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- All Subjects: Neurosciences
- Genre: Doctoral Dissertation
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- Status: Published
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
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
Background: Evidence about the purported hypoglycemic and hypolipidemic effects of nopales (prickly pear cactus pads) is limited. Objective: To evaluate the efficacy of nopales for improving cardiometabolic risk factors and oxidative stress, compared to control, in adults with hypercholesterolemia. Design: In a randomized crossover trial, participants were assigned to a 2-wk intervention with 2 cups/day of nopales or cucumbers (control), with a 2 to 3-wk washout period. The study included 16 adults (5 male; 46±14 y; BMI = 31.4±5.7 kg/m2) with moderate hypercholesterolemia (low density lipoprotein cholesterol [LDL-c] = 137±21 mg/dL), but otherwise healthy. Main outcomes measured included: dietary intake (energy, macronutrients and micronutrients), cardiometabolic risk markers (total cholesterol, LDL-c, high density lipoprotein cholesterol [HDL-c], triglycerides, cholesterol distribution in LDL and HDL subfractions, glucose, insulin, homeostasis model assessment, and C-reactive protein), and oxidative stress markers (vitamin C, total antioxidant capacity, oxidized LDL, and LDL susceptibility to oxidation). Effects of treatment, time, or interactions were assessed using repeated measures ANOVA. Results: There was no significant treatment-by-time effect for any dietary composition data, lipid profile, cardiometabolic outcomes, or oxidative stress markers. A significant time effect was observed for energy, which was decreased in both treatments (cucumber, -8.3%; nopales, -10.1%; pTime=0.026) mostly due to lower mono and polyunsaturated fatty acids intake (pTime=0.023 and pTime=0.003, respectively). Both treatments significantly increased triglyceride concentrations (cucumber, 14.8%; nopales, 15.2%; pTime=0.020). Despite the lack of significant treatment-by-time effects, great individual response variability was observed for all outcomes. After the cucumber and nopales phases, a decrease in LDL-c was observed in 44% and 63% of the participants respectively. On average LDL-c was decreased by 2.0 mg/dL (-1.4%) after the cucumber phase and 3.9 mg/dL (-2.9%) after the nopales phase (pTime=0.176). Pro-atherogenic changes in HDL subfractions were observed in both interventions over time, by decreasing the proportion of HDL-c in large HDL (cucumber, -5.1%; nopales, -5.9%; pTime=0.021) and increasing the proportion in small HDL (cucumber, 4.1%; nopales, 7.9%; pTime=0.002). Conclusions: These data do not support the purported benefits of nopales at doses of 2 cups/day for 2-wk on markers of lipoprotein profile, cardiometabolic risk, and oxidative stress in hypercholesterolemic adults.
ContributorsPereira Pignotti, Giselle Adriana (Author) / Vega-Lopez, Sonia (Thesis advisor) / Gaesser, Glenn (Committee member) / Keller, Colleen (Committee member) / Shaibi, Gabriel (Committee member) / Sweazea, Karen (Committee member) / Arizona State University (Publisher)
Created2013
Description
In October, 2009, participants of the Arizona Special Supplemental Nutrition Program for Women, Infants and Children (WIC) began receiving monthly Cash Value Vouchers (CVV) worth between six and 10 dollars towards the purchase of fresh fruits and vegetables. Data from the Arizona Department of Health Services (ADHS) showed CVV redemption rates in the first two years of the program were lower than the national average of 77% redemption. In response, the ADHS WIC Food List was expanded to also include canned and frozen fruits and vegetables. More recent data from ADHS suggest that redemption rates are improving, but variably exist among different WIC sub-populations. The purpose of this project was to identify themes related to the ease or difficulty of WIC CVV use amongst different categories of low-redeeming WIC participants. A total of 8 focus groups were conducted, four at a clinic in each of two Valley cities: Surprise and Mesa. Each of the four focus groups comprised one of four targeted WIC participant categories: pregnant, postpartum, breastfeeding, and children with participation ranging from 3-9 participants per group. Using the general inductive approach, recordings of the focus groups were transcribed, hand-coded and uploaded into qualitative analysis software resulting in four emergent themes including: interactions and shopping strategies, maximizing WIC value, redemption issues, and effect of rule change. Researchers identified twelve different subthemes related to the emergent theme of interactions and strategies to improve their experience, including economic considerations during redemption. Barriers related to interactions existed that made their purchase difficult, most notably anger from the cashier and other shoppers. However, participants made use of a number of strategies to facilitate WIC purchases or extract more value out of WIC benefits, such as pooling their CVV. Finally, it appears that the fruit and vegetable rule change was well received by those who were aware of the change. These data suggest a number of important avenues for future research, including verifying these themes are important within a larger, representative sample of Arizona WIC participants, and exploring strategies to minimize barriers identified by participants, such as use of electronic benefits transfer-style cards (EBT).
ContributorsBertmann, Farryl M. W (Author) / Wharton, Christopher (Christopher Mack), 1977- (Thesis advisor) / Ohri-Vachaspati, Punam (Committee member) / Johnston, Carol (Committee member) / Hampl, Jeffrey (Committee member) / Dixit-Joshi, Sujata (Committee member) / Barroso, Cristina (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
Description
This research is focused on two separate but related topics. The first uses an electroencephalographic (EEG) brain-computer interface (BCI) to explore the phenomenon of motor learning transfer. The second takes a closer look at the EEG-BCI itself and tests an alternate way of mapping EEG signals into machine commands. We test whether motor learning transfer is more related to use of shared neural structures between imagery and motor execution or to more generalized cognitive factors. Using an EEG-BCI, we train one group of participants to control the movements of a cursor using embodied motor imagery. A second group is trained to control the cursor using abstract motor imagery. A third control group practices moving the cursor using an arm and finger on a touch screen. We hypothesized that if motor learning transfer is related to the use of shared neural structures then the embodied motor imagery group would show more learning transfer than the abstract imaging group. If, on the other hand, motor learning transfer results from more general cognitive processes, then the abstract motor imagery group should also demonstrate motor learning transfer to the manual performance of the same task. Our findings support that motor learning transfer is due to the use of shared neural structures between imaging and motor execution of a task. The abstract group showed no motor learning transfer despite being better at EEG-BCI control than the embodied group. The fact that more participants were able to learn EEG-BCI control using abstract imagery suggests that abstract imagery may be more suitable for EEG-BCIs for some disabilities, while embodied imagery may be more suitable for others. In Part 2, EEG data collected in the above experiment was used to train an artificial neural network (ANN) to map EEG signals to machine commands. We found that our open-source ANN using spectrograms generated from SFFTs is fundamentally different and in some ways superior to Emotiv's proprietary method. Our use of novel combinations of existing technologies along with abstract and embodied imagery facilitates adaptive customization of EEG-BCI control to meet needs of individual users.
Contributorsda Silva, Flavio J. K (Author) / Mcbeath, Michael K (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Presson, Clark (Committee member) / Sugar, Thomas (Committee member) / Arizona State University (Publisher)
Created2013