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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- All Subjects: Neurosciences
- Creators: Balmer, Timothy
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
Synaptosomes are isolated nerve terminals that contain pre- and post-synapticproteins and can be used to model functionally intact synapses. While the quantification and characterization of synaptosomes have been used to study neurological conditions and diseases, relatively few studies have included the use of flow cytometry in the quantification and analytical processes. As such, this study highlights the use of flow cytometry in the synaptosomal quantification process and describes the adaptation of a previously performed synaptic flow protocol to find the optimal concentrations, protein- to-antibody ratios and gating strategies that meet the goals of this and future studies. To validate the protocol, three independent experiments measuring different treatments – traumatic brain injury (TBI), neurodevelopment, and ketamine - on synaptosomal quantity were conducted and compared to pre-existing literature. Despite the high standard deviation values between certain sample replicates, the synaptic flow protocol was validated by the right-skewed nature of the frequency distribution of the standard deviations between sample replicates and that most of the deviations fell below 40% of the maximum variance value. Further analysis showed significant differences (p < 0.05) between the ketamine and TBI groups compared to the control group while no significant differences were observed between the neurodevelopment (P30) group. This study validates the use of flow cytometry in synaptosomal quantification while providing insight to the potential of the synaptic flow protocol in future TBI and psychoplastogen studies.
ContributorsChua, Wan Rong (Author) / Lifshitz, Jonathan (Thesis advisor) / Balmer, Timothy (Thesis advisor) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023
Description
The cerebellum predicts and corrects motor outputs based on sensory feedback for smoother and more precise movements, thus contributing to motor coordination and motor learning. One area of the cerebellum, the vestibulocerebellum, integrates vestibular and visual information to regulate balance, gaze stability, and spatial orientation. Highly concentrated within the granule cell layer of this region is a class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) that receive input from mossy fibers and synapse onto multiple granule cells and other UBCs. They can be divided into ON and OFF subtypes based on their responses to synaptic stimulation. Prior research has implicated ON UBCs in motor dysfunction, but their role in motor coordination, balance, and motor learning is unclear. To test the hypothesis that ON UBCs contribute to motor coordination and balance, a transgenic mouse line (GRP-Cre) was used to express the GqDREADD (Gq designer receptors exclusively activated by designer drugs) hM3Dq in a subset of ON UBCs in the cerebellum to disrupt their electrical activity. In a second set of experiments, a Cre-dependent caspase 3 AAV (adeno-associated virus) viral vector was injected into the nodulus of the vestibulocerebellum of GRP-Cre mice to selectively ablate a subset of ON UBCs in the region and test whether they were necessary for motor learning. Motor coordination and balance were assessed using the rotor-rod and balance beam in young mice, and the forced swim test was used to assess vestibular function in older mice. Activity levels, anxiety, gross locomotion, and exploration in young mice were assessed using the open field. The results show that neither motor coordination and balance, nor motor learning, were impaired when the ON UBCs were disrupted or ablated in young mice. However, disruptions affected climbing behavior in older mice during the forced swim test, suggesting an age-dependent effect of ON UBCs on vestibular function.
ContributorsKizeev, Gabrielle (Author) / Balmer, Timothy (Thesis advisor) / Newbern, Jason (Committee member) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023