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- Genre: Doctoral Dissertation
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
It is commonly known that the left hemisphere of the brain is more efficient in the processing of verbal information, compared to the right hemisphere. One proposal suggests that hemispheric asymmetries in verbal processing are due in part to the efficient use of top-down mechanisms by the left hemisphere. Most evidence for this comes from hemispheric semantic priming, though fewer studies have investigated verbal memory in the cerebral hemispheres. The goal of the current investigations is to examine how top-down mechanisms influence hemispheric asymmetries in verbal memory, and determine the specific nature of hypothesized top-down mechanisms. Five experiments were conducted to explore the influence of top-down mechanisms on hemispheric asymmetries in verbal memory. Experiments 1 and 2 used item-method directed forgetting to examine maintenance and inhibition mechanisms. In Experiment 1, participants were cued to remember or forget certain words, and cues were presented simultaneously or after the presentation of target words. In Experiment 2, participants were cued again to remember or forget words, but each word was repeated once or four times. Experiments 3 and 4 examined the influence of cognitive load on hemispheric asymmetries in true and false memory. In Experiment 3, cognitive load was imposed during memory encoding, while in Experiment 4, cognitive load was imposed during memory retrieval. Finally, Experiment 5 investigated the association between controlled processing in hemispheric semantic priming, and top-down mechanisms used for hemispheric verbal memory. Across all experiments, divided visual field presentation was used to probe verbal memory in the cerebral hemispheres. Results from all experiments revealed several important findings. First, top-down mechanisms used by the LH primarily used to facilitate verbal processing, but also operate in a domain general manner in the face of increasing processing demands. Second, evidence indicates that the RH uses top-down mechanisms minimally, and processes verbal information in a more bottom-up manner. These data help clarify the nature of top-down mechanisms used in hemispheric memory and language processing, and build upon current theories that attempt to explain hemispheric asymmetries in language processing.
ContributorsTat, Michael J (Author) / Azuma, Tamiko (Thesis advisor) / Goldinger, Stephen D (Committee member) / Liss, Julie M (Committee member) / Arizona State University (Publisher)
Created2013
Description
Using experience, observations, data, current research, and writings in the field of volunteer management, it was determined there was a need to study the effects of leadership/management practices on the productivity outcomes of a volunteer construction workforce. A simple wood bench that would be tiled and painted was designed to test the areas of Time, Waste, Quality, Safety, and Satisfaction of different volunteer groups. The challenge was bolstered by giving the teams no power tools and limited available resources. A simple design of experiment model was used to test highs and lows in the three management techniques of Instruction, Help, and Encouragement. Each scenario was tested multiple times. Data was collected, normalized and analyzed using statistical analysis software. A few significant findings were discovered. The first; the research showed that there was no significant correlation between the management practices of the leader and the satisfaction of the volunteers. The second; the research also showed when further analyzed into specific realistic scenarios that the organizations would be better to focus on high amounts of Help and Encouragement in order to maximize the productivity of their volunteer construction workforce. This is significant as it allows NPO's and governments to focus their attention where best suited to produce results. The results were shared and the study was further validated as "significant" by conducting interviews with experts in the construction nonprofit sector.
ContributorsPrigge, Diedrich (Author) / Sullivan, Kenneth (Thesis advisor) / Wiezel, Avi (Committee member) / Badger, William (Committee member) / Arizona State University (Publisher)
Created2013
Description
Specific dendritic morphologies are a hallmark of neuronal identity, circuit assembly, and behaviorally relevant function. Despite the importance of dendrites in brain health and disease, the functional consequences of dendritic shape remain largely unknown. This dissertation addresses two fundamental and interrelated aspects of dendrite neurobiology. First, by utilizing the genetic power of Drosophila melanogaster, these studies assess the developmental mechanisms underlying single neuron morphology, and subsequently investigate the functional and behavioral consequences resulting from developmental irregularity. Significant insights into the molecular mechanisms that contribute to dendrite development come from studies of Down syndrome cell adhesion molecule (Dscam). While these findings have been garnered primarily from sensory neurons whose arbors innervate a two-dimensional plane, it is likely that the principles apply in three-dimensional central neurons that provide the structural substrate for synaptic input and neural circuit formation. As such, this dissertation supports the hypothesis that neuron type impacts the realization of Dscam function. In fact, in Drosophila motoneurons, Dscam serves a previously unknown cell-autonomous function in dendrite growth. Dscam manipulations produced a range of dendritic phenotypes with alteration in branch number and length. Subsequent experiments exploited the dendritic alterations produced by Dscam manipulations in order to correlate dendritic structure with the suggested function of these neurons. These data indicate that basic motoneuron function and behavior are maintained even in the absence of all adult dendrites within the same neuron. By contrast, dendrites are required for adjusting motoneuron responses to specific challenging behavioral requirements. Here, I establish a direct link between dendritic structure and neuronal function at the level of the single cell, thus defining the structural substrates necessary for conferring various aspects of functional motor output. Taken together, information gathered from these studies can inform the quest in deciphering how complex cell morphologies and networks form and are precisely linked to their function.
ContributorsHutchinson, Katie Marie (Author) / Duch, Carsten (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newfeld, Stuart (Committee member) / Smith, Brian (Committee member) / Orchinik, Miles (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
Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive decline, and other symptoms that reduce quality of life. To ameliorate these negative consequences, estrogen-containing hormone therapy is prescribed. Findings from clinical and pre-clinical research studies suggest that menopausal hormone therapies can benefit memory and associated neural substrates. However, findings are variable, with some studies reporting null or even detrimental cognitive and neurobiological effects of these therapies. Thus, at present, treatment options for optimal cognitive and brain health outcomes in menopausal women are limited. As such, elucidating factors that influence the cognitive and neurobiological effects of menopausal hormone therapy represents an important need relevant to every aging woman. To this end, work in this dissertation has supported the hypothesis that multiple factors, including post-treatment circulating estrogen levels, experimental handling, type of estrogen treatment, and estrogen receptor activity, can impact the realization of cognitive benefits with Premarin hormone therapy. We found that the dose-dependent working memory benefits of subcutaneous Premarin administration were potentially regulated by the ratios of circulating estrogens present following treatment (Chapter 2). When we administered Premarin orally, it impaired memory (Chapter 3). Follow-up studies revealed that this impairment was likely due to the handling associated with treatment administration and the task difficulty of the memory measurement used (Chapters 3 and 4). Further, we demonstrated that the unique cognitive impacts of estrogens that become increased in circulation following Premarin treatments, such as estrone (Chapter 5), and their interactions with the estrogen receptors (Chapter 6), may influence the realization of hormone therapy-induced cognitive benefits. Future directions include assessing the mnemonic effects of: 1) individual biologically relevant estrogens and 2) clinically-used bioidentical hormone therapy combinations of estrogens. Taken together, information gathered from these studies can inform the development of novel hormone therapies in which these parameters are optimized.
ContributorsEngler-Chiurazzi, Elizabeth (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Hoffman, Steven (Committee member) / Arizona State University (Publisher)
Created2013
Description
In this mixed-methods study, I examined the relationship between professional development based on the Common Core State Standards for Mathematics and teacher knowledge, classroom practice, and student learning. Participants were randomly assigned to experimental and control groups. The 50-hour professional development treatment was administered to the treatment group during one semester, and then a follow-up replication treatment was administered to the control group during the subsequent semester. Results revealed significant differences in teacher knowledge as a result of the treatment using two instruments. The Learning Mathematics for Teaching scales were used to detect changes in mathematical knowledge for teaching, and an online sorting task was used to detect changes in teachers' knowledge of their standards. Results also indicated differences in classroom practice between pairs of matched teachers selected to participate in classroom observations and interviews. No statistical difference was detected between the groups' student assessment scores using the district's benchmark assessment system. This efficacy study contributes to the literature in two ways. First, it provides an evidence base for a professional development model designed to promote effective implementation of the Common Core State Standards for Mathematics. Second, it addresses ways to impact and measure teachers' knowledge of curriculum in addition to their mathematical content knowledge. The treatment was designed to focus on knowledge of curriculum, but it also successfully impacted teachers' specialized content knowledge, knowledge of content and students, and knowledge of content and teaching.
ContributorsRimbey, Kimberly A (Author) / Middleton, James A. (Thesis advisor) / Sloane, Finbarr (Committee member) / Atkinson, Robert K (Committee member) / Arizona State University (Publisher)
Created2013
Description
An integral part of teacher development are teacher observations. Many teachers are observed once or twice a year to evaluate their performance and hold them accountable for meeting standards. Instructional coaches, however, observe and work with teachers to help them reflect on their performance, with the goal of improving their practice. Video-based evidence has long been used in connection with teacher reflection and as the technology necessary to record video has become more readily available, video recordings have found an increasing presence in teacher observations. In addition, more and more schools are turning to mobile technology to help record evidence during teacher observations. Several mobile applications have been developed, which are designed to help instructional coaches, administrators, and teachers make the most of teacher observations. This study looked at the use of the DataCapture mobile application to record video-based evidence in teacher observations as part of an instructional coaching program in a large public school district in the Southwestern United States. Six instructional coaches and two teachers participated in interviews at the end of the study period. Additional data was collected from the DataCapture mobile application and from a survey of instructional coaches conducted by the school district in connection with its Title I programs. Results show that instructional coaches feel that using video-based evidence for teacher reflection is effective in a number of ways. Teachers who have experienced seeing themselves on video also felt that video-based evidence is effective at improving teacher reflection, while teachers who have not yet experienced seeing themselves on video displayed extreme apprehensiveness about being video recorded in the classroom. Instructional coaches felt the DataCapture mobile application was beneficial in teacher evaluation, but there were several issues that impacted the use of the mobile application and video-based evidence, including logistics, time requirements, and administrative support. The discussion focuses on recommendations for successfully using video-based evidence in an instructional coaching context, as well as some suggestions for other researchers attempting to study how video-based evidence impacts teachers' ability to reflect on their own teaching.
ContributorsShewell, Justin Reed (Author) / Bitter, Gary (Thesis advisor) / Dawson, Edwin (Committee member) / Blair, Heidi (Committee member) / Arizona State University (Publisher)
Created2013
Description
Intracortical microstimulation (ICMS) within somatosensory cortex can produce artificial sensations including touch, pressure, and vibration. There is significant interest in using ICMS to provide sensory feedback for a prosthetic limb. In such a system, information recorded from sensors on the prosthetic would be translated into electrical stimulation and delivered directly to the brain, providing feedback about features of objects in contact with the prosthetic. To achieve this goal, multiple simultaneous streams of information will need to be encoded by ICMS in a manner that produces robust, reliable, and discriminable sensations. The first segment of this work focuses on the discriminability of sensations elicited by ICMS within somatosensory cortex. Stimulation on multiple single electrodes and near-simultaneous stimulation across multiple electrodes, driven by a multimodal tactile sensor, were both used in these experiments. A SynTouch BioTac sensor was moved across a flat surface in several directions, and a subset of the sensor's electrode impedance channels were used to drive multichannel ICMS in the somatosensory cortex of a non-human primate. The animal performed a behavioral task during this stimulation to indicate the discriminability of sensations evoked by the electrical stimulation. The animal's responses to ICMS were somewhat inconsistent across experimental sessions but indicated that discriminable sensations were evoked by both single and multichannel ICMS. The factors that affect the discriminability of stimulation-induced sensations are not well understood, in part because the relationship between ICMS and the neural activity it induces is poorly defined. The second component of this work was to develop computational models that describe the populations of neurons likely to be activated by ICMS. Models of several neurons were constructed, and their responses to ICMS were calculated. A three-dimensional cortical model was constructed using these cell models and used to identify the populations of neurons likely to be recruited by ICMS. Stimulation activated neurons in a sparse and discontinuous fashion; additionally, the type, number, and location of neurons likely to be activated by stimulation varied with electrode depth.
ContributorsOverstreet, Cynthia K (Author) / Helms Tillery, Stephen I (Thesis advisor) / Santos, Veronica (Committee member) / Buneo, Christopher (Committee member) / Otto, Kevin (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2013