This thesis describes a novel method to reversibly and safely block nerve conduction using a low frequency alternating current (LFAC) waveform at 1 Hz applied through a bipolar extrafascicular electrode. This work follows up on observations made on excised mammalian peripheral nerves and earthworm nerve cords. An<i> in-situ</i> electrophysiology setup was used to assess the LFAC<br>waveform on propagating action potentials (APs) within the cervical vagus nerve in anaesthetized Sprague-Dawley rats (n = 12). Two sets of bipolar cuff or hook electrodes were applied unilaterally to the cervical vagus nerve, which was crushed rostral to the electrodes to exclude reflex effects<br>on the animal. Pulse stimulation was applied to the rostral electrode, while the LFAC conditioning waveform was applied to the caudal electrode. The efferent volley, if unblocked, elicits acute bradycardia and hypotension. The degree of block of the vagal stimulation induced bradycardia<br>was used as a biomarker. Block was assessed by the ability to reduce the bradycardic drive by monitoring the heart rate (HR) and blood pressure (BP) during LFAC alone, LFAC with vagal stimulation, and vagal stimulation alone. LFAC applied via a hook electrode (n = 7) achieved 86.6 +/- 11% block at current levels 95 +/- 38 uAp (current to peak). When applied via a cuff electrode (n = 5) 85.3 +/- 4.60% block was achieved using current levels of 110 +/- 65 uAp. Furthermore, LFAC was explored on larger vagal afferent fibers in larger human sized nerve bundles projecting to effects mediated by a reflex. The effectiveness of LFAC was assessed in an <i>in-situ</i> electrophysiological setup on the left cervical vagus in anaesthetized domestic swine (n = 5). Two bipolar cuff electrodes were applied unilaterally to the cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar extrafascicular cuff electrode was placed most rostral on the nerve for recording of propagating APs induced by<br>electrical stimulation and blocked via the LFAC waveform.<br>Standard pulse stimulation was applied to the left cervical vagus to induce the Hering-Breuer reflex. If unblocked, the activation of the Hering-Breuer reflex would cause breathing to slow down and potentially cease. Block was quantified by the ability to reduce the effect of the Hering-Breuer<br>reflex by monitoring the breathing rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. LFAC achieved 87.2 +/- 8.8% (n = 5) block at current levels of 0.8 +/- 0.3 mAp. Compound nerve action potentials (CNAP) were monitored directly. They show changes<br>in nerve activity during LFAC, which manifests itself as the slowing and amplitude reduction of components of the CNAPs. Since the waveform is balanced, all forward reactions are reversed, leading to a blocking method that is similar in nature to DC block without the potential issues of<br>toxic byproduct production. These results suggest that LFAC can achieve a high degree of nerve block in both small and large nerve bundles, resulting in the change in behavior of a biomarker, <i>in-vivo </i>in the mammalian nervous system at low amplitudes of electrical stimulation that are within the water window of the electrode.<br>

Neuronale Verbindungen verändern sich abhängig von unseren Wahrnehmungen (synaptische Plastizität) - womöglich die Grundlage für Lernen und Gedächtnis. Diese zellulären Prozesse werden jedoch stark reguliert, und können durch den Zustand des Organismus beeinflusst werden. Diese Doktorarbeit befasst sich mit einem Mechanismus durch den zelluläre Lernprozesse in Pyramidalzellen durch lokale hemmende Neurone moduliert werden können. Dazu werden biophysikalische Modelle einzelner Zellen in Mikroschaltkreisen zu Rate gezogen. Der erste Teil dieser Arbeit zeigt, dass hemmende Neurone die Lernsignale in den Dendriten der Pyramidalzelle nach dem Alles-oder-Nichts-Prinzip modulieren. Demnach könnten sie einen binären Schalter für das Lernen darstellen. Im Speziellen modulieren sie ein wichtiges dendritisches Lernsignal: das rückwärts-gerichtete Aktionspotenzial, das die Synapsen über neuronale Aktivität unterrichten kann. Die Hemmung muss zeitlich genau erfolgen wenn es um die Blockierung dieses rückwärts-gerichteten Signals geht; insbesondere, wenn der betrachtete Mechanismus der Lernregulierung gleichzeitig den vorwärts-gerichteten Informationsfluss erhalten soll. Wie diese Arbeit zeigt, kann die gewünschte Taktung dennoch erreicht werden, wenn die hemmenden Neurone in einem gängigen inhibitorischen Feedforward-Schaltkreis eingebettet sind. In einem solchen Schaltkreis werden die hemmenden Neurone und die Pyramidenzellen von der gleichen vorgeschalteten Zellpopulation erregt, sodass die Pyramidalzelle erst erregende und dann hemmende Reize erfährt, was die genaue Taktung zwischen Erregung und Hemmung ermöglicht. Der zweite Teil der Arbeit befasst sich mit der Frage ob und wie solche zeitlich regulierten Feedforward-Schaltkreise im Gehirn etabliert werden können. Es wird demonstriert, dass konkrete Lernregeln für hemmende Synapsen in diesen Schaltkreisen diese so formen kann, dass sie für die individuellen zeitlichen Bedingungen der modulierten Zelle angemessen sind. / The neural correlate of learning is thought to be the experience-dependent adjustment of neuronal connections – synaptic plasticity. However, cellular processes mediating these changes are highly regulated, and can be influenced by the state of the organism. Limiting learning to behaviorally relevant episodes is useful if new experiences can overwrite old memories. In this thesis, we use computational modeling to explore a mechanism by which cellular learning processes in principal neurons can be modulated by another cell type: local inhibitory neurons. Although these cells are known to play a role for learning, the cellular mechanisms by which they influence synaptic plasticity are not completely understood. The aim is hence to shed light onto the cellular mechanisms underlying the regulation of synaptic plasticity. In the first part of this thesis, it is shown that inhibitory neurons can modulate dendritic signals for plasticity in principal neurons in an all-or-none manner. Thereby, inhibition can provide a binary switch for plasticity, which, as further demonstrated, can be specific for inputs arriving via different neural pathways. An important dendritic signal for plasticity is the backpropagating action potential, which informs synapses about neuronal activity and can be modulated by inhibition. We show that the timing requirement for inhibition of theses signals is tight; especially if modulation of plasticity via this mechanism ought to preserve forward-directed stimulus processing in the same neuron. Yet, we demonstrate that the desired timing can be accomplished if inhibition is embedded in a common inhibitory feedforward circuit. The second part of this thesis addresses the question whether and how appropriately timed inhibitory feedforward circuits can be established. We demonstrate that particular plasticity rules at inhibitory synapses can shape microcircuits to become properly adjusted to the individual timing requirements of the modulated neuron.

Le neurone est une cellule polarisée qui se divise en deux compartiments spécialisés : le compartiment somato-dendritique et le compartiment axonal. Généralement, le premier reçoit l'information en provenance d'autres neurones et le second génère un message en sortie lorsque la somme des entrées dépasse une valeur seuil au segment initial de l'axone. Ce signal de nature discrète appelé potentiel d'action (PA) est propagé activement jusqu'à la terminaison synaptique où il déclenche la transmission chimique de l'information. Cependant, la fonction axonale ne se résume pas à la simple transmission des séquences de PA à l'image d'un câble de télégraphe. L'axone est également capable de transmettre des variations continues de signaux électriques infraliminaires dit analogues et les combiner avec l'information digitale véhiculée par le PA. J'ai consacré la majorité de mon travail de thèse à l'étude de ce nouvel aspect de la fonction axonale dans le cadre de la transmission synaptique entre les neurones pyramidaux au sein du réseau excitateur CA3 de l'hippocampe de rat. Les résultats obtenus à partir d'enregistrements de paires de neurones pendant ma thèse mettent en évidence deux sortes de signalisation analogue et digitale qui aboutissent à la facilitation de la transmission synaptique. La facilitation analogue-digitale (FAD) a été observée lors d'une dépolarisation prolongée, mais également à la suite d'une hyperpolarisation transitoire au niveau du corps cellulaire. Ce sont deux versants d'une même plasticité à court-terme qui découle de l'état biophysique des canaux ioniques sensibles au voltage étant à l'origine du PA. / The neuron is a polarised cell divided into two specialized compartments: the somato-dendritic and the axonal compartment. Generally, the first one receives information arriving from other neurones and the second generates an output message, when the sum of inputs exceeds a threshold value at the axon initial segment. This all-or-none signal, called the action potential (AP) is propagated actively to the synaptic terminal where it triggers chemical transmission of information. However, axonal function is not limited to transmission of AP sequences like a telegraph cable. The axon is also capable of transmitting continuously changing sub-threshold electric signals called analogue signals and to combine them with the digital information carried by the AP. I devoted the majority of my thesis work to the study of these novel aspects of axonal function in the framework of synaptic transmission between pyramidal neurons in the CA3 excitatory network of the rat hippocampus. The results obtained through paired recordings brought to light two kinds of analogue and digital signalling that lead to a facilitation of synaptic transmission. Analogue-digital facilitation (ADF) was observed during prolonged presynaptic depolarization and also after a transient hyperpolarization of the neuronal cell body. These are two sides of the same form of short-term synaptic plasticity depending on the biophysical state of voltage gated ion channels responsible for AP generation. The first variant of ADF induced by depolarization (ADFD) is due to AP broadening and involves Kv1 potassium channels.

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Made available in DSpace on 2015-05-14T13:00:16Z (GMT). No. of bitstreams: 1 parte1.pdf: 4104748 bytes, checksum: 578975146349baff07079d6c3f9756b6 (MD5) Previous issue date: 2008-08-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Snake venoms contain a complex arsenal of protein bio-active components, many of these being neurotoxins (NTXs). These snakes have high neurotoxic activity venom, corresponding to the Elapidae family, which includes coral snakes (Micrurus) whose venom contains circa 90-95% of low molecular mass protein components. Among these, several are postsynaptic neurotoxins or α- NTXs (MM = 6-9 kDa). The Micrurus ibiboboca (Merren, 1820) is a snake of the Elapidae family witch is quite common in the Northeast of Brazil. In spite of the great diversity of species of Micrurus, scarce works involving the nervous system with isolated and pure toxins of those serpents has been developed in level biochemical, pharmacological and electrophysiological. The aim of this study was to purify the toxin Mic6c7NTX of the Micrurus ibiboboca venom, characterize to biochemically and electrophysiologically the toxin Mic6c7NTX in the peripheral nervous system (PNS) of rats, evaluating alterations in the record of the Compound Action Potential (CAP) of the isolate nerve and the toxin activity on the voltage-dependent sodium channels (Nav) in the neurons of the dorsal root ganglion (DRG). The venom was extracted from the Micrurus ibiboboca collected in Paraiba State (Brazil). Initially, electrophysiological tests (current clamp method) using the single sucrose gap technique were accomplished with crude venom (100μg/mL). It was observed that in this concentration the crude venom caused reduction in the CAP amplitude (25%). This neurotoxity led into an intriguing question: what components of the venom would promote to reduction in the excitability of the nerve? Based upon this question, I decided to purify the venom throughout the Liquid Chromatography of the High Performance (HPLC) of the Cation Exchange Chromatography (CIEX) and the Reverse Phase Chromatography (RPC). The molecular mass (MM) of the raw toxin was determined by mass-spectrometry (MALDI-QTOF/ MS) and N-terminal sequence by means of Edman s Degradation. The search for similarity with other toxins was accomplished against proteomic data bank. The CIEX profile showed 19 fractions and the highest peak fraction was used for the second dimension. The toxin Mic6c7NTX obtained by RPC showed elution in 26.7%of the acetonitrile (ACN) and MM 7.047.56Da. The obtained partial N-terminal sequence showed 31 aminoacid residues. The search for similarity of structure and function showed great similarity (65%) with other short chain α-NTXs Australian elapids snakes. The electrophysiological studies (single sucrose gap technique) showed that the toxin Mic6c7NTX (1 μM) reduced the excitability of the isolate nerve similarly to the reduction observed in the crude venom about 21%. Other CAP parameters such as despolarization speed (DSCAP), repolarization time (τCAP) and peak of time (PTCAP) did not show alterations. This suggests that the toxin may be affecting the Nav channels. For the confirmation of that hypothesis experiments were accomplished with whole cell patch-clamp technique in DRG neurons. This results showed that the toxin Mic6c7NTX (1 WM) abolished completely the current of Nav channels sensitive the tetrodotoxin (TTX-S). Also the Nav channels TTX resistant (TTX-R) were investigated in the presence of the Mic6c7NTX toxin previously using TTX (100 nM). This results showed that the toxin Mic6c7NTX (100 nM) abolished completely the current of Nav channels TTX-R and IC50 = 30nM. However, reversion of this blocking was not observed. The present study biochemically and electrophysiologically characterized an α-NTX of the Micrurus ibiboboca elapid snake. Furthermore, it showed a potent toxin with affinity Nav channels TTX-S and TTX-R of the PNS. This is the first α-NTX isolated and identified of the venom from the Micrurus ibiboboca (Merrem, 1820) snake. / As serpentes da família Elapidae possuem uma peçonha com alta atividade neurotóxica e capacidade de letalidade. Fazem parte dessa família as serpentes corais americanas (gênero Micrurus) com suas peçonhas contendo cerca de 90-95% de componentes protéicos, sendo na sua maior parte neurotoxinas com baixa massa molecular (6-8 kDa), podendo ser destacadas as neurotoxinas com ação pós-sinápticas ou α-Neurotoxinas (α-NTX). A Micrurus ibiboboca (Merrem, 1820) é uma serpente da família Elapidae, comum na região Nordeste. Apesar da grande diversidade de espécies do gênero Micrurus sp., escassos trabalhos envolvendo atividade de toxinas isoladas e puras destas peçonhas e sistema nervoso têm sido desenvolvidos em nível bioquímico, farmacológico ou eletrofisiológico. O objetivo desse estudo foi purificar a toxina Mic6c7NTX da peçonha de M. ibiboboca, caracterizar bioquímicamente e investigar com ferramentas eletrofisiológicas a ação da toxina no Sistema Nervoso Periférico (SNP) de ratos avaliando alterações no Potencial de Ação Composto (PAC) do nervo isquiático isolado e a atividade da toxina nos canais para sódio dependentes de voltagem (Nav) em neurônios do gânglio da raiz dorsal (DRG). A peçonha da M. ibiboboca foi extraída de serpentes coletadas no Estado da Paraíba (Brasil). Inicialmente, ensaios eletrofisiológicos com o método de current clamp utilizando a técnica de single sucrose gap foram realizados com a peçonha bruta (100 Wg/mL). Os resultados mostraram que a peçonha bruta nessa concentração promoveu redução na amplitude do PAC (25%). Esse efeito da toxina na excitabilidade do nervo levantou o questionamento: Que componentes da peçonha estariam causando essa diminuição da excitabilidade? A peçonha foi purificada por meio de Cromatografia Líquida de Alta Performance (HPLC), de troca catiônica (CIEX) e fase reversa (RPC). Na sequência, os picos da CIEX foram submetidos à RPC e posteriormente analisados por espectrometria de massas (MALDI-TOF/MS) que detectou a massa molecular da toxina Mic6c7NTX de 7.047,56 Da. Em seguida, foi determinado o seu N-terminal por Degradação de Edman que apresentou 31 resíduos de aminoácidos e serviu de estudo para a bioinformática na busca por similaridade em banco de dados proteômicos com outras toxinas protéicas, demonstrando que a toxina Mic6c7NTX apresentou similaridade (65%) com α-NTXs de cadeia curta de serpentes elapídicas australianas. Posteriormente, foi investigado o efeito da toxina isolada no SNP. Os estudos eletrofisiológicos em single sucrose gap demonstraram que a toxina Mic6c7NTX (1 WM) reduziu a excitabilidade do nervo isolado de forma similar à observada pela peçonha bruta. Não foram observadas alterações significantes em outros parâmetros do PAC, como velocidade de despolarização (VDPAC), tempo de repolarização (τPAC) e tempo de pico (PTPAC), sugerindo que a toxina atuasse num sítio de ligação específico dos [Escreva uma citação do documento ou o 11 canais Nav no SNP. Para a confirmação dessa hipótese foram realizados experimentos de voltage clamp com a técnica de whole cell patch-clamp em cultura primária de neurônios DRG da medula espinhal de ratos. Os resultados mostraram que a toxina Mic6c7NTX (1 WM) aboliu completamente as correntes dos canais Nav sensíveis à tetrodotoxina (TTX-S). Também foi investigado o efeito da toxina sobre a população de canais Nav resistentes à TTX (TTX-R), utilizando previamente TTX (100 nM) para bloquear os canais Nav TTX-S. Os registros com a toxina Mic6c7NTX (100 nM) demonstraram um bloqueio total da corrente nos canais Nav TTX-R dos DRGs e uma IC50 da toxina em torno de 30 nM. Também foi observado que essa toxina se liga aos canais Nav de forma lenta e irreversível. O presente estudo caracterizou bioquímica e eletrofisiologicamente uma α-NTX da serpente elapídica Micrurus ibiboboca. Farmacologicamente, trata-se de uma potente toxina com afinidade aos canais Nav TTX-S e TTX-R do SNP. Essa é a primeira α-NTX isolada e caracterizada da peçonha da serpente Micrurus ibiboboca (Merrem, 1820).

Informações sobre as características funcionais e estruturais da unidade motora (UM) são altamente relevantes em investigações fisiológicas e nos estudos clínicos das disfunções neuromusculares. A eletromiografia (EMG) é um método adequado para obtenção dessas informações. Entretanto, devido à dificuldade na separação da atividade individual de uma unidade motora das outras que estão simultaneamente ativas, seu uso em clínica prática se dá comumente através de métodos invasivos, empregando eletrodos de agulha ou fios implantados. Apesar da EMG de superfície ser não-invasiva e, portanto mais apropriada para aplicações clínicas, não é usada em clínica porque não há até o presente um método satisfatório para decomposição do sinal EMG de superfície. Um EMG de superfície é muito mais difícil de decompor devido a significante superposição dos Potenciais de Ação das UMs (MUAPs) e a relação sinal-ruído relativamente baixa, se comparada aos métodos invasivos. Defendemos que a separação da atividade individual das UMs pode ser feita de modo não-invasivo aliando-se técnicas de aquisição altamente especializadas com técnicas usadas em reconhecimento de padrões. Desenvolvemos um método para decomposição de EMGs de superfície, a partir do qual foi possível extrair características relevantes das UMs, que permitem seu uso em avaliação e diagnóstico de desordens neuromusculares. Em nossa abordagem, o sinal EMG é inicialmente captado sob contração isométrica fraca usando eletrodos desuperfície. O sinal EMG bruto passa em seguida por um filtro Diferencial Passa-Baixas Ponderado (DPBP) em série com um detector de picos, que detecta os picos de MUAPs e extrai suas formas de onda. Na sequência, o conjunto de MUAPs extraído é classificado por uma rede neural SOM, e os MUAPs agrupados pela similaridade de suas formas de onda. No próximo passo a informação temporal dos disparos é checada, eliminando possíveis erros de classificação, e finalmente os Trens de MUAPs (MUAPTs) das UMs individuais são reconstituídos do EMG original. As estatísticas de disparos (IPI) bem como as formas de ondas dos MUAPs das respectivas UMs são então extraídas e armazenadas para estudos posteriores. Resultados preliminares obtidos com EMGs normais e patológicos, extraídos de membros superiores sob contração fraca, indicam que, o método mostrou-se apto a decompor EMGs de superfícies, além de potencial para aplicações em estudos clínicos não-invasivos de disfunções neuromusculares.Informações sobre as características funcionais e estruturais da unidade motora (UM) são altamente relevantes em investigações fisiológicas e nos estudos clínicos das disfunções neuromusculares. A eletromiografia (EMG) é um método adequado para obtenção dessas informações. Entretanto, devido à dificuldade na separação da atividade individual de uma unidade motora das outras que estão simultaneamente ativas, seu uso em clínica prática se dá comumente através de métodos invasivos, empregando eletrodos de agulha ou fios implantados. Apesar da EMG de superfície ser não-invasiva e, portanto mais apropriada para aplicações clínicas, não é usada em clínica porque não há até o presente um método satisfatório para decomposição do sinal EMG de superfície. Um EMG de superfície é muito mais difícil de decompor devido a significante superposição dos Potenciais de Ação das UMs (MUAPs) e a relação sinal-ruído relativamente baixa, se comparada aos métodos invasivos. Defendemos que a separação da atividade individual das UMs pode ser feita de modo não-invasivo aliando-se técnicas de aquisição altamente especializadas com técnicas usadas em reconhecimento de padrões. Desenvolvemos um método para decomposição de EMGs de superfície, a partir do qual foi possível extrair características relevantes das UMs, que permitem seu uso em avaliação e diagnóstico de desordens neuromusculares. Em nossa abordagem, o sinal EMG é inicialmente captado sob contração isométrica fraca usando eletrodos desuperfície. O sinal EMG bruto passa em seguida por um filtro Diferencial Passa-Baixas Ponderado (DPBP) em série com um detector de picos, que detecta os picos de MUAPs e extrai suas formas de onda. Na sequência, o conjunto de MUAPs extraído é classificado por uma rede neural SOM, e os MUAPs agrupados pela similaridade de suas formas de onda. No próximo passo a informação temporal dos disparos é checada, eliminando possíveis erros de classificação, e finalmente os Trens de MUAPs (MUAPTs) das UMs individuais são reconstituídos do EMG original. As estatísticas de disparos (IPI) bem como as formas de ondas dos MUAPs das respectivas UMs são então extraídas e armazenadas para estudos posteriores. Resultados preliminares obtidos com EMGs normais e patológicos, extraídos de membros superiores sob contração fraca, indicam que, o método mostrou-se apto a decompor EMGs de superfícies, além de potencial para aplicações em estudos clínicos não-invasivos de disfunções neuromusculares. / Information on the functional and structural characteristics of the motor unit (MU) they are highly important in physiologic investigations and in the clinical studies of the neuromuscular dysfunctions. The electromyography (EMG) it is an appropriate method for obtaining of that information. However, due to the difficulty in the separation of the individual activity of a motor unit of the another that are simultaneously active, your use in practical clinic happen commonly through methods invasive, employing needle electrodes or implanted threads. In spite of surface EMG to be non-invasive and, therefore more appropriate for clinical applications, it is not used at clinic because there is not until the present a satisfactory method for decomposition of the surface EMG sign. A surface EMG is much more difficult of decomposing due to significant overlap of the Motor Unit Action Potentials (MUAPs) and the relationship sign-noise relatively low, if compared to the invasive methods. We defended that the separation of the individual activity of MUs can be made in way non-invasive allying highly specialized acquisition techniques with techniques used in recognition of patterns. We developed a method for decomposition of surface EMGs, starting from which was possible to extract important characteristics of MUs, which allow your use in evaluation and diagnosis of neuromuscular disorders. In our approach, the sign EMG is captured initially under weak isometriccontraction using surface electrodes. The sign EMG raw raisin soon after for a Biased Low-Pass Differential filter (BLPD) in series with a detector of peaks, that detects the peaks of MUAPs and it extracts your wave forms. In the sequence, a SOM neural network classifies the set of extracted MUAPs, and MUAPs are clustered by the similarity in your wave shape. In the next step the temporal information of the discharges is checked, eliminating possible classification mistakes, and finally the MUAPs Trains (MUAPTs) of individual MUs they are reconstituted of original EMG. The statistics of discharges (IPI) as well as the forms of waves of MUAPs of respective MUs are then extracted and stored for subsequent studies. Results preliminaries obtained with normal and pathological EMGs, extracted of superior members under weak contraction, they indicate that, the method was shown capable to decompose surfaces EMGs, besides potential for applications in clinical studies non-invasive of neuromuscular dysfunctions.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2018-11-12T14:27:26Z No. of bitstreams: 1 raffaelbechararameh.pdf: 1503042 bytes, checksum: 87e66fa77937ca9a85aac3231b27ac84 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-11-23T13:13:22Z (GMT) No. of bitstreams: 1 raffaelbechararameh.pdf: 1503042 bytes, checksum: 87e66fa77937ca9a85aac3231b27ac84 (MD5) / Made available in DSpace on 2018-11-23T13:13:22Z (GMT). No. of bitstreams: 1 raffaelbechararameh.pdf: 1503042 bytes, checksum: 87e66fa77937ca9a85aac3231b27ac84 (MD5) Previous issue date: 2018-08-31 / Para representar diferentes fenômenos e sistemas modelos matemáticos são largamente utilizados. Muitos deles são fundamentados em sistemas de equações diferenciais ordinárias (EDOs), isto é, baseiam-se em conjuntos de igualdades que envolvem variáveis dependentes, suas derivadas de primeira ordem e a variável independente. Neste trabalho, estudamos a modelagem da geração do potencial de ação em células excitáveis, como os neurônios. Existem dois modelos tradicionais e pioneiros que se destacam nessa área: Hodgkin-Huxley e FitzHugh-Nagumo. O objetivo desta dissertação é avaliar a possibilidade de modelar a geração do potencial de ação via uma única equação diferencial com atraso. Equações diferenciais com atraso são importantes por sua capacidade em reproduzir uma grande diversidade de fenômenos. Porém, seu uso na modelagem do potencial de ação de células excitáveis é ainda incipiente. Nesta dissertação, o método usado para alcançar este objetivo se baseou no desenvolvimento, inicialmente, de uma equação integro-diferencial que aproxima o sistema de EDOs. Em seguida, desenvolvemos uma aproximação para as integrais que usa termos tanto no instante atual quanto em instante anteriores, i.e., atrasados no tempo. Dessa forma, mostramos que é possível aproximar cada um dos sistemas de EDOS dos modelos de Hodgkin-Huxley e FitzHugh-Nagumo por uma única equação diferencial com atraso. Por fim, estes novos modelos são comparados com os originais, e são apontadas direções para a continuidade desta pesquisa. / To represent different phenomena and systems mathematical models are widely used. Many of them are based on systems of ordinary differential equations (ODEs), that is, they are based on sets of equalities involving dependent variables, their derivatives of first order and the independent variable. In this work, we study the modeling of action potential generation in excitable cells, such as neurons. There are two traditional and pioneering models that stand out in this area: Hodgkin-Huxley and FitzHugh-Nagumo. The objective of this dissertation is to evaluate the possibility of modeling the generation of the action potential via a single differential equation with delay. Differential equations with delay are important because of their capacity to reproduce a great diversity of phenomena. However, its use in modeling the action potential of excitable cells is still incipient. In this dissertation, the method used to achieve this goal was based on the development, initially, of an integral-differential equation that approximates the ODE system. Next, we develop an approximation for integrals that uses terms at both the current instant and the previous instant, i.e., time delayed. Thus, we show that it is possible to approximate each of the ODEs systems of the Hodgkin-Huxley and FitzHugh-Nagumo models by a single differential equation with delay. Finally, these new models are compared with the original ones, and directions are indicated for future works.

L’intéraction entre la biologie et l’électronique est une discpline en pleine essort. De nom-breux systèmes électroniques tentent de s’interconnecter avec des tissus ou des cellules vivantesafin de décoder l’information biologique. Le Potentiel d’action (PA) est au coeur de codagebiologique et par conséquent il est nécéssaire de pouvoir les repérer sur tout type de signal bio-logique. Par conséquent, nous étudions dans ce manuscrit la possibilité de concevoir un circuitélectronique couplé à un système de microélectrodes capable d’effectuer une acquisition, unedétection des PAs et un enregistrement des signaux biologiques. Que ce soit en milieu bruitéou non, nous considérons le taux de détection de PA et la contrainte de temps réel commedes notions primordiales et la consommation en silicium comme un prix à payer. Initialementdéveloppés pour l’étude de signaux neuronaux et pancréatiques, ces systèmes conviennent par-faitement pour d’autres type de cellules. / Interaction between biology and electronic is in expansion. Many electronic systems aretrying to interconnect with tissues or living cells to decode biological information. The ActionPotential (AP) is the heart of biological coding and therefore it is necessary to be able to locateit from any type of biological signal. Therefore, we study in this manuscript the possibility ofdesigning an electronic circuit coupled to microelectrodes capable of acquisition, detection ofPAs and recording of biological signals. Whether or not in a noisy environment, we consider thedetection rate of PA and the real time-computing constraint as an hard specificationand andsilicon area as a price to pay. Initially developed for the study of neural signals and pancreatic,these systems are ideal for other types of cells.

La bioélectronique est un domaine transdisciplinaire qui oeuvre, entre autres, àl’interconnexion entre des systèmes biologiques présentant une activité électrique et le mondede l’électronique. Cette communication avec le vivant implique l’observation de l’activitéélectrique des cellules considérées et nécessite donc une chaine d’acquisition électronique.L’utilisation de Multi/Micro Electrodes Array débouche sur des systèmes devantacquérir un grand nombre de canaux en parallèle, dès lors la consommation etl’encombrement des circuits d’acquisition ont un impact significatif sur la viabilité dusystème destiné à être implanté.Cette thèse propose deux réflexions à propos de ces circuits d’acquisition. Une ces desréflexions a trait aux circuits d’amplification, à leur impédance d’entrée et à leurconsommation ; l’autre concerne un détecteur de potentiels d’action analogique, samodélisation et son optimisation.Ces travaux théoriques ayant abouti à des résultats concrets, un ASIC a été conçu,fabriqué, testé et caractérisé au cours de cette thèse. Cet ASIC à huit canaux comporte doncdes amplificateurs et des détecteurs de potentiels d’action analogiques et constitue le principalapport de ce travail de thèse. / Bioelectronics is a transdisciplinary field which develops interconnection devicesbetween biological systems presenting electrical activity and the world of electronics. Thiscommunication with living tissues implies to observe the electrical activity of the cells andtherefore requires an electronic acquisition chain.The use of Multi / Micro Electrode Array leads to systems that acquire a large numberof parallel channels, thus consumption and congestion of acquisition circuits have asignificant impact on the viability of the system to be implanted.This thesis proposes two reflections about these acquisition circuits. One of thesereflections relates to amplifier circuits, their input impedance and consumption; the otherconcerns an analogue action potentials detector, its modeling and optimization.These theoretical work leading to concrete results, an ASIC was designed,manufactured, tested and characterized in this thesis. This eight-channel ASIC thereforeincludes amplifiers and analogue action potentials detector and is the main contribution of thisthesis.