Advisor | Litwa, Karen | |
Author | Rudisill, Taylor Lee | |
Date Accessioned | 2018-08-14T15:05:07Z | |
Date Available | 2021-08-01T08:01:55Z | |
Date Created | 2018-08 | |
Date of Issue | 2018-07-20 | |
xmlui.metadata.dc.date.submitted | August 2018 | |
Identifier (URI) | http://hdl.handle.net/10342/6964 | |
Description | Emerging evidence suggests that altered neural connectivity, particularly at the level of synaptic connections, contributes to the pathology of many neurodevelopmental and neurodegenerative diseases. For instance, post-mortem Autistic patient brain samples have increased numbers of excitatory to inhibitory synaptic connections, referred to as an E/I imbalance [42]. Contrastingly, post-mortem brain samples from patients diagnosed with Alzheimer's disease have decreased numbers of synaptic connections [42]. In order to understand the mechanisms that underlie the formation of these synaptic circuits, we develop 3-D human cortical organoids ('mini-brains') from human-induced pluripotent stem cells (hIPSCs). Previous research demonstrates that rearrangements of the actomyosin cytoskeleton drive neural circuit formation, in particular the development and maturation of actin-enriched spines at excitatory synapses. This thesis work investigates how pharmacological regulation of actomyosin activity affects neuronal connectivity during neurite formation in 2-D and excitatory synapse formation in 3-D 'mini-brains'. The Rho-Kinase (ROCK) inhibitor, Y-27632, both inhibits non-muscle myosin II (NM-II) and leads to a corresponding increase in Rac-driven actin polymerization. In 2-D, Y-27632 promotes neurite formation. Specifically, Y-27632 increases the number, length, and branching of neurites in hIPSC-derived neurons. Furthermore, Y-27632 increases neurite persistence, while decreasing neurite protrusion and retraction rates. However, in 3-D, acute Y-27632 treatment increases excitatory synapse area, consistent with an increase in Rac-driven actin polymerization [39]. Thus, Y-27632 increases both neurite outgrowth and excitatory synapse formation and may serve as a potential therapeutic for neurodegenerative diseases associated with synapse loss such as Alzheimer's disease. This study demonstrates the need for physiologically-relevant brain models, such as 3-D cortical organoids, to assess the impact of drug therapies on developing neural circuits to potentially treat neurodevelopmental and neurodegenerative disorders. | |
Mimetype | application/pdf | |
Language | en | |
Publisher | East Carolina University | |
Subject | 'Mini-Brains' | |
Subject | Y-27632 | |
Medical Subject Headings | Neural Pathways | |
Medical Subject Headings | Neurons | |
Medical Subject Headings | Induced Pluripotent Stem Cells | |
Title | Pharmacological Regulation of Neural Circuit Formation in hIPSC-Derived Neurons and ‘Mini-Brains’ | |
Type | Master's Thesis | |
xmlui.metadata.dc.date.updated | 2018-08-09T20:02:11Z | |
Department | Anatomy and Cell Biology | |
xmlui.metadata.dc.degree.name | M.S. | |
xmlui.metadata.dc.degree.level | Masters | |
xmlui.metadata.dc.degree.discipline | MS-Biomedical Science | |
xmlui.metadata.dc.degree.grantor | East Carolina University | |
xmlui.metadata.dc.degree.department | Anatomy and Cell Biology | |
xmlui.metadata.dc.access.option | Open Access | |
xmlui.metadata.dc.embargo.lift | 2021-08-01(one year extension) | |
xmlui.metadata.dc.type.material | text | |