Introdução: Plasticidade auditiva refere-se a mudanças que ocorrem no sistema sensorial responsável pela transmissão da informação acústica. A plasticidade do sistema nervoso auditivo central está relacionada a capacidade de adaptação através da reintrodução de estímulos por meio de aparelhos de amplificação sonora ou implante coclear. Essas mudanças são observadas a partir do desempenho de pacientes com o uso do aparelho de amplificação sonora, e podem ser verificadas por meio dos potenciais evocados auditivos de longa latência. Objetivo: caracterizar os Potenciais Evocados Auditivos de Longa Latência (PEALL) em adultos e idosos com perda auditiva neurossensorial, verificando os efeitos da estimulação auditiva por meio da comparação destes potenciais pré e pós adaptação do Aparelho de Amplificação Sonora Individual (AASI). Metodologia: Participaram deste estudo 15 indivíduos adultos e idosos, de ambos os gêneros, de 55 a 85 anos de idade, com perda auditiva neurossensorial de grau leve a moderado com simetria entre as orelhas, sem experiência prévia com qualquer tipo de dispositivo de amplificação sonora. Os indivíduos foram encaminhados pelas empresas de aparelho auditivo WIDEX, Audibel e o Espaço Reouvir, tratando-se de novos usuários de AASI. Os PEALL foram realizados nas condições com e sem AASI, a 60 e 75 dBnNA em campo sonoro, em dois momentos: primeira avaliação realizada até uma semana após a adaptação do AASI e a segunda avaliação realizada após 6 meses da adaptação do AASI. Resultados: Na comparação da primeira avaliação com a segunda avaliação, na condição sem AASI a 60 dBnNA, observou-se diferença estatisticamente significante na latência do componente P1 (p-valor= 0,034). Na condição sem AASI a 75 dBnNA, observou-se diferença estatisticamente significante para a latência do componente P300 (p-valor 0,031) e para a amplitude P2N2 (p-valor 0,024), com diminuição da latência e aumento da amplitude na segunda avaliação. Por sua vez, na comparação da primeira avaliação com a segunda avaliação, na condição com AASI a 75 dBnNA, obteve-se uma diferença estatisticamente significante na latência do componente N2 (p-valor 0,009) e na amplitude P2N2 (p-valor 0,024), com aumento da amplitude na segunda avaliação. Evidenciou-se, também, diferença significante na amplitude P1N1 (p-valor 0,024) na condição com AASI a 60 dBnNA. Conclusão: Os PEALL com estímulo de fala demonstraram ser um importante procedimento para ser utilizado na prática clínica, visando monitorar a plasticidade neuronal do Sistema Nervoso Auditivo Central frente à estimulação auditiva (uso de AASI), em adultos e idosos com perda auditiva neurossensorial de grau leve a moderado / Introduction: Auditory plasticity refers to changes that occur in the sensory system responsible for the transmission of acoustic information. The plasticity of the central auditory nervous system is related to the capacity of adaptation through the reintroduction of stimuli of sound amplification devices or cochlear implants. These changes are observed from the performance of patients with the use of the sound amplification apparatus, and can be verified by long-latency auditory evoked potentials. Purpose: To characterize long latency auditory evoked potentials (LLAEP) in adults with sensorineural hearing loss, verifying the effects of auditory stimulation by comparing these before and after adaptation potentials of the Individual Sound Amplification (AASI). Methodology: Fifteen adult and elderly individuals of both genders, aged 55 to 85 years, with mild to moderate sensorineural hearing loss with symmetry between the ears, without prior experience with any type of sound amplification device. The subjects were referred by hearing aid companies WIDEX, Audibel and Espaço Reouvir, in the case of new hearing aids users. The LLAEP were performed in the conditions with and without AASI, at 60 and 75 dBnNA in sound field, in two moments: first evaluation performed up to one week after AASI adaptation and the second evaluation performed after 6 months of AASI adaptation. Results: In the comparison of the first evaluation with the second evaluation, in the condition without AASI at 60 dBnNA, a statistically significant difference was observed in the latency of the P1 component (p-value = 0.034). In the condition without AASI at 75 dBnNA, a statistically significant difference was observed for the latency of the P300 component (p-value 0.031) and for the P2N2 amplitude (p-value 0.024), with latency decrease and amplitude increase in the second evaluation. In the comparison of the first evaluation with the second evaluation, in the condition with AASI at 75 dBnNA, there was a statistically significant difference in the latency of the N2 component (p-value 0.009) and in the P2N2 amplitude (p-value 0.024) , With amplitude increase in the second evaluation. There was also a significant difference in P1N1 amplitude (p-value 0.024) in the condition with AASI at 60 dBnNA. Conclusion: The LLAEP was an important procedure to be used in clinical practice, aiming to monitor the neural plasticity of the Central Auditory Nervous System in front of auditory stimulation (hearing aids use) in adults and elderly patients with mild to moderate sensorineural hearing loss of amplification and the importance of neural plasticity of the Central Auditory Nervous System

Leung, Yeung Yeung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 134-154). / Abstracts in English and Chinese. / CONTENTS --- p.i / ACKNOWLEDGEMENTS --- p.iv / ABSTRACT --- p.v / 論文摘要 --- p.viii / LIST OF FIGURES --- p.x / LIST OF TABLES --- p.xiv / LIST OF ABBREVIATIONS --- p.xv / Chapter 1. --- INTRODUCTION --- p.1 / Chapter 1.1 --- Brain iron function and diseases --- p.1 / Chapter 1.1.1 --- Function of iron in the brain --- p.1 / Chapter 1.1.2 --- Iron involved oxidative damage --- p.2 / Chapter 1.1.3 --- Role of iron in neurodegenerative diseases --- p.6 / Chapter 1.1.4 --- Role of iron in Alzheimer's disease --- p.7 / Chapter 1.1.5 --- Deleterious effects of iron in memory function --- p.9 / Chapter 1.2 --- Iron regulation in the brain --- p.10 / Chapter 1.2.1 --- Transport and storage of brain iron --- p.10 / Chapter 1.2.2 --- Iron homeostasis in the brain --- p.14 / Chapter 1.2.3 --- Transport of iron in axon and synapse --- p.17 / Chapter 1.3 --- The hippocampus --- p.19 / Chapter 1.3.1 --- Hippocampus and memory function --- p.19 / Chapter 1.3.2 --- Structure of the hippocampus --- p.20 / Chapter 1.3.3 --- Cell composition in the hippocampus --- p.26 / Chapter 1.3.4 --- Wiring in the hippocampus --- p.28 / Chapter 1.4 --- Synaptic plasticity and long term potentiation --- p.30 / Chapter 1.4.1 --- Basic theory of synaptic plasticity --- p.30 / Chapter 1.4.2 --- Types of synaptic plasticity --- p.30 / Chapter 1.4.3 --- The discovery of long term potentiation --- p.31 / Chapter 1.4.4 --- Long term potentiation --- p.32 / Chapter 1.4.5 --- Cellular mechanism of long term potentiation --- p.33 / Chapter 1.4.6 --- Role of reactive oxygen species in long term potentiation --- p.36 / Chapter 1.5 --- Aim of the study --- p.38 / Chapter 2. --- MATERIALS AND METHODS --- p.39 / Chapter 2.1 --- Rat model of iron overload --- p.39 / Chapter 2.2 --- Multi-electrode field potential measurement --- p.40 / Chapter 2.2.1 --- Acute preparation of hippocampal slices --- p.40 / Chapter 2.2.2 --- Multi-electrode array recording system --- p.41 / Chapter 2.2.3 --- Recording of field excitatory postsynaptic potentials --- p.42 / Chapter 2.2.4 --- Induction of LTP --- p.47 / Chapter 2.2.5 --- Recording of paired-pulse ratio --- p.48 / Chapter 2.3 --- Whole cell patch-clamp recordings --- p.50 / Chapter 2.4 --- Biochemical assays --- p.57 / Chapter 2.4.1 --- Preparation of brain homogenate --- p.57 / Chapter 2.4.2 --- Total iron measurement --- p.57 / Chapter 2.4.3 --- Protein carbonyl measurement --- p.58 / Chapter 2.4.4 --- Determination of reactive oxygen species --- p.60 / Chapter 2.5 --- Drugs and data analysis --- p.61 / Chapter 3. --- RESULTS --- p.62 / Chapter 3.1 --- The acute effects of extracellular iron on synaptic transmission and long-term synaptic plasticity in the hippocampus in vitro --- p.63 / Chapter 3.1.1 --- Effects of ferric ion on basal synaptic transmission --- p.63 / Chapter 3.1.1.1 --- Effect of FAC on basal fEPSPs --- p.63 / Chapter 3.1.1.2 --- Comparison with the effect of AC on basal fEPSPs --- p.69 / Chapter 3.1.2 --- Effects of ferric ion on long-term synaptic plasticity --- p.72 / Chapter 3.1.2.1 --- Effect of acute FAC treatment on LTP --- p.72 / Chapter 3.1.2.2 --- Comparison with the effect of AC on LTP --- p.75 / Chapter 3.1.3 --- Effects of ferric chloride --- p.78 / Chapter 3.1.4 --- Effects of ascorbic acid on the action of FAC --- p.81 / Chapter 3.2 --- "The acute, in vitro effect of extracellular iron on the membrane properties and excitability of hippocampal CA1 neurons" --- p.86 / Chapter 3.2.1 --- Membrane input resistance --- p.86 / Chapter 3.2.2 --- Voltage-Current relationship --- p.88 / Chapter 3.2.3 --- Membrane excitability --- p.90 / Chapter 3.2.3.1 --- Threshold current --- p.90 / Chapter 3.2.3.2 --- Action potential firing frequency --- p.92 / Chapter 3.2.4 --- Action potential characteristics --- p.95 / Chapter 3.2.4.1 --- "Action potential amplitude, area and width" --- p.95 / Chapter 3.2.4.2 --- Rise and decay kinetics of action potential --- p.98 / Chapter 3.3 --- The chronic effects of iron-loading in the brain on hippocampal long-term synaptic plasticity --- p.100 / Chapter 3.3.1 --- Validation of the iron-overload model --- p.100 / Chapter 3.3.1.1 --- Short-term (1 week) treatment --- p.100 / Chapter 3.3.1.2 --- Long-term (4 weeks) treatment --- p.103 / Chapter 3.3.2 --- Effects of chornic iron-overloading on LTP --- p.105 / Chapter 3.3.2.1 --- Short term iron treatment --- p.105 / Chapter 3.3.2.2 --- Long term iron treatment --- p.108 / Chapter 3.3.3 --- Oxidative stress measurement --- p.111 / Chapter 3.3.3.1 --- Protein oxidation --- p.111 / Chapter 3.3.3.2 --- Reactive oxidative species level --- p.116 / Chapter 4. --- DISCUSSION --- p.120 / Chapter 4.1 --- "Acute, in vitro effects" --- p.121 / Chapter 4.2 --- "Chronic, in vivo effects" --- p.125 / Chapter 5. --- REFERENCES --- p.134

Introdução: Plasticidade auditiva refere-se a mudanças que ocorrem no sistema sensorial responsável pela transmissão da informação acústica. A plasticidade do sistema nervoso auditivo central está relacionada a capacidade de adaptação através da reintrodução de estímulos por meio de aparelhos de amplificação sonora ou implante coclear. Essas mudanças são observadas a partir do desempenho de pacientes com o uso do aparelho de amplificação sonora, e podem ser verificadas por meio dos potenciais evocados auditivos de longa latência. Objetivo: caracterizar os Potenciais Evocados Auditivos de Longa Latência (PEALL) em adultos e idosos com perda auditiva neurossensorial, verificando os efeitos da estimulação auditiva por meio da comparação destes potenciais pré e pós adaptação do Aparelho de Amplificação Sonora Individual (AASI). Metodologia: Participaram deste estudo 15 indivíduos adultos e idosos, de ambos os gêneros, de 55 a 85 anos de idade, com perda auditiva neurossensorial de grau leve a moderado com simetria entre as orelhas, sem experiência prévia com qualquer tipo de dispositivo de amplificação sonora. Os indivíduos foram encaminhados pelas empresas de aparelho auditivo WIDEX, Audibel e o Espaço Reouvir, tratando-se de novos usuários de AASI. Os PEALL foram realizados nas condições com e sem AASI, a 60 e 75 dBnNA em campo sonoro, em dois momentos: primeira avaliação realizada até uma semana após a adaptação do AASI e a segunda avaliação realizada após 6 meses da adaptação do AASI. Resultados: Na comparação da primeira avaliação com a segunda avaliação, na condição sem AASI a 60 dBnNA, observou-se diferença estatisticamente significante na latência do componente P1 (p-valor= 0,034). Na condição sem AASI a 75 dBnNA, observou-se diferença estatisticamente significante para a latência do componente P300 (p-valor 0,031) e para a amplitude P2N2 (p-valor 0,024), com diminuição da latência e aumento da amplitude na segunda avaliação. Por sua vez, na comparação da primeira avaliação com a segunda avaliação, na condição com AASI a 75 dBnNA, obteve-se uma diferença estatisticamente significante na latência do componente N2 (p-valor 0,009) e na amplitude P2N2 (p-valor 0,024), com aumento da amplitude na segunda avaliação. Evidenciou-se, também, diferença significante na amplitude P1N1 (p-valor 0,024) na condição com AASI a 60 dBnNA. Conclusão: Os PEALL com estímulo de fala demonstraram ser um importante procedimento para ser utilizado na prática clínica, visando monitorar a plasticidade neuronal do Sistema Nervoso Auditivo Central frente à estimulação auditiva (uso de AASI), em adultos e idosos com perda auditiva neurossensorial de grau leve a moderado / Introduction: Auditory plasticity refers to changes that occur in the sensory system responsible for the transmission of acoustic information. The plasticity of the central auditory nervous system is related to the capacity of adaptation through the reintroduction of stimuli of sound amplification devices or cochlear implants. These changes are observed from the performance of patients with the use of the sound amplification apparatus, and can be verified by long-latency auditory evoked potentials. Purpose: To characterize long latency auditory evoked potentials (LLAEP) in adults with sensorineural hearing loss, verifying the effects of auditory stimulation by comparing these before and after adaptation potentials of the Individual Sound Amplification (AASI). Methodology: Fifteen adult and elderly individuals of both genders, aged 55 to 85 years, with mild to moderate sensorineural hearing loss with symmetry between the ears, without prior experience with any type of sound amplification device. The subjects were referred by hearing aid companies WIDEX, Audibel and Espaço Reouvir, in the case of new hearing aids users. The LLAEP were performed in the conditions with and without AASI, at 60 and 75 dBnNA in sound field, in two moments: first evaluation performed up to one week after AASI adaptation and the second evaluation performed after 6 months of AASI adaptation. Results: In the comparison of the first evaluation with the second evaluation, in the condition without AASI at 60 dBnNA, a statistically significant difference was observed in the latency of the P1 component (p-value = 0.034). In the condition without AASI at 75 dBnNA, a statistically significant difference was observed for the latency of the P300 component (p-value 0.031) and for the P2N2 amplitude (p-value 0.024), with latency decrease and amplitude increase in the second evaluation. In the comparison of the first evaluation with the second evaluation, in the condition with AASI at 75 dBnNA, there was a statistically significant difference in the latency of the N2 component (p-value 0.009) and in the P2N2 amplitude (p-value 0.024) , With amplitude increase in the second evaluation. There was also a significant difference in P1N1 amplitude (p-value 0.024) in the condition with AASI at 60 dBnNA. Conclusion: The LLAEP was an important procedure to be used in clinical practice, aiming to monitor the neural plasticity of the Central Auditory Nervous System in front of auditory stimulation (hearing aids use) in adults and elderly patients with mild to moderate sensorineural hearing loss of amplification and the importance of neural plasticity of the Central Auditory Nervous System

Tinnitus, die Wahrnehmung eines Phantomgeräuschs, geht in den meisten Fällen mit Hörverlust einher. Es ist jedoch unbekannt, wie Hörverlust zu Tinnitus führen könnte. In Tierversuchen wurde gezeigt, dass Verhaltensanzeichen für Tinnitus nach Hörverlust mit erhöhten spontanen Feuerraten von Neuronen im zentralen auditorischen System korreliert sind. Zunächst untersuchen wir ob sich bei lärmbedingtem Hörverlust die Audiogramme von Patienten mit und ohne Tinnitus unterscheiden. Im Vergleich zu Patienten ohne Tinnitus haben Tinnituspatienten im Mittel weniger Hörverlust, einen steileren Abfall des Audiogramms, und die Audiogrammkante befindet sich bei höheren Frequenzen. Mit einem theoretischen Modell zeigen wir, wie tinnitusartige Hyperaktivität durch eine Stabilisierung der mittleren Feuerrate von Neuronen im zentralen Hörsystem mittels homöostatischer Plastizität entstehen kann: verringerte Aktivität von Hörnervfasern nach Hörverlust wird kompensiert durch eine Erhöhung der neuronalen Verstärkung. Dies stabilisiert die mittlere Rate, kann jedoch zu einer Erhöhung der spontanen Feuerraten führen, die dann von Art und Stärke der cochlearen Schädigung abhängen. Wir testen das Modell, indem wir es auf die Audiogramme von Patienten mit tonalem Tinnitus und Lärmschwerhörigkeit anwenden. Für jedes Audiogramm sagen wir mit dem Modell Veränderungen in der Spontanaktivität von auditorischen Neuronen vorher. Das resultierende Hyperaktivitätsmuster hat typischerweise eine deutliche Spitze, die mit einem steilen Abfall des Audiogramms einhergeht. Wenn solch eine Spitze als Grundlage für einen tonalen Tinnitus interpretiert wird, dann sagt das Modell Tinnitusfrequenzen nahe den empfundenen Tinnitustonhöhen vorher. Unser Modell stellt also eine plausible Hypothese, wie Hörverlust zu Tinnitus führen könnte, dar. Basierend auf dem Modell zeigen wir außerdem wie Hyperaktivität und somit eventuell auch Tinnitus, durch zusätzliche akustische Stimulation reduziert werden könnte. / Tinnitus is a phantom auditory sensation that is associated with hearing loss, but how hearing loss can lead to tinnitus has remained unclear. In animals, hearing loss through cochlear damage can lead to behavioral signs of tinnitus and can increase the spontaneous firing rates of central auditory neurons. To study the relation between hearing loss and tinnitus, we first analyze audiometric differences between patients with hearing loss and tinnitus and patients with hearing loss but without tinnitus. We find that tinnitus patients have on average less hearing loss, a steeper slope of the audiogram, and the audiogram edge is located at higher frequencies compared to patients without tinnitus. We then derive a computational model that demonstrates how tinnitus-related hyperactivity could arise as a consequence of a stabilization of the mean firing rates of central auditory neurons through homeostatic plasticity: decreased auditory nerve activity after hearing loss is counteracted through an increase of the neuronal response gain. This restores the mean rate, but can also lead to increased spontaneous firing rates, which depend on the type and degree of cochlear damage. Finally, we test the ability of our model to predict tinnitus pitch by applying it to audiograms from patients with noise-induced hearing loss and tone-like tinnitus. Given an audiogram, the model is used to predict changes in the spontaneous firing rates of central auditory neurons. The resulting hyperactivity pattern typically exhibits a distinct peak that is associated with a steep drop in the audiogram. If such a peak is interpreted as the basis for a tone-like tinnitus sensation, the model predicts a tinnitus frequency that is close to the patient''s tinnitus pitch. Thus, our model presents a plausible hypothesis of how hearing loss could lead to tinnitus. Based on this model, we also show how hyperactivity, and possibly also tinnitus, could be alleviated through additional acoustic stimulation.

Diss. Uppsala : Uppsala universitet, 2009.

Made available in DSpace on 2015-07-22T20:50:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-01-31 / Objetivo: Verificar os efeitos de um programa de treinamento auditivo formal em indivíduos adultos portadores de deficiência auditiva neurossensorial de grau leve a moderado, usuários de próteses auditivas intra-aurais, utilizando testes comportamentais para avaliar a função auditiva central, um questionário de autoavaliação e a captação do potencial de longa latência P300. Método: Foram selecionados 14 adultos deficientes auditivos usuários de próteses auditivas intraaurais em adaptação binaural, divididos em dois grupos: sete com e sete sem treinamento auditivo. Os indivíduos do grupo experimental foram submetidos a um programa de treinamento auditivo formal em cabina acústica com próteses auditivas, organizado em oito sessões de 45 minutos cada, visando o treinamento das habilidades auditivas de fechamento auditivo, figura-fundo para sons verbais e não verbais e ordenação temporal dos sons (aspectos de freqüência e duração). As sessões e as atividades dentro de cada sessão foram organizadas em ordem crescente de complexidade de modo a desafiar o sistema auditivo. Para verificar a eficácia do treinamento auditivo, todos os pacientes foram submetidos à avaliação comportamental e eletrofisiológica do processamento auditivo e foram solicitados a responder o questionário de auto-avaliação APHAB em duas oportunidades: antes e após o treinamento auditivo no grupo experimental e na avaliação inicial e final no grupo controle. Resultados: A análise dos resultados não revelou diferenças significantes entre os canais auditivos tanto nas medidas de latência e amplitude do P300 como nos testes comportamentais do processamento auditivo. Na avaliação final verificamos que o grupo experimental apresentou menor latência do componente P3, melhor desempenho em todos os testes comportamentais do processamento auditivo e maior benefício nas situações de ruído avaliado pelo questionário APHAB do que o grupo controle. Conclusões: A análise crítica dos resultados nos permitiu concluir que o treinamento auditivo formal em adultos usuários de próteses auditivas possibilita: a redução na latência do componente P3; a adequação das habilidades auditivas de memória para sons verbais e não verbais em seqüência, fechamento auditivo e figurafundo para sons verbais; maior benefício com o uso das próteses auditivas em ambientes ruidosos e reverberantes. / Objective: To verify the effects of a formal auditory training program in adult hearing aid users with mild to moderate sensorineural hearing loss using behavioral auditory processing tests, a self-report benefit scale and long latency auditory evoked potential – P300. Method: Fourteen intra-aural hearing aid users were divided into two groups: seven with auditory training and seven without auditory training. Subjects from experimental group have undergone a formal auditory training program with hearing aids, organized in eight sessions of 45 minutes each, twice a week, aiming at improving auditory closure, figure-to-ground for verbal and nonverbal sounds and temporal processing (frequency and duration of sounds) skills. The program itself and the activities within the session were proposed in progressive complexity in order to challenge the auditory system. Auditory training efficiency was verified by evaluating all subjects in two different occasions: pre and post-training in the Experimental Group and in the initial and final evaluations in the Control Group, including electrophysiologic and behavioral auditory processing evaluations and the application of the self-report benefit scale APHAB. Results: Neither amplitude and latency of P300 nor the behavioral central auditory tests used revealed significant differences for the right or left ears. In the post-training evaluation Experimental Group presented statistically significant reduction in P3 latency, improved performance in all behavioral auditory processing tests and higher benefit in noisy situations as demonstrated in the self-report benefit scale APHAB than the Control Group. Conclusions: We could conclude that formal auditory training in adult hearing aid users lead to reduction in P3 latency; improvements in memory for verbal and nonverbal sounds in sequence, auditory closure, figure-to-ground for verbal sounds and higher benefit in reverberant and noisy environments / TEDE / BV UNIFESP: Teses e dissertações

Synaptic plasticity, the ability of synapses to change in strength, underlies complex brain functions such as learning and memory, yet little is known about the precise molecular mechanisms and downstream signaling pathways involved. The major goal of my doctoral thesis was to understand these molecular mechanisms and cellular processes underlying synaptic plasticity using the Drosophilalarval neuromuscular junction (NMJ) as a model system. My work centered on a signaling pathway, the Wg/Wnt signaling pathway, which was found to be crucial for activity-driven synapse formation. The Wg/Wnt family of secreted proteins, besides its well-characterized roles in embryonic patterning, cell growth and cancer, is beginning to be recognized as a pivotal player during synaptic differentiation and plasticity in the brain. At the DrosophilaNMJ, the Wnt-1 homolog Wingless (Wg) is secreted from presynaptic terminals and binds to Frizzled-2 (DFz2) receptors in the postsynaptic muscle. Perturbations in Wg signaling lead to poorly differentiated NMJs, containing synaptic sites that lack both neurotransmitter release sites and postsynaptic structures. In collaboration with other members of the Budnik lab, I set out to unravel the mechanisms by which Wg regulates synapse differentiation. We identified a novel transduction pathway that provides communication between the postsynaptic membrane and the nucleus, and which is responsible for proper synapse development. In this novel Frizzled Nuclear Import (FNI) pathway, the DFz2 receptor is internalized and transported towards the nucleus. The C-terminus of DFz2 is subsequently cleaved and imported into the postsynaptic nucleus for potential transcriptional regulation of synapse development (Mathews, Ataman, et al. Science (2005) 310:1344). My studies also centered on the genetic analysis of Glutamate Receptor (GluR) Interacting Protein (dGRIP), which in mammals has been suggested to regulate the localization of GluRs and more recently, synapse development. I generated mutations in the gene, transgenic strains carrying a dGRIP-RNAi and fluorescently tagged dGRIP, and antibodies against the protein. Remarkably, I found dgrip mutants had synaptic phenotypes that closely resembled those in mutations altering the FNI pathway. Through the genetic analysis of dgrip and components of the FNI pathway, immunoprecipitation studies, electron microscopy, in vivotrafficking assays, time-lapse imaging, and yeast two-hybrid assays, I demonstrated that dGRIP had a hitherto unknown role as an essential component of the FNI pathway. dGRIP was found in trafficking vesicles that contain internalized DFz2. Further, DFz2 and dGRIP likely interact directly. Through the use of pulse chase experiments I found that dGRIP is required for the transport of DFz2 from the synapse to the nucleus. These studies thus provided a molecular mechanism by which the Wnt receptor, DFz2, is trafficked from the postsynaptic membrane to the nucleus during synapse development and implicated dGRIP as an essential component of the FNI pathway (Ataman et al. PNAS (2006) 103:7841). In the final part of my dissertation, I concentrated on understanding the mechanisms by which neuronal activity regulates synapse formation, and the role of the Wnt pathway in this process. I found that acute changes in patterned activity lead to rapid modifications in synaptic structure and function, resulting in the formation of undifferentiated synaptic sites and to the potentiation of spontaneous neurotransmitter release. I also found that these rapid modifications required a bidirectional Wg transduction pathway. Evoked activity induced Wg release from synaptic sites, which stimulated both the postsynaptic FNI pathway, as well as an alternative presynaptic Wg pathway involving GSK-3ß/Shaggy. I suggest that the concurrent activation of these alternative pathways by the same ligand is employed as a mechanism for the simultaneous and coordinated assembly of the pre- and postsynaptic apparatus during activity-dependent synapse remodeling (Ataman et al. Neuron (2008) in press). In summary, my thesis work identified and characterized a previously unrecognized synaptic Wg/Wnt transduction pathway. Further, it established a mechanistic link between activity-dependent synaptic plasticity and bidirectional Wg/Wnt signaling. These findings provide novel mechanistic insight into synaptic plasticity.

O sistema canabinóide parece participar de vários processos neurobiológicos, incluindo neuroproteção e plasticidade. Os objetivos deste estudo foram avaliar os efeitos de ablações retinianas sobre a expressão do receptor canabinóide CB1 e de proteínas estruturais no tecto óptico de pintos pelos métodos de imuno-histoquímica, immunoblotting e PCR em tempo real. Além disso, avaliamos os efeitos do tratamento com agonistas e antagonistas canabinóides em culturas de células do tecto óptico expostas ao NMDA por citometria de fluxo e quanto à morfologia. A ablação retiniana parece gerar um aumento da expressão da proteína CB1 no tecto óptico desaferentado, mas não dos níveis de RNAm. O tratamento das culturas com o agonista canabinóide diminuiu o número de células inviáveis e de DNA fragmentado gerados pelo NMDA. O aumento da expressão de CB1 após a ablação indica uma localização pós-sináptica desses receptores e sugere um papel do sistema canabinóide em processos de plasticidade. Os resultados da cultura de células sugerem um papel neuroprotetor do sistema canabinóide. / The cannabinoid system (CS) seems to have a role in several neurobiological processes, including neuroprotection and neuronal plasticity. The aims of this study were to verify the effects of unilateral retinal ablation on the expression of cannabinoid receptor CB1 and other structural proteins in the optic tectum of chick brain by immunohistochemistry, immunoblotting and real time PCR. Moreover, we evaluated the effects of cannabinoids agonists and antagonists treatment in optic tectum cell cultures exposed to the NMDA by flow cytometry and in the morphology. The retinal ablation seems to generate an increase in the expression of protein CB1 in the deafferented optic tectum, but not in the levels of mRNA. The treatment of the cultures with the cannabinoid agonist decreased the number of unviable cells and fragmented DNAs generated by NMDA. This increase of CB1 expression indicates a post-synaptic localization of these receptors and suggests a role of the CS in plasticity processes. The results of cell culture suggest neuroprotector role of the CS.

Orientador: Edson Bim / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação / Made available in DSpace on 2018-08-09T08:39:36Z (GMT). No. of bitstreams: 1 SguareziFilho_AlfeuJoaozinho_M.pdf: 4747025 bytes, checksum: 077f211f88c422646414f234628ad798 (MD5) Previous issue date: 2007 / Resumo: Este trabalho visa o estudo de métodos de projeto de controladores mediante o emprego da função de transferência complexa; o controle em baixas velocidades de um motor de indução trifásico orientado no fluxo do rotor, bem como no do estator, é o objetivo a ser alcançado. A formulação do modelo vetorial do motor de indução com emprego da função de transferência complexa e do controle vetorial são apresentados. Para validar a proposta, um controlador de ganho proporcional complexo é realizado. Resultados de simulação e de experimentos são obtidos / Abstract: This work aims the study of tunning methods for controllers on vector control using the complex transfer function; low speed control by using the rotor or stator flux orientation on the induction motor is the objetctive. The complex transfer function formulation, its aplication on induction machine model and vector control are presented. To validate the proposal, a proportional complex gains is proposed. Simulation and experimentally results are presented. / Mestrado / Energia Eletrica / Mestre em Engenharia Elétrica

INTRODUÇÃO: O uso de testes eletrofisiológicos associados a avaliação comportamental, vem se tornando uma prática clínica cada vez mais freqüente no campo da audiologia, possibilitando um diagnóstico e monitoramento do Transtorno de Processamento Auditivo mais preciso. OBJETIVOS: O objetivo geral deste estudo foi verificar as características (latência e amplitude) do complexo N1-P2-N2 em crianças com Transtorno de Processamento Auditivo, além de verificar a evolução dessas características após o Treinamento Auditivo. MÉTODOS: Foram selecionados 30 indivíduos com Transtorno de Processamento Auditivo e 22 indivíduos sem Transtorno de Processamento Auditivo, com idades entre oito e 16 anos que constituíram respectivamente o Grupo Estudo (GE) e o Grupo Controle (GC). Todos os indivíduos do nosso estudo passaram por uma avaliação inicial do Processamento Auditivo e do Potencial Eletrofisiológico de Longa Latência o complexo N1-P2-N2 (1ª avaliação). O GE foi submetido a um programa de treinamento auditivo em cabina acústica durante oito sessões e posteriormente reavaliado tanto por testes comportamentais quanto pelo teste eletrofisiológico (2ª avaliação). O GC, como não foi submetido a um programa de treinamento auditivo, foi reavaliado (2ª avaliação) após três meses da avaliação inicial. RESULTADOS: Para os testes comportamentais utilizados na Avaliação do Processamento Auditivo, houve diferença estatisticamente significante em todos os testes quando comparados o GE e o GC na 1ª avaliação e nas situações pré e pós o treinamento auditivo no GE. Quanto ao complexo N1-P2-N2 houve diferença estatisticamente significante para a latência da onda N1 e a amplitude da onda P2 na 1ª avaliação quando comparados o GE e o GC. Na situação pré e pós treinamento no GE, houve diferença estatisticamente significante para a latência da onda P2 e amplitude das ondas N1 e P2. No GC, quando comparadas na situação inicial e após três meses não houve diferença estatisticamente significante. CONCLUSÕES: As medidas eletrofisiológicas do Complexo N1-P2-N2 parecem ser um bom instrumento no auxilio do diagnóstico e monitoramento da terapia em crianças com Transtorno de Processamento Auditivo uma vez que essas crianças apresentaram diferenças nas medidas de latência e amplitude deste potencial após treinamento auditivo. / INTRODUCTION: The use of electrophysiological tests associated to behavioral evaluation has become a frequent practice in the audiology field enabling a more precise diagnosis and monitoring of the Auditory Processing Disorder. AIM: the aim of this study was to verify the N1-P2-N2 complex characteristics (latency and amplitude) in children with Auditory Processing Disorder, and also to verify the evolution of such characteristics after Auditory Training. MÉTHODS: 30 individuals with Auditory Processing Disorder and 22 individuals without Auditory Processing Disorder were selected, ranging in age from eight to 16 years old, composing respectively the Study Group (SG) and the Control Group (CG). All individuals underwent an initial evaluation of the Auditory Processing and of the N1-P2-N2 complex Long Latency Electrophysiological Potential (1st evaluation). The SG was submitted to an auditory training program in acoustic booth during 8 sessions and was reevaluated later by both behavioral and electrophysiological tests (2nd evaluation). The CG was not submitted to an auditory training program, and was reevaluated (2nd evaluation) three months after the initial evaluation. RESULTS: There was a significant statistical difference in all behavioral tests used in the Auditory Processing Evaluation when comparing the SG and the CG in the 1st evaluation, and in the situations pre and post auditory training in the SG. Concerning the N1-P2-N2 complex, there was a significant statistical difference for the latency of wave N1 and the amplitude of wave P2 in the 1st evaluation when comparing the SG and the CG. In the pre and post auditory training situations, there was a significant statistical difference for the latency of wave P2 and the amplitude of waves N1 and P2. In the CG there was no significant difference between the initial and the 2nd evaluation three months later. CONCLUSIONS: The electrophysiological measures of the N1-P2-N2 complex seem to be a good instrument for assisting the diagnosis and the therapy monitoring of children with Auditory Processing Disorder, once these children presented differences in the latency and amplitude measures of such potential after auditory training.