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Description
Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia.
ContributorsMaple, Amanda (Author) / Hammer, Ronald P. (Thesis advisor) / Olive, Michael F (Committee member) / Gallitano, Amelia L (Committee member) / Conrad, Cheryl D. (Committee member) / Nikulina, Ella M (Committee member) / Arizona State University (Publisher)
Created2013
Description
The purpose of this study was to evaluate existing data from the Arizona Youth Survey (AYS) to give policymakers and representatives from the Arizona Criminal Justice Commission some insight into the high rates of youth prescription drug abuse. This study examined trends in prescription drug consumption among Pima County, Arizona adolescents, as well as the contexts in which these drugs were used and the numerous consequences resulting from such actions. The results of this research will allow professionals at the Arizona Criminal Justice Commission to inform state officials on the most cost-effective methods of prescription drug abuse prevention and intervention.
ContributorsLewis, Melissa (Author) / Roosa, Mark (Thesis director) / Dumka, Larry (Committee member) / Malone, Shane (Committee member) / Barrett, The Honors College (Contributor)
Created2013-05
Description
According to my 2016 survey of ASU undergraduate students, 33% have used stimulant medications (e.g. Adderall or Ritalin) without a prescription to study. I view this practice as a step towards cognitive enhancement, which is the deliberate application of biotechnology to radically alter the human condition. From a foresight perspective, the ability to actively improve human beings, to take our evolutionary destiny into our own hands, may be a turning point on par with agriculture or the use of fossil fuels. The existential risks, however, may be greater than the benefits—and many of the most radical technologies have made little documented progress.
I turn to an actual example where people are trying to make themselves marginally better at academic tasks, as a guide to how future transformative development in human enhancement may be incorporated into everyday practice. This project examines the history and context that led to the widespread use of stimulant medication on college campuses. I describe how Attention Deficit Hyperactivity Disorder (ADHD), for which stimulant medication is prescribed and diverted, governs students, negotiates relationships between parents and school authorities, and manages anxieties resulting from a competitive neoliberal educational system. I extend this archeology of ADHD through the actions and ethical beliefs of college students, and the bioethical arguments for and against human enhancement. Through this work, I open a new space for an expanded role for universities as institutions capable of creating experimental communities supporting ethical cognitive enhancement.
I turn to an actual example where people are trying to make themselves marginally better at academic tasks, as a guide to how future transformative development in human enhancement may be incorporated into everyday practice. This project examines the history and context that led to the widespread use of stimulant medication on college campuses. I describe how Attention Deficit Hyperactivity Disorder (ADHD), for which stimulant medication is prescribed and diverted, governs students, negotiates relationships between parents and school authorities, and manages anxieties resulting from a competitive neoliberal educational system. I extend this archeology of ADHD through the actions and ethical beliefs of college students, and the bioethical arguments for and against human enhancement. Through this work, I open a new space for an expanded role for universities as institutions capable of creating experimental communities supporting ethical cognitive enhancement.
ContributorsBurnam-Fink, Michael (Author) / Miller, Clark (Thesis advisor) / Hurlbut, Ben (Thesis advisor) / Wetmore, Jameson (Committee member) / Arizona State University (Publisher)
Created2016
Description
Intermittent social defeat stress produces vulnerability to drugs of abuse, a phenomena known as cross-sensitization, which is proceeded by a corresponding upregulation of ventral tegmental area (VTA) mu-opioid receptors (MORs). Since VTA MORs are implicated in the expression of psychostimulant sensitization, they may also mediate social stress-induced vulnerability to drugs of abuse. Social stress and drugs of abuse increase mesolimbic brain-derived neurotrophic factor (BDNF) signaling with its receptor, tropomyosin-related kinase B (TrkB). These studies examined whether VTA MOR signaling is important for the behavioral and cellular consequences of social stress. First, the function of VTA MORs in the behavioral consequences of intermittent social defeat stress was investigated. Lentivirus-mediated knockdown of VTA MORs prevented social stress-induced cross-sensitization, as well as stress-induced social avoidance and weight gain deficits. Next it was examined whether VTA MOR expression is critical for stress-induced alterations in the mesocorticolimbic circuit. At the time cross-sensitization was known to occur, lentivirus-mediated knockdown of VTA MORs prevented stress-induced increases in VTA BDNF and its receptor, TrkB in the nucleus accumbens (NAc), and attenuated NAc expression of delta FosB. There was no effect of either stress or virus on BDNF expression in the prefrontal cortex. Since social stress-induced upregulation of VTA MORs is necessary for consequences of social stress, next activity dependent changes in AKT, a downstream target of MOR stimulation associated with sensitization to psychostimulant drugs, were investigated. Using fluorescent immunohistochemical double labeling for the active form of AKT (pAKT) and markers of either GABA or dopamine neurons in the VTA, it was determined that social stress significantly increased the expression of pAKT in GABA, but not dopamine neurons, and that this effect was dependent on VTA MOR expression. Moreover, intra-VTA inhibition of pAKT during stress prevented stress-induced weight gain deficits, while acute inhibition of VTA pAKT blocked the expression of cross-sensitization in subjects that had previously exhibited sensitized locomotor activity. Together these results suggest that social stress upregulates MORs on VTA GABA neurons, resulting in AKT phosphorylation, and that increased VTA MOR-pAKT signaling may represent a novel therapeutic target for the intervention of substance abuse disorders.
ContributorsJohnston, Caitlin (Author) / Hammer, Ronald P. (Thesis advisor) / Nikulina, Ella M. (Thesis advisor) / Neisewander, Janet L. (Committee member) / Wu, Jie (Committee member) / Olive, Michael F. (Committee member) / Arizona State University (Publisher)
Created2015
Description
This dissertation explores the megamachine, a prominent metaphor in American humanist and philosopher of technology, Lewis Mumford's Myth of the Machine series. The term refers critically to dynamic, regimented human capacities that drive scientific and technical innovation in society. Mumford's view of the nature of collectives focuses on qualities and patterns that emerge from the behavior of groups, societies, systems, and ecologies. It is my aim to reenergize key concepts about collective capacities drawn from Lewis Mumford's critique of historical and modern sociotechnical arrangements. I investigate the possibility of accessing those capacities through improved design for Technology Assessment (TA), formal practices that engage experts and lay citizens in the evaluation of complex scientific and technical issues.
I analyze the components of Mumford's megamachine and align key concerns in two pivotal works that characterize the impact of collective capacities on society: Bruno Latour's Pasteurization of France (1988) and Elias Canetti's Crowds and Power (1962). As I create a model of collective capacities in the sociotechnical according to the parameters of Mumford's megamachine, I rehabilitate two established ideas about the behavior of crowds and about the undue influence of technological systems on human behavior. I depart from Mumford's tactics and those of Canetti and Latour and propose a novel focus for STS on "sociotechnical crowds" as a meaningful unit of social measure. I make clear that Mumford's critique of the sociotechnical status quo still informs the conditions for innovation today.
Using mixed mode qualitative methods in two types of empirical field studies, I then investigate how a focus on the characteristics and components of collective human capacities in sociotechnical systems can affect the design and performance of TA. I propose a new model of TA, Emergent Technology Assessment (ETA), which includes greater public participation and recognizes the interrelationship among experience, affect and the material in mediating the innovation process. The resulting model -- the "soft" megamachine --introduces new strategies to build capacity for responsible innovation in society.
I analyze the components of Mumford's megamachine and align key concerns in two pivotal works that characterize the impact of collective capacities on society: Bruno Latour's Pasteurization of France (1988) and Elias Canetti's Crowds and Power (1962). As I create a model of collective capacities in the sociotechnical according to the parameters of Mumford's megamachine, I rehabilitate two established ideas about the behavior of crowds and about the undue influence of technological systems on human behavior. I depart from Mumford's tactics and those of Canetti and Latour and propose a novel focus for STS on "sociotechnical crowds" as a meaningful unit of social measure. I make clear that Mumford's critique of the sociotechnical status quo still informs the conditions for innovation today.
Using mixed mode qualitative methods in two types of empirical field studies, I then investigate how a focus on the characteristics and components of collective human capacities in sociotechnical systems can affect the design and performance of TA. I propose a new model of TA, Emergent Technology Assessment (ETA), which includes greater public participation and recognizes the interrelationship among experience, affect and the material in mediating the innovation process. The resulting model -- the "soft" megamachine --introduces new strategies to build capacity for responsible innovation in society.
ContributorsGano, Gretchen (Author) / Guston, David (Thesis advisor) / Miller, Clark (Thesis advisor) / Selin, Cynthia (Committee member) / Wetmore, Jameson (Committee member) / Arizona State University (Publisher)
Created2014
Description
Intermittent social defeat stress induces psychostimulant cross-sensitization, as well as long-lasting social avoidance behavior. Previous data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunits in rat ventral tegmental area (VTA), which occurs concurrently with social stress-induced amphetamine (AMPH) cross-sensitization. These studies described herein examined whether VTA GluA1 AMPARs are important for the behavioral consequences of social stress and investigated the role of the infralimbic (IL) to VTA pathway in the induction of these responses. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization without affecting social avoidance behavior, while GluA1 overexpression in VTA DA neurons mimicked the effects of stress on AMPH sensitization. Female rats were more sensitive to the effects of stress on AMPH administration than males, specifically during proestrus/estrus, which is characterized by higher circulating estradiol. Fluorescent immunohistochemistry revealed that females expressed higher GluA1 in VTA DA neurons as a result of intermittent social defeat stress, independent of estrus stage; by contrast, females during proestrus/estrus displayed higher tyrosine kinase receptor type 2 (TrkB) expression, which is the receptor for brain derived neurotrophic factor (BDNF), in VTA DA neurons, independent of stress exposure. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization and overexpression mimicked the effects of stress on AMPH sensitization. This suggests that BDNF-TrkB signaling may work concomitantly with GluA1 signaling in the VTA to drive sex-dependent differences in stress-induced locomotor sensitization effects. Optogenetic inhibition of the IL-VTA pathway in male rats prevented stress-induced AMPH sensitization compared to control animals. In addition, fluorescent immunohistochemistry displayed less Fos labeling in the nucleus accumbens (NAc) of rats with IL-VTA light inhibition compared to control animals. This suggests that the IL-VTA pathway plays a critical role in the induction of stress-induced sensitivity to AMPH, and blocking this pathway prevents mesolimbic DA signaling to the NAc. We conclude that IL glutamate projections onto GluA1-homomeric AMPA receptors in VTA DA neurons play a critical role in driving the stress-induced sensitization response in males and females. Therefore, GluA1 VTA DA neurons could potentially be a therapeutic target to prevent stress-induced drug susceptibility in the future.
ContributorsRudolph, Megan Leigh (Author) / Hammer, Ronald P. (Thesis advisor) / Olive, Michael F (Thesis advisor) / Nikulina, Ella M (Committee member) / Ferguson, Deveroux (Committee member) / Qiu, Shenfeng (Committee member) / Arizona State University (Publisher)
Created2020