Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Apr. 16, 2010). Includes bibliographical references (p. 36-37).

Made available in DSpace on 2014-06-11T19:30:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-08-26Bitstream added on 2014-06-13T20:20:53Z : No. of bitstreams: 1 mueller_sf_dr_botfm.pdf: 3632407 bytes, checksum: 5c96dde184f5286d0dd7bdf6d6ecf7a0 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Neste trabalho, propomos um modelo experimental para tratamento de lesões parciais do plexo braquial e estudamos a regeneração axonial em enxertos de nervo suturados com neurorrafia término-lateral entre os troncos do plexo braquial, mais precisamente entre o tronco superior e tronco inferior e entre tronco médio e tronco inferior. Foram utilizados 30 ratos Wistar, adultos, machos, divididos nos grupos Desnervado (GD), Neurorrafia (GN) e Controle (GC). Em um primeiro momento cirúrgico foi retirado um segmento de 1 cm do nervo cutâneo sural caudal direito. Em seguida, realizada a avulsão total das raízes de C8 e T1(tronco inferior). No Grupo Neurorrafia o enxerto de nervo autólogo foi dividido em dois segmentos. Um segmento fixado à face lateral intacta do tronco superior a ao tronco inferior avulsionado, sem janela epineural, e o outro segmento fixado entre a face lateral do tronco médio e tronco inferior. No grupo desnervado, somente foi realizada a avulsão do tronco inferior. O grupo controle não foi submetido a procedimento cirúrgico. Foi realizado o “Grasping Test” e também estudo eletrofisiológico. Amostras dos enxertos e músculo foram coletadas no período de 16 semanas após a cirurgia e processadas para microscopia óptica. As imagens capturadas dos cortes semifinos foram utilizadas para as análises quantitativas dos axônios regenerados. A observação histológica confirmou a presença de axônios mielínicos nos enxertos e tronco inferior de ambos os grupos. A análise estatística foi realizada com a Análise de Variância (ANOVA), seguida pelo Teste de Tukey, quando detectada diferença estatística. No pós-operatório tardio... / In this work, we propose an experimental model for treatment of partially brachial plexus injury and studied the regeneration of axons in nerve grafts sutured with endto- side neurorrhaphy between the trunks of brachial plexus, more precisely between the upper and lower trunk and middleand lower trunk. We used 30adult, male rats, divided in to groups denervated (DG), neuorraphy (GN) and control (CG). At first it was surgically removed a segment of 1 cm of the right sural nerve. After perform the total avulsion of the roots C8 and T1 (lower trunk). In NG the graft was divided into two segments. A segment attached to the side of intact upper trunk to the lower trunk avulsioned without epineural window, and another segment set between the side of the middle trunk and lower trunk. In DG, was held to only avulsion of the lower trunk. The CG was not undergo a surgical procedure. It was carried out Grasping Test and also electrophysiological study. Samples of the grafts and muscle were collected in the period of 16 weeks after surgery and processed for light microscopy. Captured images of the thin cuts were used for quantitative analyses of regenerated axons. The observation confirmed the presence of histological myelin axons in grafts and lower trunk of both groups. The statistical analysis was performed with the analysis of variance (ANOVA), followed by Tukey test, when detected statistical difference. In the late postoperative period, Grasping Test showed statistically significant differences between groups, and NG> GD (p <0001); GC> GD (p <0001); NG <GC (p <0001). In electrophysiological study, showed statistically significant differences in scale, and (GN> GD (p = 0004); GC> GD (p <0001); NG <GC (p <0001)). As the field of nerve fiber, the area of axons and thickness... (Complete abstract click electronic access below)

Abstract The arm includes a large number of nerve fibres that transfer information between the central nervous system and the receptors, muscles and glands of the arm. In the nervous system there is continuous traffic. At rest, when only the receptors send information continuously towards the central nervous system, the traffic is not as intensive as during stress, e.g. during movements of the arm, when the central nervous system sends information towards the muscles, as well. From an information and communication engineering perspective the nervous system of the arm is an information channel, the other end of which is in the central nervous system and the other end at the periphery of the arm. One principal question about such a communication system is what the maximum information transmission capacity of the channel is, e.g. how the information channel is dimensioned. The arm is a highly complex system with over sixty muscles moving it, and a huge number of sensory receptors in it. Nature has dimensioned the information channel of the arm to satisfy the requirements of the nervous system. In this thesis a specific mathematical model is built in order to evaluate the maximum information transmission capacity of the nervous system of the arm. The model handles the nervous system of the arm as an entity in the light of information theory. The model uses the physiological and functional properties of the nervous system of the arm as the input and gives the estimate of the maximum information transmission capacity as the output. The modelling yielded the result that the maximum information transmission capacity of the arm is about 10 Mbit/s. Hence, if a complete neural prosthesis of the arm were built, a single USB bus (12 Mbit/s) would suffice as a communication channel for each arm. The mathematical model developed can also be applied to other parts of the peripheral nervous system. The aim of future research is to apply the developed model comprehensively to the human peripheral nervous system and to estimate the maximum information transmission capacity of the whole human peripheral nervous system.

Clearance of molecularly damaged and misfolded synaptic vesicle (SV) proteins is vital for the maintenance of healthy, functional synapses. However, this process poses significant trafficking challenges for neurons, as the majority of degradative organelles and machinery are localized in the somatodendritic compartment, far from SV pools in presynaptic terminals. Our previous work showed that SV protein degradation is mediated by the endosomal sorting complex required for transport (ESCRT) pathway in an activity-dependent manner. Moreover, we found that neuronal activity increased ESCRT protein recruitment to axons and SV pools, suggesting a novel mechanism for regulating the trafficking of this critical degradative machinery, whose localization and transport in neurons has been unexplored. Here, we characterize the axonal transport of ESCRT-0 proteins Hrs and STAM1, the first components of the ESCRT pathway, which are critical for initiating SV protein degradation. We find that Hrs- and STAM1-positive transport vesicles exhibit increased anterograde and bidirectional motility in response to neuronal activity, as well as frequent contact with SV pools. ESCRT-0 vesicles typically colocalize with early endosome marker Rab5, but their transport dynamics do not mirror those of the total Rab5 vesicle pool. Moreover, other ESCRT pathway components and effectors do not show activity-dependent changes to motility, indicating that neuronal firing specifically regulates the motility of the ESCRT-0+ subset of Rab5+ structures in axons. Finally, we identify kinesin-3 motor protein KIF13A as essential for the activity-dependent transport of ESCRT-0 vesicles as well as the degradation of SV membrane proteins. Altogether, these studies demonstrate a novel activity-dependent mechanism for mobilizing the axonal transport of a newly characterized endosomal subtype carrying ESCRT machinery. This activity-induced transport is necessary for ESCRT-mediated degradation of synaptic vesicle proteins.

Neurons establish complex networks within the nervous system allowing for rapid cell-cell communication via their long, thin axonal processes. These wire-thin projections are susceptible to a number of insults or injuries, and axonal damage can lead to disruption in signal propagation and an overall dysfunction of the neural network. Recent research focused on investigating the underlying mechanisms of injury-induced axon degeneration led to the discovery of a number of endogenous, pro-degenerative molecules such as dSarm/Sarm1, Highwire/Phr1, and Axundead. These signaling molecules are thought to execute axon degeneration in response to injury locally within the distal severed axon, but the exact mechanism of action is unclear. To further identify novel participants of the axon death signaling cascade, we performed an unbiased forward genetic mutagenesis screen using the sensory neurons within the adult wing of Drosophila melanogaster. We identified a novel role for the C2H2 zinc finger transcription factor, Pebbled (Peb)/Ras-responsive element binding protein 1 (RREB1) in partially suppressing injury-induced axon degeneration. Loss of function peb mutant glutamatergic neurons present two distinct axon degeneration defects: either complete protection from axotomy, or they exhibit a novel phenotype in which axons fragment into long, continuous pieces instead of undergoing complete degeneration. Additionally, we show an enhancement of the peb protective phenotype when dSarm levels are decreased, but not with reduced levels of axundead. These data provide the first evidence of a transcription factor involved in regulating injury-induced axon degeneration signaling in vivo.

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Developmental and epileptic encephalopathies (DEE) represent a set of rare but devastating and largely intractable childhood epilepsies. While mouse models have made innumerable contributions to understanding the genetic basis of neurological diseases, only a small fraction of missense, gain-of-function DEE variants has been modeled in mice. In this dissertation, we focus on one DEE gene, ARHGEF9. With fewer than fifty ARHGEF9 patients reported to date, ARHGEF9 can be considered one of the rare players in DEE. ARHGEF9 encodes a brain-specific protein also known as collybistin (CB), a guanine nucleotide exchange factor and an essential regulator of inhibitory postsynaptic density. In Chapter 3 and Chapter 4, we present results and ongoing studies from our efforts to unravel the pathological mechanism of ARHGEF9 DEE. We studied the G55A variant on the SH3 domain, which was discovered in one severe case of DEE. Using a novel Arhgef9G55A mouse model, we examined behavioral, cellular, and electrophysiological consequences of Arhgef9G55A. Results demonstrate that the Arhgef9G55A mouse model is an adequate ARHGEF9 DEE model, because it phenocopies key aspects of human ARHGEF9 DEE. We showed the interesting protein aggregation phenotype caused by the G55A variant. Specifically, in Arhgef9G55A/Y neurons, CB forms protein aggregates at the proximal AIS, leading to dramatic disruptions in inhibitory postsynaptic components at the AIS. Furthermore, electrophysiological studies revealed significant changes in intrinsic neuronal excitability and synaptic transmission in Arhgef9G55A/Y brains. The work within this dissertation shows that the G55A variant disrupts axon initial segment structure and functions. In Chapter 2, we review and summarize current understandings on AIS structure and functions. We highlight the central role of the AIS in initiating action potential and integrating synaptic inputs through axo-axonic synapses. Based on our experimental results, we propose that disruptions in AIS function are closely tied to the pathophysiology of ARHGEF9 DEE. Aside from the clinical significance of our study, we demonstrate the important role of CB at the AIS. We propose that CB is a specific stabilizer of axo-axonic synapses. The difference in the requirement of CB in inhibitory synapse formation in different neuronal compartments could be a core molecular machinery underlying the functional diversity of inhibitory inputs.

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The AMP-activated protein kinase (AMPK) is a master metabolic regulator and energy sensor that has been extensively studied in the context of cancer and metabolic disorders. However, its role in neuronal function and morphology remains largely unexplored. This dissertation aims to bridge this gap by investigating the roles of AMPK in maintaining axon homeostasis and regulating mitochondrial morphology in neurons. By identifying novel regulators of AMPK across different cellular compartments, this thesis sheds light on the multifaceted functions of AMPK in shaping neuronal and mitochondrial architecture. The dissertation is organized into five chapters. Chapter 1 provides a brief background on AMPK, its activation mechanisms, and the downstream pathways it regulates. Chapter 2 introduces with-no-lysine kinase (WNK), a novel axon morphogenic kinase with dual roles in terminal axon branch development and maintenance in mature axons. Chapter 3 investigates the role of AMPK in mediating the loss-of-WNK axonal phenotypes, revealing a critical link between AMPK and axonal integrity. Chapter 4 shifts focus to the mitochondrial, characterizing mitochondrial fission regulator 1-like (MTFR1L) as a novel AMPK-activated protein that regulates mitochondrial morphology. Finally, Chapter 5 explores the role of AMPK in mediating activity-dependent mitochondrial morphology in hippocampal CA1 neurons, highlighting the dynamic interplay between neuronal activity and mitochondrial dynamics. Collectively, these findings provide novel insights into the multifaceted roles of AMPK in neuronal development, degeneration, and organelle regulation, underscoring the importance of this master kinase in maintaining neuronal health and homeostasis.