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035 a| (Sirsi) o1056953874;

035 a| (OCoLC)1056953874;

049 a| EREE;

100 1 a| Rudisill, Taylor Lee,e| author.?| UNAUTHORIZED;

245 10 a| Pharmacological regulation of neural circuit formation in hIPSC-derived neurons and 'mini-brains' /c| by Taylor Lee Rudisill.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2018.;

300 a| 87 pages :b| illustrations (chiefly color).;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 18.93 MB2| rda;

490 1 a| ECU Brody School of Medicine thesis;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| M.S.c| East Carolina Universityd| 2018;

500 a| Presented to the faculty of the Department of Anatomy and Cell Biology;

500 a| Advisor: Karen Litwa;

500 a| Title from PDF t.p. (viewed February 5, 2019).;

520 3 a| 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.;

504 a| Includes bibliographical references.;

650 2 a| Neural Pathways.=| ^A920379;

650 2 a| Neurons.=| ^A918878;

650 2 a| Induced Pluripotent Stem Cells.=| ^A1098933;

653 a| 'Mini-Brains';

653 a| Y-27632;

655 7 a| Academic theses.2| lcgft;

700 1 a| Litwa, Karen,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Anatomy and Cell Biology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/6964;

949 o| wjh;

994 a| C0b| ERE;

096 a| WL 101;

596 a| 1 4;

998 a| 4931030;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4931030-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 10/15/2018x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4931030-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 10/15/2018x| ETDz| HERESOURCE;

Pharmacological regulation of neural circuit formation in hIPSC-derived neurons and 'mini-brains' / by Taylor Lee Rudisill.

Author/creator	Rudisill, Taylor Lee author.
Other author	Litwa, Karen, degree supervisor.
Other author	East Carolina University. Department of Anatomy and Cell Biology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2018.
Description	87 pages : illustrations (chiefly color).
Supplemental Content	Access via ScholarShip
Subjects	Neural Pathways. Neurons. Induced Pluripotent Stem Cells.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	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.
General note	Presented to the faculty of the Department of Anatomy and Cell Biology
General note	Advisor: Karen Litwa
General note	Title from PDF t.p. (viewed February 5, 2019).
Dissertation note	M.S. East Carolina University 2018
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.
Genre/form	Academic theses.

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Pharmacological regulation of neural circuit formation in hIPSC-derived neurons and 'mini-brains' / by Taylor Lee Rudisill.

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