ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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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
Spatiotemporal processing in the mammalian olfactory bulb (OB), and its analog, the invertebrate antennal lobe (AL), is subject to plasticity driven by biogenic amines. I study plasticity using honey bees, which have been extensively studied with respect to nonassociative and associative based olfactory learning and memory. Octopamine (OA) release in the AL is the functional analog to epinephrine in the OB. Blockade of OA receptors in the AL blocks plasticity induced changes in behavior. I have now begun to test specific hypotheses related to how this biogenic amine might be involved in plasticity in neural circuits within the AL. OA acts via different receptor subtypes, AmOA1, which gates calcium release from intracellular stores, and AmOA-beta, which results in an increase of cAMP. Calcium also enters AL interneurons via nicotinic acetylcholine receptors, which are driven by acetylcholine release from sensory neuron terminals, as well as through voltage-gated calcium channels. I employ 2-photon excitation (2PE) microscopy using fluorescent calcium indicators to investigate potential sources of plasticity as revealed by calcium fluctuations in AL projection neuron (PN) dendrites in vivo. PNs are analogous to mitral cells in the OB and have dendritic processes that show calcium increases in response to odor stimulation. These calcium signals frequently change after association of odor with appetitive reinforcement. However, it is unclear whether the reported plasticity in calcium signals are due to changes intrinsic to the PNs or to changes in other neural components of the network. My studies were aimed toward understanding the role of OA for establishing associative plasticity in the AL network. Accordingly, I developed a treatment that isolates intact, functioning PNs in vivo. A second study revealed that cAMP is a likely component of plasticity in the AL, thus implicating the AmOA-beta; receptors. Finally, I developed a method for loading calcium indicators into neural components of the AL that have yet to be studied in detail. These manipulations are now revealing the molecular mechanisms contributing to associative plasticity in the AL. These studies will allow for a greater understanding of plasticity in several neural components of the honey bee AL and mammalian OB.
ContributorsProtas, Danielle (Author) / Smith, Brian H. (Thesis advisor) / Neisewander, Janet (Committee member) / Anderson, Trent (Committee member) / Tyler, William (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2014
Description
Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how experiences throughout an individual's life influence such interactions. The core question of this thesis is how individuals’ experience contributes to within-caste behavioral variation in a social group. I investigate the effects of individual history, including physical injury and food-related experience, on individuals' social food sharing behavior, responses to food-related stimuli, and the associated neural biogenic amine signaling pathways. I use the eusocial honey bee (Apis mellifera) system, one in which individuals exhibit a high degree of plasticity in responses to environmental stimuli and there is a richness of communicatory pathways for food-related information. Foraging exposes honey bees to aversive experiences such as predation, con-specific competition, and environmental toxins. I show that foraging experience changes individuals' response thresholds to sucrose, a main component of adults’ diets, depending on whether foraging conditions are benign or aversive. Bodily injury is demonstrated to reduce individuals' appetitive responses to new, potentially food-predictive odors. Aversive conditions also impact an individual's social food sharing behavior; mouth-to-mouse trophallaxis with particular groupmates is modulated by aversive foraging conditions both for foragers who directly experienced these conditions and non-foragers who were influenced via social contact with foragers. Although the mechanisms underlying these behavioral changes have yet to be resolved, my results implicate biogenic amine signaling pathways as a potential component. Serotonin and octopamine concentrations are shown to undergo long-term change due to distinct foraging experiences. My work serves to highlight the malleability of a social individual's food-related behavior, suggesting that environmental conditions shape how individuals respond to food and share information with group-mates. This thesis contributes to a deeper understanding of inter-individual variation in animal behavior.
ContributorsFinkelstein, Abigail (Author) / Amdam, Gro V (Thesis advisor) / Conrad, Cheryl (Committee member) / Smith, Brian (Committee member) / Neisewander, Janet (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2017
Description
The RASopathies are a collection of developmental diseases caused by germline mutations in components of the RAS/MAPK signaling pathway and is one of the world’s most common set of genetic diseases. A majority of these mutations result in an upregulation of RAS/MAPK signaling and cause a variety of both physical and neurological symptoms. Neurodevelopmental symptoms of the RASopathies include cognitive and motor delays, learning and intellectual disabilities, and various behavioral problems. Recent noninvasive imaging studies have detected widespread abnormalities within white matter tracts in the brains of RASopathy patients. These abnormalities are believed to be indicative of underlying connectivity deficits and a possible source of the behavioral and cognitive deficits. To evaluate these long-range connectivity and behavioral issues in a cell-autonomous manner, MEK1 loss- and gain-of-function (LoF and GoF) mutations were induced solely in the cortical glutamatergic neurons using a Nex:Cre mouse model. Layer autonomous effects of the cortex were also tested in the GoF mouse using a layer 5 specific Rbp4:Cre mouse. Immunohistochemical analysis showed that activated ERK1/2 (P-ERK1/2) was expressed in high levels in the axonal compartments and reduced levels in the soma when compared to control mice. Axonal tract tracing using a lipophilic dye and an adeno-associated viral (AAV) tract tracing vector, identified significant corticospinal tract (CST) elongation deficits in the LoF and GoF Nex:Cre mouse and in the GoF Rbp4:Cre mouse. AAV tract tracing was further used to identify significant deficits in axonal innervation of the contralateral cortex, the dorsal striatum, and the hind brain of the Nex:Cre GoF mouse and the contralateral cortex and dorsal striatum of the Rbp4:Cre mouse. Behavioral testing of the Nex:Cre GoF mouse indicated deficits in motor learning acquisition while the Rbp4:Cre GoF mouse showed no failure to acquire motor skills as tested. Analysis of the expression levels of the immediate early gene ARC in Nex:Cre and Rbp4:Cre mice showed a specific reduction in a cell- and layer-autonomous manner. These findings suggest that hyperactivation of the RAS/MAPK pathway in cortical glutamatergic neurons, induces changes to the expression patterns of P-ERK1/2, disrupts axonal elongation and innervation patterns, and disrupts motor learning abilities.
ContributorsBjorklund, George Reed (Author) / Newbern, Jason M (Thesis advisor) / Neisewander, Janet (Committee member) / Smith, Brian (Committee member) / Orchinik, Miles (Committee member) / Mangone, Marco (Committee member) / Arizona State University (Publisher)
Created2018
Description
Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
Description
Schizophrenia is considered a multifactorial disorder with complex genetic variants in response to environmental stimuli. However, the specific genetic contribution to schizophrenia risk is largely unknown. The transcription factor early growth response gene 3 (EGR3) can be activated rapidly after stimuli and thus may translate environmental stimuli into gene changes that influence schizophrenia risk. However, the downstream genes that may be regulated by EGR3 are not clear. While the 5-Hydroxytryptamine receptor 2A (5HT2AR) - encoding gene Htr2a has been implicated in the etiology of schizophrenia, the mechanisms by which Htr2a influences susceptibility to this illness are poorly understood. We previously found that in addition to schizophrenia-like abnormalities, Egr3 -/- mice have approximately 70% deduction of 5HT2AR level in the prefrontal cortex, which underlines their resistant to the sedating effect of clozapine. These findings indicate that the two schizophrenia candidate genes are in the same biological pathway that integrates multiple components resulting in schizophrenia. This dissertation is aimed to identify the mechanisms by which Egr3 regulates the expression of Htr2a in response to environmental stimuli like stress.
To determine if Egr3 alters Htr2a transcription under stress, I examined messenger ribonucleic acid (mRNA) levels of these two genes in wildtype (WT) and Egr3 -/- mice after 6hrs of sleep deprivation (SD). I found both genes are increased in WT mice after SD compared with controls. In addition, Egr3 is required for Htr2a induction because SD fails to induce Htr2a expression in Egr3 -/- mice. Next, I performed chromatin immunoprecipitation (ChIP) to determine if EGR3 binds to Htr2a promoter in vivo. I found a significant increase of EGR3 binding to Htr2a distal promoter 2hrs after seizure. To determine the functionality of this binding, I co-transfected the CMV- EGR3 vector or CMV- vector alone with the Htr2a distal promoter reporter clone. I found overexpression of EGR3 activates the Htr2a distal promoter-driven luciferase gene. Although the ChIP assay shows no direct binding of EGR3 to Htr2a proximal promoter, I found EGR3 overexpression activates Htr2a proximal promoter-driven luciferase gene. These findings suggest that EGR3 regulates Htr2a probably through both direct and indirect ways.
To determine if Egr3 alters Htr2a transcription under stress, I examined messenger ribonucleic acid (mRNA) levels of these two genes in wildtype (WT) and Egr3 -/- mice after 6hrs of sleep deprivation (SD). I found both genes are increased in WT mice after SD compared with controls. In addition, Egr3 is required for Htr2a induction because SD fails to induce Htr2a expression in Egr3 -/- mice. Next, I performed chromatin immunoprecipitation (ChIP) to determine if EGR3 binds to Htr2a promoter in vivo. I found a significant increase of EGR3 binding to Htr2a distal promoter 2hrs after seizure. To determine the functionality of this binding, I co-transfected the CMV- EGR3 vector or CMV- vector alone with the Htr2a distal promoter reporter clone. I found overexpression of EGR3 activates the Htr2a distal promoter-driven luciferase gene. Although the ChIP assay shows no direct binding of EGR3 to Htr2a proximal promoter, I found EGR3 overexpression activates Htr2a proximal promoter-driven luciferase gene. These findings suggest that EGR3 regulates Htr2a probably through both direct and indirect ways.
ContributorsZhao, Xiuli (Author) / Gallitano, Amelia (Thesis advisor) / Van Keuren-Jensen, Kendall (Committee member) / Lifshitz, Jonathan (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2017
Description
Animals must learn to ignore stimuli that are irrelevant to survival, which is a process referred to as ‘latent inhibition’. This process has been shown to be genetically heritable (Latshaw JS, Mazade R, Sinakevitch I, Mustard JA, Gadau J, Smith BH (submitted)). The locus containing the AmTYR1 gene has been shown through quantitative trait loci mapping to be linked to strong latent inhibition in honey bees. The Smith lab has been able to show a correlation between learning and the AmTYR1 receptor gene through pharmacological inhibition of the receptor. In order to further confirm this finding, experiments were designed to test how honey bees learn with this receptor knocked out. Here this G-protein coupled receptor for the biogenic amine tyramine is implemented as an important factor underlying latent inhibition in honey bees. It is shown that double-stranded RNA (dsRNA) and Dicer-substrate small interfering RNA (dsiRNA) that are targeted to disrupt the tyramine receptors specifically affects latent inhibition but not excitatory associative conditioning. The results therefore identify a distinct reinforcement pathway for latent inhibition in insects.
ContributorsPetersen, Mary Margaret (Author) / Smith, Brian H. (Thesis advisor) / Wang, Ying (Committee member) / Neisewander, Janet (Committee member) / Sinakavich, Irina (Committee member) / Arizona State University (Publisher)
Created2017
Description
Sensory gating is a process by which the nervous system preferentially admits stimuli that are important for the organism while filtering out those that may be meaningless. An optimal sensory gate cannot be static or inflexible, but rather plastic and informed by past experiences. Learning enables sensory gates to recognize stimuli that are emotionally salient and potentially predictive of positive or negative outcomes essential to survival. Olfaction is the only sensory modality in mammals where sensory inputs bypass conventional thalamic gating before entering higher emotional or cognitive brain regions. Thus, olfactory bulb circuits may have a heavier burden of sensory gating compared to other primary sensory circuits. How do the primary synapses in an olfactory system "learn"' in order to optimally gate or filter sensory stimuli? I hypothesize that centrifugal neuromodulator serotonin serves as a signaling mechanism by which primary olfactory circuits can experience learning informed sensory gating. To test my hypothesis, I conditioned genetically-modified mice using reward or fear olfactory-cued learning paradigms and used pharmacological, electrophysiological, immunohistochemical, and optical imaging approaches to assay changes in serotonin signaling or functional changes in primary olfactory circuits. My results indicate serotonin is a key mediator in the acquisition of olfactory fear memories through the activation of its type 2A receptors in the olfactory bulb. Functionally within the first synaptic relay of olfactory glomeruli, serotonin type 2A receptor activation decreases excitatory glutamatergic drive of olfactory sensory neurons through both presynaptic and postsynaptic mechanisms. I propose that serotonergic signaling decreases excitatory drive, thereby disconnecting olfactory sensory neurons from odor responses once information is learned and its behavioral significance is consolidated. I found that learning induced chronic changes in the density of serotonin fibers and receptors, which persisted in glomeruli encoding the conditioning odor. Such persistent changes could represent a sensory gate stabilized by memory. I hypothesize this ensures that the glomerulus encoding meaningful odors are much more sensitive to future serotonin signaling as such arousal cues arrive from centrifugal pathways originating in the dorsal raphe nucleus. The results advocate that a simple associative memory trace can be formed at primary sensory synapses to facilitate optimal sensory gating in mammalian olfaction.
ContributorsLi, Monica (Author) / Tyler, William J (Thesis advisor) / Smith, Brian H. (Thesis advisor) / Duch, Carsten (Committee member) / Neisewander, Janet (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2012
Description
The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH) causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.
ContributorsLewis, Candace (Author) / Olive, Micheal F (Thesis advisor) / Conrad, Cheryl (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
LKB1/STK11 is a serine/threonine kinase first identified in C.elegans as a gene important for cell polarity and proliferation. Mutations in LKB1 are the primary cause of Peutz-Jegher’s cancer syndrome, an autosomal dominantly inherited disease, in which patients are predisposed to benign and malignant tumors. Past studies have focused on defining LKB1 functions in various tissue types, for example LKB1 regulates axonal polarization and dendritic arborization by activating downstream substrates in excitatory neurons of the developing neocortex. However, the implications of LKB1, specifically in the developing cortical inhibitory GABAergic interneurons is unknown. LKB1 deletion was achieved by using Cre-lox technology to induce LKB1 loss in cells localized in the medial ganglionic eminence (MGE) that express Nkx2.1 and generate cortical GABAergic neurons. In this research study it is suggested that LKB1 plays a role in GABAergic interneuron specification by specifically regulating the expression of parvalbumin during the development of fast-spiking interneurons. Preliminary evidence suggest LKB1 also modulates the number of Nkx2.1-derived oligodendrocytes in the cortex. By utilizing a GABAergic neuron specific LKB1 deletion mutant, we confirmed that the loss of parvalbumin expression was due to a GABAergic neuron autonomous function for LKB1. These data provide new insight into the cell specific functions of LKB1 in the developing brain.
ContributorsSebastian, Rebecca (Author) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Gipson-Reichardt, Cassandra (Committee member) / Arizona State University (Publisher)
Created2019