Matching Items (14)
Filtering by
- All Subjects: Neurosciences
- All Subjects: Biology
- Genre: Doctoral Dissertation
- Creators: Newbern, Jason
- Status: Published
Description
Simultaneously culture heroes and stumbling buffoons, Tricksters bring cultural tools to the people and make the world more habitable. There are common themes in these figures that remain fruitful for the advancement of culture, theory, and critical praxis. This dissertation develops a method for opening a dialogue with Trickster figures. It draws from established literature to present a newly conceived and more flexible Trickster archetype. This archetype is more than a collection of traits; it builds on itself processually to form a method for analysis. The critical Trickster archetype includes the fundamental act of crossing borders; the twin ontologies of ambiguity and liminality; the particular tactics of humor, duplicity, and shape shifting; and the overarching cultural roles of culture hero and stumbling buffoon. Running parallel to each archetypal element, though, are Trickster's overarching critical spirit of Quixotic utopianism and underlying telos of manipulating human relationships. The character 'Q' from Star Trek: The Next Generation is used to demonstrate the critical Trickster archetype. To be more useful for critical cultural studies, Trickster figures must also be connected to their socio-cultural and historical contexts. Thus, this dissertation offers a second set of analytics, a dialogical method that connects Tricksters to the worlds they make more habitable. This dialogical method, developed from the work of M. M. Bakhtin and others, consists of three analytical tools: utterance, intertextuality, and chronotope. Utterance bounds the text for analysis. Intertextuality connects the utterance, the text, to its context. Chronotope suggests particular spatio-temporal relationships that help reveal the cultural significance of a dialogical performance. Performance artists Andre Stitt, Ann Liv Young, and Steven Leyba are used to demonstrate the method of Trickster dialogics. A concluding discussion of Trickster's unique chronotope reveals its contributions to conceptions of utopia and futurity. This dissertation offers theoretical advancements about the significance and tactics of subversive communication practices. It offers a new and unique method for cultural and performative analyses that can be expanded into different kinds of dialogics. Trickster dialogics can also be used generatively to direct and guide the further development of performative praxis.
ContributorsSalinas, Chema (Author) / de la Garza, Amira (Thesis advisor) / Carlson, Cheree (Committee member) / Olson, Clark (Committee member) / Ellsworth, Angela (Committee member) / Arizona State University (Publisher)
Created2013
Description
Adults with autism spectrum disorder (ASD) face heightened risk of co-occurring psychiatric conditions, especially depression and anxiety disorders, which contribute to seven-fold higher suicide rates than the general population. Mindfulness-based stress reduction (MBSR) is an 8-week meditation intervention centered around training continuous redirection of attention toward present moment experience, and has been shown to improve mental health in autistic adults. However, the underlying therapeutic neural mechanisms and whether behavioral and brain changes are mindfulness-specific have yet to be elucidated. In this randomized clinical trial, I utilized functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to characterize fMRI functional activity (Study 1) and connectivity (Study 2) and EEG neurophysiological (Study 3) changes between MBSR and a social support/relaxation education (SE) active control group. Study 1 revealed an MBSR-specific increase in the midcingulate cortex fMRI blood oxygen level dependent signal which was associated with reduced depression. Study 2 identified nonspecific intervention improvements in depression, anxiety, and autistic, and MBSR-specific improvements in the mindfulness trait ‘nonjudgment toward experience’ and in the executive functioning domain of working memory. MBSR-specific decreases in insula-thalamus and frontal pole-posterior cingulate functional connectivity was associated with improvements in anxiety, mindfulness traits, and working memory abilities. Both MBSR and SE groups showed decreased amygdala-sensorimotor and frontal pole-insula connectivity which correlated with reduced depression. Study 3 consisted of an EEG spectral power analysis at high-frequency brainwaves associated with default mode network (DMN) activity. Results showed MBSR-specific and nonspecific decreases in beta- and gamma-band power, with effects being generally more robust in the MBSR group; additionally, MBSR-specific decreases in posterior gamma correlated with anxiolytic effects. Collectively, these studies suggest: 1) social support is sufficient for improvements in depression, anxiety, and autistic traits; 2) MBSR provides additional benefits related to mindfulness traits and working memory; and 3) distinct and shared neural mechanisms of mindfulness training in adults with ASD, implicating the salience and default mode networks and high-frequency neurophysiology. Findings bear relevance to the development of personalized medicine approaches for psychiatric co-morbidity in ASD, provide putative targets for neurostimulation research, and warrant replication and extension using advanced multimodal imaging approaches.
ContributorsPagni, Broc (Author) / Braden, B. Blair (Thesis advisor) / Newbern, Jason (Thesis advisor) / Davis, Mary (Committee member) / Brewer, Gene (Committee member) / Arizona State University (Publisher)
Created2022
Description
Development of the central nervous system is an incredible process that relies on multiple extracellular signaling cues and complex intracellular interactions. Approximately 1500 genes are associated with neurodevelopmental disorders, many of which are linked to a specific biochemical signaling cascade known as Extracellular-Signal Regulated Kinase (ERK1/2). Clearly defined mutations in regulators of the ERK1/2 pathway cause syndromes known as the RASopathies. Symptoms include intellectual disability, developmental delay, cranio-facial and cardiac deficits. Treatments for RASopathies are limited due to an in complete understanding of ERK1/2’s role in brain development. Individuals with Neurofibromatosis Type and Noonan Syndrome, the two most common RASopathies, exhibit aberrant functional and white matter organization in non-invasive imaging studies, however, the contributions of neuronal versus oligodendrocyte deficits to this phenotype are not fully understood. To define the cellular functions of ERK1/2 in motor circuit formation, this body of work focuses on two long-range projection neuron subtypes defined by their neurotransmitter. With genetic mouse models, pathological ERK1/2 in glutamatergic neurons reduces axonal outgrowth, resulting in deficits in activity dependent gene expression and the ability to learn a motor skill task. Restricting pathological ERK1/2 within cortical layer V recapitulates these wiring deficits but not the behavioral learning phenotype. Moreover, it is uncovered that pathological ERK1/2 results in compartmentalized expression pattern of phosphorylated ERK1/2. It is not clear whether ERK1/2 functions are similar in cholinergic neuron populations that mediate attention, memory, and motor control. Basal forebrain cholinergic neuron development relies heavily on NGF-TrKA neurotrophic signaling known to activate ERK1/2. Yet the function of ERK1/2 during cholinergic neuronal specification and differentiation is poorly understood. By selectively deleting ERK1/2 in cholinergic neurons, ERK1/2 is required for activity-dependent maturation of neuromuscular junctions in juvenile mice, but not the establishment of lower motor neuron number. Moreover, ERK1/2 is not required for specification of choline acetyltransferase expressing basal forebrain cholinergic neurons by 14 days of age. However, ERK1/2 may be necessary for BFCN maturation by adulthood. Collectively, these data indicate that glutamatergic neuron-autonomous decreases in long-range axonal outgrowth and modest effects on later stages of cholinergic neuron maintenance may be important aspects of neuropathogenesis in RASopathies.
ContributorsRees, Katherina Pavy (Author) / Newbern, Jason (Thesis advisor) / Olive, Foster (Committee member) / Qiu, Shenfeng (Committee member) / Sattler, Rita (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2024
Description
The GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common genetic abnormality associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastatingly progressive neurodegenerative diseases. The discovery of this genetic link confirmed that ALS and FTD reside along a spectrum with clinical and pathological commonalities. Historically understood as diseases resulting in neuronal death, the role of non-neuronal cells like astrocytes is still wholly unresolved. With evidence of cortical neurodegeneration leading to cognitive impairments in C9orf72-ALS/FTD, there is a need to investigate the role of cortical astrocytes in this disease spectrum. Here, a patient-derived induced pluripotent stem cell (iPSC) cortical astrocyte model was developed to investigate consequences of C9orf72-HRE pathogenic features in this cell type. Although there were no significant C9orf72-HRE pathogenic features in cortical astrocytes, transcriptomic, proteomic and phosphoproteomic profiles elucidated global disease-related phenotypes. Specifically, aberrant expression of astrocytic-synapse proteins and secreted factors were identified. SPARCL1, a pro-synaptogenic secreted astrocyte factor was found to be selectively decreased in C9orf72-ALS/FTD iPSC-cortical astrocytes. This finding was further validated in human tissue analyses, indicating that cortical astrocytes in C9orf72-ALS/FTD exhibit a reactive transformation that is characterized by a decrease in SPARCL1 expression. Considering the evidence for substantial astrogliosis and synaptic failure leading to cognitive impairments in C9orf72-ALS/FTD, these findings represent a novel understanding of how cortical astrocytes may contribute to the cortical neurodegeneration in this disease spectrum.
ContributorsBustos, Lynette (Author) / Sattler, Rita (Thesis advisor) / Newbern, Jason (Committee member) / Zarnescu, Daniela (Committee member) / Brafman, David (Committee member) / Mehta, Shwetal (Committee member) / Arizona State University (Publisher)
Created2023
Description
The process of brain development is magnificently complex, requiring the coordination of millions of cells and thousands of genes across space and time. It is therefore unsurprising that brain development is frequently disrupted. Numerous genetic mutations underlying altered neurodevelopment have been identified and aligned with behavioral changes. However, the cellular mechanisms linking genetics with behavior are incompletely understood. The goal of my research is to understand how intracellular kinase signaling contributes to the development of ventrally derived glia and neurons. Of particular interest are GABAergic interneurons in the cerebral cortex, as GABAergic disruption is observed in multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism spectrum disorders. In addition, I investigated how kinase signaling influences the number and distribution of ventral born oligodendrocyte lineage cells to gain insight into white matter abnormalities observed in developmental disorders. This work primarily investigates the mitogen associated protein kinase (MAPK) signaling cascade, which is ubiquitously expressed but is particularly important for brain development. Hyperactive MAPK signaling causes RASopathies, a group of neurodevelopmental disorders where affected individuals often exhibit learning disability. MAPK haploinsufficiency, such as in 16p11.2 deletion syndrome, also results in intellectual disability. In both cases, the cells driving cognitive dysfunction are unknown. Using genetically modified mouse models, I found that hyperactivation of MAPK signaling disrupts a subtype of GABAergic neurons that express parvalbumin, though the same cells are resilient to MAPK deletion. In contrast, somatostatin expressing neurons require MAPK for normal development but are less responsive to hyperactivation. Oligodendrocyte lineage cells have a bidirectional response to MAPK signaling, where hyperactivating MAPK increases cell number and deletion reduces glial number.
MAPK signaling activates several hundred downstream cues, but one of particular interest to this work is called Liver Kinase B1 (LKB1). LKB1 is a protein kinase which can regulate cell proliferation, survival, and metabolism. Here, I discovered that LKB1 is necessary for the development of parvalbumin expressing neurons. Collectively, these data identify disruption to certain ventral derivatives as a candidate pathogenic mechanism in neurodevelopmental conditions.
ContributorsKnowles, Sara Jane (Author) / Newbern, Jason (Thesis advisor) / Sattler, Rita (Committee member) / Balmer, Timothy (Committee member) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023
Description
Many animals possess a blood-brain barrier, which is a layer of cells that restricts the passage of molecules into the central nervous system. The primary function of the blood-brain barrier is to preserve ionic homeostasis within the brain; however, it is also responsible for selectively importing an array of nutritional and signaling molecules to support brain function and for exporting metabolic waste. Across the species in which it has been studied, the structure and function of the blood-brain barrier dynamically regulates the interaction between the brain and peripheral physiological systems. Honeybee (Apis mellifera) workers are a firmly established neurobiological model which can be utilized to answer questions about the physiological and environmental mechanisms that regulate central nervous system health and behavior. It is likely that the honeybee blood-brain barrier plays an important role mediating the interactions between the brain and its environment, however, the blood-brain barrier is largely unconsidered in the realm of honeybee neurobiological research. In this dissertation, I provide the first in depth characterizations of the structure and function of the honeybee blood-brain barrier. First, I characterized the ultrastructural organization of the honeybee blood-brain barrier. The results of this study demonstrate its structural heterogeneity, including how this heterogeneity compares between two age groups. Next, I assessed two dimensions of blood-brain barrier permeability among three honeybee age groups and among honeybees exposed to varying amounts of infestation with the parasitic mite Varroa destructor. This study demonstrated that paracellular permeability has greater resilience than transcellular permeability, the latter of which is particularly increased by a high parasitic load. Finally, I developed a novel technique combining stable isotope labelling and Nanoscale Secondary Ion Mass Spectrometry (NanoSIMS) to demonstrate that the large, pro-social protein vitellogenin is able to cross the honeybee blood-brain barrier into the brain. Together, these studies represent the first in-depth analysis of the honeybee blood-brain barrier, establishing new directions for understanding the regulation of honeybee health, disease, and behavior.
ContributorsQuigley, Tyler (Author) / Amdam, Gro V. (Thesis advisor) / Bose, Maitrayee (Committee member) / Newbern, Jason (Committee member) / Bimonte-Nelson, Heather (Committee member) / Oland, Lynne (Committee member) / Arizona State University (Publisher)
Created2024
Description
Serotonin 1B receptors (5-HT1BRs) are involved in cocaine reward via regulating activity of dopamine neurons. The 5-HT1BR agonist CP-94,253 or 5-HT1BR overexpression in the nucleus accumbens shell (NAcSh) enhances cocaine intake during maintenance of daily self-administration (SA) but inhibits intake after 21 days of abstinence in male rats. My central hypothesis is that CP-94,253 acts at 5-HT1BRs located on the terminals of NAcSh GABA neurons that undergo regulatory changes in response to cocaine SA and subsequent abstinence resulting in an abstinence-induced switch in the functional effects of CP-94,253 in both male and female rats. In the first series of experiments, I compared the functional effects of CP-94,253 in female rats to male rats: 1) during maintenance of daily cocaine SA, 2) after 21-60 days abstinence, and 3) during the resumption of cocaine SA after abstinence (i.e. model of relapse). I found that CP-94,253 enhanced cocaine intake and breakpoints on a high-effort progressive ratio schedule of cocaine reinforcement during maintenance regardless of sex. By contrast, CP-94,253 attenuated cocaine intake after 21 days of abstinence and during the relapse test, regardless of sex. These findings suggest: 1) an abstinence-induced inhibitory effect of the 5-HT1BR agonist occurs in both sexes, 2) these inhibitory effects are long-lasting, and 3) the agonist may provide a novel therapeutic for cocaine use disorders. I next used RNAscope in situ hybridization to measure regulatory changes in 5-HT1BR mRNA expression and its co-expression with GABAergic and glutamatergic cell markers in the lateral and medial NAcSh subregions after abstinence from cocaine. I found no significant changes in these measures in either subregion of NAcSh after prolonged abstinence in either sex; however, I did observe that 95% of 5-HT1BR mRNA is co-localized in GABAergic neurons, whereas <2% is co-localized in glutamatergic cells. Future research investigating abstinence-induced, functional changes in 5-HT1BRs in subregions of the NAcSh is an alternate approach to further test my hypothesis. This research is important for the development of 5-HT1BR agonists as putative treatments of cocaine use disorders.
ContributorsScott, Samantha N (Author) / Neisewander, Janet L (Thesis advisor) / Newbern, Jason (Committee member) / Olive, Michael F (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2024
Description
The ability to detect and appropriately respond to chemical stimuli is important for many organisms, ranging from bacteria to multicellular animals. Responses to these stimuli can be plastic over multiple time scales. In the short-term, the synaptic strengths of neurons embedded in neural circuits can be modified and result in various forms of learning. In the long-term, the overall developmental trajectory of the olfactory network can be altered and synaptic strengths can be modified on a broad scale as a direct result of long-term (chronic) stimulus experience. Over evolutionary time the olfactory system can impose selection pressures that affect the odorants used in communication networks. On short time scales, I measured the effects of repeated alarm pheromone exposure on the colony-level defense behaviors in a social bee. I found that the responses to the alarm pheromone were plastic. This suggests that there may be mechanisms that affect individual plasticity to pheromones and regulate how these individuals act in groups to coordinate nest defense. On longer time scales, I measured the behavioral and neural affects of bees given a single chronic odor experience versus bees that had a natural, more diverse olfactory experience. The central brains of bees with a deprived odor experience responded more similarly to odorants in imaging studies, and did not develop a fully mature olfactory network. Additionally, these immature networks showed behavioral deficits when recalling odor mixture components. Over evolutionary time, signals need to engage the attention of and be easily recognized by bees. I measured responses of bees to a floral mixture and its constituent monomolecular components. I found that natural floral mixtures engage the orientation of bees’ antennae more strongly than single-component odorants and also provide more consistent central brain responses between stimulations. Together, these studies highlight the importance of olfactory experience on different scales and how the nervous system might impose pressures to select the stimuli used as signals in communication networks.
ContributorsJernigan, Christopher (Author) / Smith, Brian H. (Thesis advisor) / Newbern, Jason (Committee member) / Harrisoin, Jon (Committee member) / Rutowski, Ronald (Committee member) / Pratt, Stephen (Committee member) / Arizona State University (Publisher)
Created2018
Description
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. When TBI occurs in children it often results in severe cognitive and behavioral deficits. Post-injury, the pediatric brain may be sensitive to the effects of TBI while undergoing a number of age-dependent physiological and neurobiological changes. Due to the nature of the developing cortex, it is important to understand how a pediatric brain recovers from a severe TBI (sTBI) compared to an adult. Investigating major cortical and cellular changes after sTBI in a pediatric model can elucidate why pediatrics go on to suffer more neurological damage than an adult after head trauma. To model pediatric sTBI, I use controlled cortical impact (CCI) in juvenile mice (P22). First, I show that by 14 days after injury, animals begin to show recurrent, non-injury induced, electrographic seizures. Also, using whole-cell patch clamp, layer V pyramidal neurons in the peri-injury area show no changes except single-cell excitatory and inhibitory synaptic bursts. These results demonstrate that CCI induces epileptiform activity and distinct synaptic bursting within 14 days of injury without altering the intrinsic properties of layer V pyramidal neurons. Second, I characterized changes to the cortical inhibitory network and how fast-spiking (FS) interneurons in the peri-injury region function after CCI. I found that there is no loss of interneurons in the injury zone, but a 70% loss of parvalbumin immunoreactivity (PV-IR). FS neurons received less inhibitory input and greater excitatory input. Finally, I show that the cortical interneuron network is also affected in the contralateral motor cortex. The contralateral motor cortex shows a loss of interneurons and loss of PV-IR. Contralateral FS neurons in the motor cortex synaptically showed greater excitatory input and less inhibitory input 14 days after injury. In summary, this work demonstrates that by 14 days after injury, the pediatric cortex develops epileptiform activity likely due to cortical inhibitory network dysfunction. These findings provide novel insight into how pediatric cortical networks function in the injured brain and suggest potential circuit level mechanisms that may contribute to neurological disorders as a result of TBI.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Qiu, Shenfeng (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2015
Description
MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the Knowledgebase of Addiction-Related Genes (KARG) database and to be highly expressed in the nucleus accumbens (NAc), a pivotal brain region involved in reward and motivation. The central hypothesis of this dissertation is that NAc miR-495 regulates drug abuse-related behavior by targeting several addiction-related genes (ARGs). I tested this hypothesis in two ways: 1) by examining the effects of viral-mediated miR-495 overexpression or inhibition in the NAc of rats on cocaine abuse-related behaviors and gene expression, and 2) by examining changes in NAc miR-495 and ARG expression as a result of brief (i.e., 1 day) or prolonged (i.e., 22 days) cocaine self-administration. I found that behavioral measures known to be sensitive to motivation for cocaine were attenuated by NAc miR-495 overexpression, including resistance to extinction of cocaine conditioned place preference (CPP), cocaine self-administration on a high effort progressive ratio schedule of reinforcement, and cocaine-seeking behavior during both extinction and cocaine-primed reinstatement. These effects appeared specific to cocaine, as there was no effect of NAc miR-495 overexpression on a progressive ratio schedule of food reinforcement. In contrast, behavioral measures known to be sensitive to cocaine reward were not altered, including expression of cocaine CPP and cocaine self-administration under a low effort FR5 schedule of reinforcement. Importantly, the effects were accompanied by decreases in NAc ARG expression, consistent with my hypothesis. In further support, I found that NAc miR-495 levels were reduced and ARG levels were increased in rats following prolonged, but not brief, cocaine self-administration experience. Surprisingly, inhibition of NAc miR-495 expression also decreased both cocaine-seeking behavior during extinction and NAc ARG expression, which may reflect compensatory changes or unexplained complexities in miR-495 regulatory effects. Collectively, the findings suggest that NAc miR-495 regulates ARG expression involved in motivation for cocaine. Therefore, using microRNAs as tools to target several ARGs simultaneously may be useful for future development of addiction therapeutics.
ContributorsBastle, Ryan (Author) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Nikulina, Ella (Committee member) / Perrone-Bizzozero, Nora (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2016