Theses and Dissertations
This collection includes both ASU Theses and Dissertations, submitted by graduate students, and the Barrett, Honors College theses submitted by undergraduate students.
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Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
Induced pluripotent stem cells (iPSCs) are an intriguing approach for neurological disease modeling, because neural lineage-specific cell types that retain the donors' complex genetics can be established in vitro. The statistical power of these iPSC-based models, however, is dependent on accurate diagnoses of the somatic cell donors; unfortunately, many neurodegenerative diseases are commonly misdiagnosed in live human subjects. Postmortem histopathological examination of a donor's brain, combined with premortem clinical criteria, is often the most robust approach to correctly classify an individual as a disease-specific case or unaffected control. We describe the establishment of primary dermal fibroblasts cells lines from 28 autopsy donors. These fibroblasts were used to examine the proliferative effects of establishment protocol, tissue amount, biopsy site, and donor age. As proof-of-principle, iPSCs were generated from fibroblasts from a 75-year-old male, whole body donor, defined as an unaffected neurological control by both clinical and histopathological criteria. To our knowledge, this is the first study describing autopsy donor-derived somatic cells being used for iPSC generation and subsequent neural differentiation. This unique approach also enables us to compare iPSC-derived cell cultures to endogenous tissues from the same donor. We utilized RNA sequencing (RNA-Seq) to evaluate the transcriptional progression of in vitro-differentiated neural cells (over a timecourse of 0, 35, 70, 105 and 140 days), and compared this with donor-identical temporal lobe tissue. We observed in vitro progression towards the reference brain tissue, supported by (i) a significant increasing monotonic correlation between the days of our timecourse and the number of actively transcribed protein-coding genes and long intergenic non-coding RNAs (lincRNAs) (P < 0.05), consistent with the transcriptional complexity of the brain, (ii) an increase in CpG methylation after neural differentiation that resembled the epigenomic signature of the endogenous tissue, and (iii) a significant decreasing monotonic correlation between the days of our timecourse and the percent of in vitro to brain-tissue differences (P < 0.05) for tissue-specific protein-coding genes and all putative lincRNAs. These studies support the utility of autopsy donors' somatic cells for iPSC-based neurological disease models, and provide evidence that in vitro neural differentiation can result in physiologically progression.
ContributorsHjelm, Brooke E (Author) / Craig, David W. (Thesis advisor) / Wilson-Rawls, Norma J. (Thesis advisor) / Huentelman, Matthew J. (Committee member) / Mason, Hugh S. (Committee member) / Kusumi, Kenro (Committee member) / Arizona State University (Publisher)
Created2013
Description
Alzheimer's Disease (AD) is a progressive neurodegenerative disease accounting for 50-80% of dementia cases in the country. This disease is characterized by the deposition of extracellular plaques occurring in regions of the brain important for cognitive function. A primary component of these plaques is the amyloid-beta protein. While a natively unfolded protein, amyloid-beta can misfold and aggregate generating a variety of different species including numerous different soluble oligomeric species some of which are precursors to the neurofibrillary plaques. Various of the soluble amyloid-beta oligomeric species have been shown to be toxic to cells and their presence may correlate with progression of AD. Current treatment options target the dementia symptoms, but there is no effective cure or alternative to delay the progression of the disease once it occurs. Amyloid-beta aggregates show up many years before symptoms develop, so detection of various amyloid-beta aggregate species has great promise as an early biomarker for AD. Therefore reagents that can selectively identify key early oligomeric amyloid-beta species have value both as potential diagnostics for early detection of AD and as well as therapeutics that selectively target only the toxic amyloid-beta aggregate species. Earlier work in the lab includes development of several different single chain antibody fragments (scFvs) against different oligomeric amyloid-beta species. This includes isolation of C6 scFv against human AD brain derived oligomeric amyloid-beta (Kasturirangan et al., 2013). This thesis furthers research in this direction by improving the yields and investigating the specificity of modified C6 scFv as a diagnostic for AD. It is motivated by experiments reporting low yields of the C6 scFv. We also used the C6T scFv to characterize the variation in concentration of this particular oligomeric amyloid-beta species with age in a triple transgenic AD mouse model. We also show that C6T can be used to differentiate between post-mortem human AD, Parkinson's disease (PD) and healthy human brain samples. These results indicate that C6T has potential value as a diagnostic tool for early detection of AD.
ContributorsVenkataraman, Lalitha (Author) / Sierks, Michael (Thesis advisor) / Rege, Kaushal (Committee member) / Pauken, Christine (Committee member) / Arizona State University (Publisher)
Created2013
Description
Speciation is the fundamental process that has generated the vast diversity of life on earth. The hallmark of speciation is the evolution of barriers to gene flow. These barriers may reduce gene flow either by keeping incipient species from hybridizing at all (pre-zygotic), or by reducing the fitness of hybrids (post-zygotic). To understand the genetic architecture of these barriers and how they evolve, I studied a genus of wasps that exhibits barriers to gene flow that act both pre- and post-zygotically. Nasonia is a genus of four species of parasitoid wasps that can be hybridized in the laboratory. When two of these species, N. vitripennis and N. giraulti are mated, their offspring suffer, depending on the generation and cross examined, up to 80% mortality during larval development due to incompatible genic interactions between their nuclear and mitochondrial genomes. These species also exhibit pre-zygotic isolation, meaning they are more likely to mate with their own species when given the choice. I examined these two species and their hybrids to determine the genetic and physiological bases of both speciation mechanisms and to understand the evolutionary forces leading to them. I present results that indicate that the oxidative phosphorylation (OXPHOS) pathway, an essential pathway that is responsible for mitochondrial energy generation, is impaired in hybrids of these two species. These results indicate that this impairment is due to the unique evolutionary dynamics of the combined nuclear and mitochondrial origin of this pathway. I also present results showing that, as larvae, these hybrids experience retarded growth linked to the previously observed mortality and I explore possible physiological mechanisms for this. Finally, I show that the pre-mating isolation is due to a change in a single pheromone component in N. vitripennis males, that this change is under simple genetic control, and that it evolved neutrally before being co-opted as a species recognition signal. These results are an important addition to our overall understanding of the mechanisms of speciation and showcase Nasonia as an emerging model for the study of the genetics of speciation.
ContributorsGibson, Joshua D (Author) / Gadau, Jürgen (Thesis advisor) / Harrison, Jon (Committee member) / Pratt, Stephen (Committee member) / Verrelli, Brian (Committee member) / Willis, Wayne (Committee member) / Arizona State University (Publisher)
Created2013
Description
Modified and artificial water sources can be used as a management tool for game and non-game wildlife species. State, federal, and private agencies allocate significant resources to install and maintain artificial water sources (AWS) annually. Capture mark recapture methods were used to sample small mammal communities in the vicinity of five AWS and five paired control sites (treatments) in the surrounding Sonoran desert from October 2011 to May 2012. I measured plant species richness, density, and percent cover in the spring of 2012. A Multi-response Permutation Procedure was used to identify differences in small mammal community abundance, biomass, and species richness by season and treatment. I used Principle Component Analysis to reduce 11 habitat characteristics to five habitat factors. I related rodent occurrence to habitat characteristics using multiple and logistic regression. A total of 370 individual mammals representing three genera and eight species of rodents were captured across 4800 trap nights. Desert pocket mouse (Chaetodipus penicillatus) was the most common species in both seasons and treatments. Whereas rodent community abundance, biomass, and richness were similar between seasons, community variables of AWS were greater than CS. Rodent diversity was similar between treatments. Desert pocket mouse abundance and biomass were twice as high at AWS when compared to controls. Biomass of white-throated woodrat (Neotoma albigula) was five times greater at AWS. Habitat characteristics were similar between treatments. Neither presence of water nor distance to water explained substantial habitat variation. Occurrence of rodent species was associated with habitat characteristics. Desert rodent communities are adapted for arid environments (i.e. Heteromyids) and are not dependent on "free water". Higher abundances of desert pocket mouse at AWS were most likely related to increased disturbance and debris and not the presence of water. The results of this study and previous studies suggest that more investigation is needed and that short term studies may not be able to detect interactions (if any) between AWS and desert small mammal communities.
ContributorsSwitalski, Aaron (Author) / Bateman, Heather L (Thesis advisor) / Miller, William (Committee member) / Alford, Eddie (Committee member) / Arizona State University (Publisher)
Created2013
Description
Niche variation among sexes and life stages within a population has been documented in many species, yet few studies have investigated niche variation within demographic groups or across ecological contexts. We examined the extent to which pregnant California sea lions (Zalophus californianus) at each of three breeding colonies target alternative prey resources and habitats. The three colonies are distributed across distinct regions of the Gulf of California, Mexico and have divergent population dynamics. We compared the nature of niche variation among colonies and investigated the fitness consequences of different foraging strategies within each colony. We analyzed the δ13C and δ15N values from fur collected from 206 suckling pups to characterize relative maternal foraging locations (δ13C) and trophic levels (δ15N) during the metabolically demanding late stages of gestation and lactation that occur simultaneously in California sea lions. The δ13C and δ15N values were regressed against pup body condition index values to compare the relative individual-level fitness benefits of different maternal foraging strategies. We found that the nature and extent of niche variation differed among colonies. Niche variation was most pronounced at the two largest colonies that appear to experience the highest levels of intraspecific competition and the variation was consistent with habitat features. One colony (Granito) displayed two distinct foraging groups with indistinguishable median pup body condition values, whereas the second (San Jorge) exhibited continuous niche variation and pup body condition varied in relation to maternal foraging location and trophic level, suggesting disparities among alternative foraging strategies. For the smallest colony (Los Islotes), females occupy similar niches with a few outliers. Body condition values of pups at this colony were most variable, but did not vary with maternal foraging strategy. Our results provide evidence for intrapopulation niche variation among demographically similar individuals during a period of high metabolic stress and reproductive importance. This work suggests possible fitness benefits conferred by alternative foraging strategies, and calls into question the common assumption that members of a population are ecologically equivalent. Future research aimed at understanding animal foraging strategies should consider the nature and extent of niche variation in the context of local ecological conditions.
ContributorsCrawford, Tara Gancos (Author) / Gerber, Leah R. (Thesis advisor) / Ogle, Kiona (Committee member) / Kurle, Carolyn M (Committee member) / Arizona State University (Publisher)
Created2013
Description
Synechocystis sp PCC 6803 is a photosynthetic cyanobacterium that can be easily transformed to produce molecules of interest; this has increased Synechocystis’ popularity as a clean energy platform. Synechocystis has been shown to produce and excrete molecules such as fatty acids, isoprene, etc. after appropriate genetic modification. Challenges faced for large–scale growth of modified Synechocystis include abiotic stress, microbial contamination and high processing costs of product and cell material. Research reported in this dissertation contributes to solutions to these challenges. First, abiotic stress was addressed by overexpression of the heat shock protein ClpB1. In contrast to the wild type, the ClpB1 overexpression mutant (Slr1641+) tolerated rapid temperature changes, but no difference was found between the strains when temperature shifts were slower. Combination of ClpB1 overexpression with DnaK2 overexpression (Slr1641+/Sll0170+) further increased thermotolerance. Next, we used a Synechocystis strain that carries an introduced isoprene synthase gene (IspS+) and that therefore produces isoprene. We attempted to increase isoprene yields by overexpression of key enzymes in the methyl erythritol phosphate (MEP) pathway that leads to synthesis of the isoprene precursor. Isoprene production was not increased greatly by MEP pathway induction, likely because of limitations in the affinity of the isoprene synthase for the substrate. Finally, two extraction principles, two–phase liquid extraction (e.g., with an organic and aqueous phase) and solid–liquid extraction (e.g., with a resin) were tested. Two–phase liquid extraction is suitable for separating isoprene but not fatty acids from the culture medium. Fatty acid removal required acidification or surfactant addition, which affected biocompatibility. Therefore, improvements of both the organism and product–harvesting methods can contribute to enhancing the potential of cyanobacteria as solar–powered biocatalysts for the production of petroleum substitutes.
ContributorsGonzalez Esquer, Cesar Raul (Author) / Vermaas, Willem (Thesis advisor) / Chandler, Douglas (Committee member) / Bingham, Scott (Committee member) / Nielsen, David (Committee member) / Arizona State University (Publisher)
Created2013
Description
Human activity has increased loading of reactive nitrogen (N) in the environment, with important and often deleterious impacts on biodiversity, climate, and human health. Since the fate of N in the ecosystem is mainly controlled by microorganisms, understanding the factors that shape microbial communities becomes relevant and urgent. In arid land soils, these microbial communities and factors are not well understood. I aimed to study the role of N cycling microbes, such as the ammonia-oxidizing bacteria (AOB), the recently discovered ammonia-oxidizing archaea (AOA), and various fungal groups, in soils of arid lands. I also tested if niche differentiation among microbial populations is a driver of differential biogeochemical outcomes. I found that N cycling microbial communities in arid lands are structured by environmental factors to a stronger degree than what is generally observed in mesic systems. For example, in biological soil crusts, temperature selected for AOA in warmer deserts and for AOB in colder deserts. Land-use change also affects niche differentiation, with fungi being the major agents of N2O production in natural arid lands, whereas emissions could be attributed to bacteria in mesic urban lawns. By contrast, NO3- production in the native desert and managed soils was mainly controlled by autotrophic microbes (i.e., AOB and AOA) rather than by heterotrophic fungi. I could also determine that AOA surprisingly responded positively to inorganic N availability in both short (one month) and long-term (seven years) experimental manipulations in an arid land soil, while environmental N enrichment in other ecosystem types is known to favor AOB over AOA. This work improves our predictions of ecosystem response to anthropogenic N increase and shows that paradigms derived from mesic systems are not always applicable to arid lands. My dissertation also highlights the unique ecology of ammonia oxidizers and draws attention to the importance of N cycling in desert soils.
ContributorsMarusenko, Yevgeniy (Author) / Hall, Sharon J (Thesis advisor) / Garcia-Pichel, Ferran (Thesis advisor) / Mclain, Jean E (Committee member) / Schwartz, Egbert (Committee member) / Arizona State University (Publisher)
Created2013
Description
This dissertation investigates spatial and temporal changes in land cover and plant species distributions on Cyprus in the past, present and future (1973-2070). Landsat image analysis supports inference of land cover changes following the political division of the island of Cyprus in 1974. Urban growth in Nicosia, Larnaka and Limasol, as well as increased development along the southern coastline, is clearly evident between 1973 and 2011. Forests of the Troodos and Kyrenia Ranges remain relatively stable, with transitions occurring most frequently between agricultural land covers and shrub/herbaceous land covers. Vegetation models were constructed for twenty-two plant species of Cyprus using Maxent to predict potentially suitable areas of occurrence. Modern vegetation models were constructed from presence-only data collected by field surveys conducted between 2008 and 2011. These models provide a baseline for the assessment of potential species distributions under two climate change scenarios (A1b and A2) for the years 2030, 2050, and 2070. Climate change in Cyprus is likely to influence habitat availability, particularly for high elevation species as the relatively low elevation mountain ranges and small latitudinal range prevent species from shifting to areas of suitable environmental conditions. The loss of suitable habitat for some species may allow the introduction of non-native plant species or the expansion of generalists currently excluded from these areas. Results from future projections indicate the loss of suitable areas for most species by the year 2030 under both climate regimes and all four endemic species (Cedrus brevifolia, Helianthemum obtusifolium, Pterocephalus multiflorus, and Quercus alnifolia) are predicted to lose all suitable environments as soon as 2030. As striking exceptions Prunus dulcis (almond), Ficus carica (fig), Punica granatum (pomegranate) and Olea europaea (olive), which occur as both wild varieties and orchard cultigens, will expand under both scenarios. Land cover and species distribution maps are evaluated in concert to create a more detailed interpretation of the Cypriot landscape and to discuss the potential implications of climate change for land cover and plant species distributions.
ContributorsRidder, Elizabeth (Author) / Fall, Patricia L. (Thesis advisor) / Myint, Soe W (Committee member) / Hirt, Paul W (Committee member) / Arizona State University (Publisher)
Created2013
Description
Stroke remains the leading cause of adult disability in developed countries. Most survivors live with residual motor impairments that severely diminish independence and quality of life. After stroke, the only accepted treatment for these patients is motor rehabilitation. However, the amount and kind of rehabilitation required to induce clinically significant improvements in motor function is rarely given due to the constraints of our current health care system. Research reported in this dissertation contributes towards developing adjuvant therapies that may augment the impact of motor rehabilitation and improve functional outcome. These studies have demonstrated reorganization of maps within motor cortex as a function of experience in both healthy and brain-injured animals by using intracortical microstimulation technique. Furthermore, synaptic plasticity has been identified as a key neural mechanism in directing motor map plasticity, evidenced by restoration of movement representations within the spared cortical tissue accompanied by increase in synapse number translating into motor improvement after stroke. There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Unfortunately, BDNF itself is a poor candidate because of its short half-life, low penetration through the blood brain barrier, and activating multiple receptor units, p75 and TrkB on the neuronal membrane. In order to circumvent this problem efficacy of two recently developed novel TrkB agonists, LM22A-4 and 7,8-dihydroxyflavone, that actively penetrate the blood brain barrier and enhance functional recovery. Findings from these dissertation studies indicate that administration of these pharmacological compounds, accompanied by motor rehabilitation provide a powerful therapeutic tool for stroke recovery.
ContributorsWarraich, Zuha (Author) / Kleim, Jeffrey A (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Tillery, Stephen-Helms (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2013