ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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Description
Alzheimer's Disease (AD) is a debilitating neurodegenerative disease. The disease leads to dementia and loss of cognitive functions and affects about 4.5 million people in the United States. It is the 7th leading cause of death and is a huge financial burden on the healthcare industry. There are no means of diagnosing the disease before neurodegeneration is significant and sadly there is no cure that controls its progression. The protein beta-amyloid or Aâ plays an important role in the progression of the disease. It is formed from the cleavage of the Amyloid Precursor Protein by two enzymes - â and ã-secretases and is found in the plaques that are deposits found in Alzheimer brains. This work describes the generation of therapeutics based on inhibition of the cleavage by â-secretase. Using in-vitro recombinant antibody display libraries to screen for single chain variable fragment (scFv) antibodies; this work describes the isolation and characterization of scFv that target the â-secretase cleavage site on APP. This approach is especially relevant since non-specific inhibition of the enzyme may have undesirable effects since the enzyme has been shown to have other important substrates. The scFv iBSEC1 successfully recognized APP, reduced â-secretase cleavage of APP and reduced Aâ levels in a cell model of Alzheimer's Disease. This work then describes the first application of bispecific antibody therapeutics to Alzheimer's Disease. iBSEC1 scFv was combined with a proteolytic scFv that enhances the "good" pathway (á-secretase cleavage) that results in alternative cleavage of APP to generate the bispecific tandem scFv - DIA10D. DIA10D reduced APP cleavage by â-secretase and steered it towards the "good" pathway thus increasing the generation of the fragment sAPPá which is neuroprotective. Finally, treatment with iBSEC1 is evaluated for reduced oxidative stress, which is observed in cells over expressing APP when they are exposed to stress. Recombinant antibody based therapeutics like scFv have several advantages since they retain the high specificity of the antibodies but are safer since they lack the constant region and are smaller, potentially facilitating easier delivery to the brain
ContributorsBoddapati, Shanta (Author) / Sierks, Michael (Thesis advisor) / Arizona State University (Publisher)
Created2011
Description
Libertarians affirm the right to liberty, i.e., the right to do what one wants free from interference. Libertarians also affirm the right to private property. One objection to libertarianism is that private property relations restrict liberty. This objection appears to have the consequence that libertarianism is an incoherent position. I examine Jan Narveson's version of the libertarian view and his defense of its coherence. Narveson understands the right to liberty as a prohibition on the initiation of force. I argue that if that is what the right to liberty is, then the enforcement of property rights violates it. I also examine Narveson's attempt to support private property with his distinction between interference with and mere prevention of activity and argue that this distinction does not do the work that he needs it to do. My conclusion is that libertarianism is, in a sense, impossible because conceptually unsound.
ContributorsSchimke, Christopher (Author) / de Marneffe, Peter (Thesis advisor) / McGregor, Joan (Committee member) / Blackson, Thomas (Committee member) / Arizona State University (Publisher)
Created2011
Description
Neurostimulation methods currently include deep brain stimulation (DBS), optogenetic, transcranial direct-current stimulation (tDCS), and transcranial magnetic stimulation (TMS). TMS and tDCS are noninvasive techniques whereas DBS and optogenetic require surgical implantation of electrodes or light emitting devices. All approaches, except for optogenetic, have been implemented in clinical settings because they have demonstrated therapeutic utility and clinical efficacy for neurological and psychiatric disorders. When applied for therapeutic applications, these techniques suffer from limitations that hinder the progression of its intended use to treat compromised brain function. DBS requires an invasive surgical procedure that surfaces complications from infection, longevity of electrical components, and immune responses to foreign materials. Both TMS and tDCS circumvent the problems seen with DBS as they are noninvasive procedures, but they fail to produce the spatial resolution required to target specific brain structures. Realizing these restrictions, we sought out to use ultrasound as a neurostimulation modality. Ultrasound is capable of achieving greater resolution than TMS and tDCS, as we have demonstrated a ~2mm lateral resolution, which can be delivered noninvasively. These characteristics place ultrasound superior to current neurostimulation methods. For these reasons, this dissertation provides a developed protocol to use transcranial pulsed ultrasound (TPU) as a neurostimulation technique. These investigations implement electrophysiological, optophysiological, immunohistological, and behavioral methods to elucidate the effects of ultrasound on the central nervous system and raise questions about the functional consequences. Intriguingly, we showed that TPU was also capable of stimulating intact sub-cortical circuits in the anesthetized mouse. These data reveal that TPU can evoke synchronous oscillations in the hippocampus in addition to increasing expression of brain-derived neurotrophic factor (BDNF). Considering these observations, and the ability to noninvasively stimulate neuronal activity on a mesoscale resolution, reveals a potential avenue to be effective in clinical settings where current brain stimulation techniques have shown to be beneficial. Thus, the results explained by this dissertation help to pronounce the significance for these protocols to gain translational recognition.
ContributorsTufail, Yusuf Zahid (Author) / Tyler, William J (Thesis advisor) / Duch, Carsten (Committee member) / Muthuswamy, Jitendran (Committee member) / Santello, Marco (Committee member) / Tillery, Stephen H (Committee member) / Arizona State University (Publisher)
Created2011
Description
Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used.
ContributorsCole, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Thesis advisor) / Bimonte-Nelson, Heather A. (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2011
Description
Patients with Alzheimer's disease (AD) exhibit a significantly higher incidence of unprovoked seizures compared to age-matched non-AD controls, and animal models of AD (i.e., transgenic human amyloid precursor protein, hAPP mice) display neural hyper-excitation and epileptic seizures. Hyperexcitation is particularly important because it contributes to the high incidence of epilepsy in AD patients as well as AD-related synaptic deficits and neurodegeneration. Given that there is significant amyloid-β (Aβ) accumulation and deposition in AD brain, Aβ exposure ultimately may be responsible for neural hyper-excitation in both AD patients and animal models. Emerging evidence indicates that α7 nicotinic acetylcholine receptors (α7-nAChR) are involved in AD pathology, because synaptic impairment and learning and memory deficits in a hAPPα7-/- mouse model are decreased by nAChR α7 subunit gene deletion. Given that Aβ potently modulates α7-nAChR function, that α7-nAChR expression is significantly enhanced in both AD patients and animal models, and that α7-nAChR play an important role in regulating neuronal excitability, it is reasonable that α7-nAChRs may contribute to Aβ-induced neural hyperexcitation. We hypothesize that increased α7-nAChR expression and function as a consequence of Aβ exposure is important in Aβ-induced neural hyperexcitation. In this project, we found that exposure of Aβ aggregates at a nanomolar range induces neuronal hyperexcitation and toxicity via an upregulation of α7-nAChR in cultured hippocampus pyramidal neurons. Aβ up-regulates α7-nAChRs function and expression through a post translational mechanism. α7-nAChR up-regulation occurs prior to Aβ-induced neuronal hyperexcitation and toxicity. Moreover, inhibition of α7-nAChR or deletion of α7-nAChR prevented Aβ induced neuronal hyperexcitation and toxicity, which suggests that α7-nAChRs are required for Aβ induced neuronal hyperexcitation and toxicity. These results reveal a profound role for α7-nAChR in mediating Aβ-induced neuronal hyperexcitation and toxicity and predict that Aβ-induced up-regulation of α7-nAChR could be an early and critical event in AD etiopathogenesis. Drugs targeting α7-nAChR or seizure activity could be viable therapies for AD treatment.
ContributorsLiu, Qiang (Author) / Wu, Jie (Thesis advisor) / Lukas, Ronald J (Committee member) / Chang, Yongchang (Committee member) / Sierks, Michael (Committee member) / Smith, Brian (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2011
Description
Systemic lupus erytematosus (SLE) is an autoimmune disease where the immune system is reactive to self antigens resulting in manifestations like glomerulonephritis and arthritis. The immune system also affects the central nervous system (known as CNS-SLE) leading to neuropsychiatric manifestations such as depression, cognitive impairment, psychosis and seizures. A subset of pathogenic brain-reactive autoantibodies (BRAA) is hypothesized to bind to integral membrane brain proteins, affecting their function, leading to CNS-SLE. I have tested this BRAA hypothesis, using our lupus-mouse model the MRL/lpr mice, and have found it to be a reasonable explanation for some of the manifestations of CNS-SLE. Even when the MRL/lpr had a reduced autoimmune phenotype, their low BRAA sera levels correlated with CNS involvement. The correlation existed between BRAA levels to integral membrane protein and depressive-like behavior. These results were the first to show a correlation between behavioral changes and BRAA levels from brain membrane antigen as oppose to cultured neuronal cells. More accurate means of predicting and diagnosing lupus and CNS-SLE is necessary. Using microarray technology I was able to determine peptide sets that could be predictive and diagnostic of lupus and each specific CNS manifestation. To knowledge no test currently exists that can effectively diagnose lupus and distinguish between each CNS manifestations. Using the peptide sets, I was able to determine possible natural protein biomarkers for each set as well as for five monoclonal BRAA from one MRL/lpr. These biomarkers can provide specific targets for therapy depending on the manifestation. It was necessary to investigate how these BRAA enter the brain. I hypothesized that substance P plays a role in altering the blood-brain barrier (BBB) allowing these BRAA to enter and affect brain function, when bound to its neurokinin-1 receptor (NK-1R). Western blotting results revealed an increase in the levels of NK-1R in the brain of the MRL/lpr compared to the MRL/mp. These MRL/lpr with increased levels of both NK-1R and BRAA displayed CNS dysfunction. Together, these results demonstrate that NK-1R may play a role in CNS manifestations. Overall, the research conducted here, add to the role that BRAA are playing in CNS-lupus.
ContributorsWilliams, Stephanie (Author) / Hoffman, Steven A (Thesis advisor) / Conrad, Cheryl (Committee member) / Chen, Julian (Committee member) / Orchinik, Miles (Committee member) / Arizona State University (Publisher)
Created2011
Description
Cognitive function is multidimensional and complex, and research indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogen-facilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory. Collectively, this dissertation elucidates many parameters that dictate the outcome, and even the direction, of the effects that cognitive practice and estrogens have on cognition during aging. Indeed, many parameters including the ones described here are important considerations when designing future putative behavioral interventions, behavioral therapies, and hormone therapies. Ideally, the parameters described here will be used to help design the next generation of interventions, therapies, and nootropic agents that will allow individuals to maintain their cognitive capacity when aged, above and beyond what is currently possible, thus enacting lasting improvement in women's health and public health in general.
ContributorsTalboom, Joshua S (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / West, Stephen G. (Committee member) / Arizona State University (Publisher)
Created2011
Description
An accurate sense of upper limb position is crucial to reaching movements where sensory information about upper limb position and target location is combined to specify critical features of the movement plan. This dissertation was dedicated to studying the mechanisms of how the brain estimates the limb position in space and the consequences of misestimation of limb position on movements. Two independent but related studies were performed. The first involved characterizing the neural mechanisms of limb position estimation in the non-human primate brain. Single unit recordings were obtained in area 5 of the posterior parietal cortex in order to examine the role of this area in estimating limb position based on visual and somatic signals (proprioceptive, efference copy). When examined individually, many area 5 neurons were tuned to the position of the limb in the workspace but very few neurons were modulated by visual feedback. At the population level however decoding of limb position was somewhat more accurate when visual feedback was provided. These findings support a role for area 5 in limb position estimation but also suggest that visual signals regarding limb position are only weakly represented in this area, and only at the population level. The second part of this dissertation focused on the consequences of misestimation of limb position for movement production. It is well known that limb movements are inherently variable. This variability could be the result of noise arising at one or more stages of movement production. Here we used biomechanical modeling and simulation techniques to characterize movement variability resulting from noise in estimating limb position ('sensing noise') and in planning required movement vectors ('planning noise'), and compared that to the variability expected due to noise in movement execution. We found that the effects of sensing and planning related noise on movement variability were dependent upon both the planned movement direction and the initial configuration of the arm and were different in many respects from the effects of execution noise.
ContributorsShi, Ying (Author) / Buneo, Christopher A (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Santello, Marco (Committee member) / He, Jiping (Committee member) / Santos, Veronica (Committee member) / Arizona State University (Publisher)
Created2011
Description
This dissertation puts forth an account of moral responsibility. The central claim defended is that an agent's responsibility supervenes on the agent's mental states at the time of the action. I call the mental states that determine responsibility the agent's quality of will (QOW). QOW is taken to concern the agent's action, understood from an internal perspective, along with the agent's motivations, her actual beliefs about the action, and the beliefs she ought to have had about the action. This approach to responsibility has a number of surprising implications. First, blameworthiness can come apart from wrongness, and praiseworthiness from rightness. This is because responsibility is an internal notion and rightness and wrongness are external notions. Furthermore, agents can only be responsible for their QOW. It follows that agents cannot be responsible for the consequences of their actions. I further argue that one's QOW is determined by what one cares about. And the fact that we react to the QOW of others with morally reactive emotions, such as resentment and gratitude, shows that we care about QOW. The reactive attitudes can therefore be understood as ways in which we care about what others care about. Responsibility can be assessed by comparing one's actual QOW to the QOW one ought to have had.
ContributorsKhoury, Andrew (Author) / French, Peter A. (Thesis advisor) / Calhoun, Cheshire (Committee member) / Portmore, Douglas W. (Committee member) / Arizona State University (Publisher)
Created2011
Description
Given the success of science, weak forms of mind-brain dependence are commonly treated as uncontroversial within contemporary philosophies of mind. More controversial are the different metaphysical claims inferred from this dependence, many ascribing ontological priority to the brain. Consider the following three propositions: (i) neurological events are essentially identified by their role in material systems, laws, and causes that are constitutively non-rational; (ii) at least some mental events are essentially identified in virtue of their role in the use of reason; (iii) all mental events are realized by, identical to, or composed out of, neurological events. (i) is uncontroversial. However, (iii) is strictly materialistic. (i), (ii) and (iii) taken together appear incoherent. A fruitful task for philosophy is to resolve this apparent incoherence. In his 1997 book The Last Word Thomas Nagel offers an explication of reason that conceptually transcends the nature of material substrate. In his 2010 article "Modest Dualism" Tyler Burge offers reasons to think of propositional thought as irreducible to the concepts of the material sciences. Both focus on rationality as a unique form of intentionality. Both philosophers also reject materialism (iii). On their accounts it's reasonable to take 'rational intentionality' as exhibiting a logical priority of the mind with respect to the brain in inquiries into the nature of mind. Granting this, the diminished conception of mind presupposed by prevailing contemporary theories is seen to be the result of a more general failure to recognize the logical priority and intricate nature of rationality. The robust views of rationality expressed by Nagel and Burge constitute grounds for argument against even the weakest form of materialism. I develop such an argument in this thesis, showing that the propositional attitudes exhibited in thought and speech preclude all materialistic notions of mind. Furthermore, I take the nature of propositional attitudes to suggest a perspective for exploring the fundamental nature of mind, one that focuses not on composition but on rational powers.
ContributorsGoodrich, Gregory (Author) / Kobes, Bernard W (Thesis advisor) / White, Michael J. (Committee member) / Anderson, Owen (Committee member) / Arizona State University (Publisher)
Created2011