to be a significant mechanism of transport throughout the brain. Observations and analyses from this work contribute further evidence to a circulatory-like system in the brain with relatively rapid convection along periarterial space, branching throughout the brain tissue and slower convection across that tissue, in the interstitial spaces of the brain. Transport models developed in this work are demonstrated to be useful tools for gleaning further information from experimental data.Item Regarding policy in chronic traumatic encephalopathy as a transhistoric disorder(Montana State University - Bozeman, College of Letters & Science, 2019) Negri, Adam Christopher; Chairperson, Graduate Committee: Michael ReidyAn individual historian can be categorized as belonging to one of two mutually exclusive and exhaustive groups: transhistoricists, those that believe in an object's existence independent of external forces and its ability to remain fundamentally unaffected across time, or culturalists, believing an object's quality or features are dependent on the time and place of its reference. Disease entities have been examined through both perspectives quite fruitfully, expanding the whole of academia's appreciation of the relationship between disease and history. However, chronic traumatic encephalopathy, or CTE, has recently been embroiled in a nationwide National Football League scandal wherein the livelihood of many affected retired players depends on the court's decision in the accompanying tort case to deal out appropriate justice. The nosological understanding of CTE is crucial in the debate - to include all affected players, despite dramatic revisions in our understanding of CTE as a disease across the 20th-century, all parties must recognize CTE, originating in a 1928 case study as 'punch drunk syndrome,' as a timeless entity that has undergone progressive iterations in categorization. In this instance, the culturalist perspective would render the disease's history sufficiently fragmented and prevent a cohesive narrative that includes all manner of diagnostic varieties. Even if antithetical to the present state of the humanities, the transhistoric approach is the only satisfactory perspective to uphold justice in the case of suffering football players.Item Determining function of the IKAP protein in the peripheral nervous system for targeted therapeutic intervention in familial dysautonomia(Montana State University - Bozeman, College of Letters & Science, 2017) Ohlen, Sarah Beth; Chairperson, Graduate Committee: Frances Lefcort; Magdalena L. Russell, Michael J. Brownstein and Frances Lefcort were co-authors of the article, 'BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia' in the journal 'Proceedings of the National Academy of Sciences' which is contained within this thesis.Familial Dysautonomia (FD) is a recessive genetic disorder that leads to devastation of the peripheral nervous system and is the result of incomplete neurodevelopment and progressive neurodegeneration. The disorder is also marked by a continual loss of retinal ganglion cells that leads to blindness. Even with early identification and treatment, the disorder is ultimately fatal. FD is caused by mutation in the IKBKAP gene that leads to cell-type specific loss of the IKAP protein, also known as ELP1. IKAP functions as a part of the six-unit Elongator complex. The role of Elongator is unresolved, although data has accumulated that support Elongator function in tRNA modification and efficient translation of proteins and that its absence leads to cell stress and neurological impairment. We have a mouse model of FD in which mouse Ikbkap is deleted from the peripheral nervous system, and it recapitulates the death of autonomic and TrkA+ sensory neurons observed in FD patients. As we can culture TrkA+ neurons in vitro, while also studying this neuronal population in vivo, we have a system to investigate our goals of (1) determining cellular processes that go awry in absence of Ikap and (2) targeting these cell types and events to prevent their progressive death. We have determined that mitochondrial and cytoskeletal function are disrupted in Ikbkap -/-, TrkA+ neurons and show activation of stress signaling. Interestingly, disrupted mitochondrial function is an emerging hallmark common to most neurodegenerative diseases. We have identified that the compound, BGP-15, is able to restore aspects of mitochondrial function and stress signaling in vitro and can restore neuronal survival of TrkA+ neurons lacking Ikap in vitro and in vivo. BGP-15 also improves actin cytoskeletal function and target innervation. Additionally, we have determined that introduction of the C-terminal half of human IKAP is sufficient to increase neuronal survival in vitro. This smaller protein fragment is compatible with viral delivery to retinal ganglion cells and could be utilized for gene therapy, potentially preventing this neuronal death that lead to blindness. Our goals now are to further explore stress pathways common to many neurodegenerative disorders and optimize rescue strategies in vivo.Item Olfactory behavior as an indicator of prion infection(Montana State University - Bozeman, College of Letters & Science, 2011) Williams, Nikolas Scott; Chairperson, Graduate Committee: A. Michael BabcockThe current project sought to identify changes in olfactory-related behavior in hamsters infected with the HY transmissible mink encephalopathy (HY TME) strain of the pathological form of the prion protein. Experiment 1 was conducted to validate an olfactory preference paradigm for use with Syrian golden hamsters. An experimental group was induced with anosmia by treating them with methimazole. In an olfactory preference test in which the time subjects spent investigating attractive, aversive, and neutral olfactory stimuli were assessed, control animals spent a significantly longer amount of time investigating the attractive versus aversive scents. The methimazole-treated group did not demonstrate this pattern. Experiment 2 investigated changes in olfactory behavior as a result of prion infection. A group of hamsters was infected with HY TME and subjected to olfactory preference testing at four time points: 20, 40, 60, and 80 days post inoculation. In addition, parallel subjects were sacrificed and submitted to immunohistochemical analysis in order to examine the proliferation of HY TME throughout olfactory-related brain structures with the intention of relating behavioral changes to the progression of prion infection. Results indicated that HY TME subjects lost their ability to perceive the attractive scent early in the disease. However, avoidance of the aversive scent was retained until much later. The immunohistochemistry revealed an initial appearance of the pathologic prion at 20 days post inoculation in the glomeruli of the olfactory bulb. Widespread infection throughout all olfactory structures was observed at 40 days post inoculation and beyond. These results suggested a differential sensory loss to the olfactory stimuli that may have been due to initial infection in the glomeruli and later infection in other olfactory structures. These findings support the utility of discrimination paradigms for the diagnosis of prion diseases.