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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
The academic literature on science communication widely acknowledges a problem: science communication between experts and lay audiences is important, but it is not done well. General audience popular science books, however, carry a reputation for clear science communication and are understudied in the academic literature. For this doctoral dissertation, I utilize Sam Harris's The Moral Landscape, a general audience science book on the particularly thorny topic of neuroscientific approaches to morality, as a case-study to explore the possibility of using general audience science books as models for science communication more broadly. I conduct a literary analysis of the text that delimits the scope of its project, its intended audience, and the domains of science to be communicated. I also identify seven literary aspects of the text: three positive aspects that facilitate clarity and four negative aspects that interfere with lay public engagement. I conclude that The Moral Landscape relies on an assumed knowledge base and intuitions of its audience that cannot reasonably be expected of lay audiences; therefore, it cannot properly be construed as popular science communication. It nevertheless contains normative lessons for the broader science project, both in literary aspects to be salvaged and literary aspects and concepts to consciously be avoided and combated. I note that The Moral Landscape's failings can also be taken as an indication that typical descriptions of science communication offer under-detailed taxonomies of both audiences for science communication and the varieties of science communication aimed at those audiences. Future directions of study include rethinking appropriate target audiences for science literacy projects and developing a more discriminating taxonomy of both science communication and lay publics.
ContributorsJohnson, Nathan W (Author) / Robert, Jason S (Thesis advisor) / Creath, Richard (Committee member) / Martinez, Jacqueline (Committee member) / Sylvester, Edward (Committee member) / Lynch, John (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
After decades of dormancy, character is re-emerging as an important research topic among organizational leadership researchers in response to the need to better explain the source of certain exemplary and ethical leader performance (Hannah & Avolio, 2011; Leonard, 1997; Thompson & Riggio, 2010; Wright & Goodstein, 2007). However, efforts to operationalize character are criticized for their abstract and idealistic trait-based conceptualizations that fail to capture the reality of leadership and situational dynamics (Conger & Hollenbeck, 2010). The purpose of this study is to develop a more robust theoretical approach to character that is empirically grounded in the real life complexities of leadership. Combat provides the context for this study because the adversity of such an extreme context tends to make character a more salient and readily observable phenomenon than in more conventional organizational contexts (Wright & Quick, 2011; Hannah, Uhl-Bien, Avolio, & Cavarretta, 2009). I employed an ethnographic grounded theory design to gain a unique insider's perspective absent in many studies of leader character (Charmaz, 2009; Parry & Meindl, 2002). Data collection involved (1) physically embedding for six months with U.S. Army small unit infantry leaders operating in combat in Afghanistan; (2) participant observation in the full range of combat activities engaged in by these leaders; and (3) in-depth semi-structured interviews with key informants. An important contribution of this study is that the emergent concept of leader character is fully situated in the leader's social and environmental context represented by the leader's inner struggle to resist the adversity of combat and uphold the standards of leadership. In this dialectical framework, certain agentic resources important to resolving this inner struggle emerge as the locus of leader character. This agency-based concept of character is rooted in the internalization of the standards of leadership through identity-conferring normative commitments and entails particular motivational and volitional capacities. These produce a distinct mode of functioning--a strong form of personal moral agency--characterized by the leader's willingness to sacrifice in upholding standards in the face of adversity. This primacy of leader agency over adversity is the hallmark of leader character--what I call the character to lead.
ContributorsJennings, Peter L. (Author) / Corley, Kevin (Thesis advisor) / Waldman, David (Thesis advisor) / Hannah, Sean T (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
Description
The entire history of HIV-1 is hidden in its ten thousand bases, where information regarding its evolutionary traversal through the human population can only be unlocked with fine-scale sequence analysis. Measurable footprints of mutation and recombination have imparted upon us a wealth of knowledge, from multiple chimpanzee-to-human transmissions to patterns of neutralizing antibody and drug resistance. Extracting maximum understanding from such diverse data can only be accomplished by analyzing the viral population from many angles. This body of work explores two primary aspects of HIV sequence evolution, point mutation and recombination, through cross-sectional (inter-individual) and longitudinal (intra-individual) investigations, respectively. Cross-sectional Analysis: The role of Haiti in the subtype B pandemic has been hotly debated for years; while there have been many studies, up to this point, no one has incorporated the well-known mechanism of retroviral recombination into their biological model. Prior to the use of recombination detection, multiple analyses produced trees where subtype B appears to have first entered Haiti, followed by a jump into the rest of the world. The results presented here contest the Haiti-first theory of the pandemic and instead suggest simultaneous entries of subtype B into Haiti and the rest of the world. Longitudinal Analysis: Potential N-linked glycosylation sites (PNGS) are the most evolutionarily dynamic component of one of the most evolutionarily dynamic proteins known to date. While the number of mutations associated with the increase or decrease of PNGS frequency over time is high, there are a set of relatively stable sites that persist within and between longitudinally sampled individuals. Here, I identify the most conserved stable PNGSs and suggest their potential roles in host-virus interplay. In addition, I have identified, for the first time, what may be a gp-120-based environmental preference for N-linked glycosylation sites.
ContributorsHepp, Crystal Marie, 1981- (Author) / Rosenberg, Michael S. (Thesis advisor) / Hedrick, Philip (Committee member) / Escalante, Ananias (Committee member) / Kumar, Sudhir (Committee member) / Arizona State University (Publisher)
Created2013
Description
"YouTube Shakespeares" is a study of Shakespeare online videos and the people who create, upload, and view them on YouTube. Employing an interdisciplinary approach, this work is a remix of theories and methodologies from literary, performance, (social) media, fan, and Internet studies that expands the field of Shakespeare studies. This dissertation explores the role of YouTube users and their activities, the expansion of literary research methods onto digital media venues, YouTube as site of Shakespeare performance, and YouTube Shakespeares' fan communities. It analyzes a broad array of Shakespeare visual performances including professional and user-generated mashups, remixes, film clips, auditions, and high school performances. A rich avenue for the study of people's viewing and reception of Shakespeare, YouTube tests the (un)limitations of Shakespeare adaptation. This work explores the ethical implications of researching performances that include human subjects, arguing that their presence frequently complicates common concepts of public and private identities. Although YouTube is a "published" forum for social interactivity and video repository, this work urges digital humanities scholars to recognize and honor the human users entailed in the videos not as text, but as human subjects. Shifting the study focus to human subjects demands a revision of research methods and publications protocols as the researcher repositions herself into the role of virtual ethnographer. "YouTube Shakespeares" develops its own ethics-based, online research method, which includes seeking Institutional Board Review approval and online interviews. The second half of the dissertation shifts from methodology to theorizing YouTube Shakespeares' performance spaces as analogs to the interactive and imaginary areas of Shakespeare's early modern theatre. Additionally, this work argues that YouTube Shakespeares' creators and commentators are fans. "YouTube Shakespeares" is one of the first Shakespeare-centric studies to employ fan studies as a critical lens to explore the cultural significance and etiquette of people's online Shakespeare performance activities. The work ends with a conversation about the issues of ephemerality, obsolescence, and concerns about the instability of digital and online materials, noting the risk of evidentiary loss of research materials is far outweighed by a scholarly critical registration of YouTube in the genealogy of Shakespeare performance.
ContributorsFazel, Valerie Margaret (Author) / Thompson, Ayanna (Thesis advisor) / Ryner, Bradley (Committee member) / Fox, Cora (Committee member) / Arizona State University (Publisher)
Created2013