A Esclerose Lateral Amiotrófica (ELA) é uma doença neurodegenerativa progressiva e incurável, caracterizada pela perda seletiva dos neurônios motores (NM) superiores e inferiores com uma sobrevida média de 3 anos. As manifestações clínicas dependem da topografia e comprometimento dos NM. De causa desconhecida, descrições apontam para a participação das células gliais (astrócitos, microglia e célula de Schwann) na toxicidade neuronal. A retração precoce do axônio no músculo esquelético sugere a participação da célula de Schwann na morte neuronal retrógrada (dying back). Este estudo descreveu as alterações na expressão gênica no nervo motor extensor curto do hálux ainda funcionante dos pacientes ELA e o ramo motor do nervo acessório de sujeitos-controle (19 ELA, sendo 9 ELA espinhal e 5 ELA bulbar; 5 controles), utilizando-se plataformas expandidas de microarranjos de DNA (microarray) e análises de bioinformática (DAVID e os seus bancos de dados Kyoto Encyclopedia of Genes and Genomes e o Gene Onthology Consorciun Anottation). Os resultados foram validados por PCRq e Redes de Interação de Proteínas foram geradas pelo Cytoscape. Foram encontrados 138 genes diferencialmente expressos entre esses grupos. O ribossomo e a síntese proteica foram apontados como elementos centrais no estudo em eventos relacionados tanto à neurotoxicidade quanto a protetivos. As Redes destacaram o gene EPS8 na ELA (ambas as formas, ELA bulbar e espinhal) em relação aos controles e o gene FAU na ELA bulbar em relação à ELA espinhal. Os genes e as vias apontados neste estudo deverão ser testados como alvos terapêuticos em estudos futuros envolvendo a ELA / Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons (MN), with a median survival of 3 years. Clinical manifestations depend on onset site and involvement of the MN. Although the cause of ALS is unknown, reports point towards the participation of glial cells (astrocytes, microglia and Schwann cells) in the neuronal toxicity. The early retraction of the axonium indicates a participation of the Schwann cells in retrograde neuronal death (dying back). The current study described the abnormalities in the genic expression of the functioning extensor hallucis brevis motor neuron from ALS subjects, and the motor branch of the accessory nerve from control subjects (19 ALS, being 9 spinal and 5 bulbar types; 5 controls), through an expanded platform of DNA microarrays and bioinformatics analyses (DAVID, Kyoto Encyclopedia of Genes and Genomes, and Gene Onthology Consortium Annotation databases). The results were validated by Quantitative PCR (PCRq) and Protein-Protein interaction network generated by Cytoscape. A total of 138 differentially expressed genes were found in these groups. In this study, the ribosome and protein synthesis were pointed as central elements related both to neurotoxicity and protective events. These networks highlighted the EPS8 gene in ALS (in both types, bulbar and spinal) when correlated to controls, and the FAU gene in bulbar ALS in relation to spinal ALS. The genes and pathways identified in this study should be tested as therapeutic targets in future studies approaching ALS

A neurociência computacional é uma vasta área que tem como objeto de estudo o entendimento ou a emulação da dinâmica cerebral em diversos níveis. Neste trabalho atenta-se ao estudo da dinâmica de neurônios, os quais, no consenso atual, acredita-se serem as unidades fundamentais do processamento cerebral. A importância do estudo sobre o comportamento de neurônios se encontra na diversidade de propriedades que eles podem apresentar. O estudo se torna mais rico quando há interações de sistemas internos ao neurônio em diferentes escalas de tempo, criando propriedades como adaptação, latência e comportamento em rajada, o que pode acarretar em diferentes papéis que os neurônios podem ter na rede. Nesta dissertação é feita uma análise sob o ponto de vista de sistemas dinâmicos e de análise de sensibilidade de seis modelos ao estilo de Hodgkin-Huxley e compartimentais de neurônios encontrados no córtex visual primário de mamíferos. Esses modelos correspondem a seis classes eletrofisiológicas de neurônios corticais e o estudo feito nesta dissertação oferece uma contribuição ao entendimento dos princípios de sistemas dinâmicos subjacentes a essa classificação. / Computational neuroscience is a vast scientific area which has as subject of study the unsderstanding or emulation of brain dynamics at different levels. This work studies the dynamics of neurons, which are believed, according to present consensus, to be the fundamental processing units of the brain. The importance of studying neuronal behavior comes from the diversity of properties they may have. This study becomes richer when there are interactions between distintic neuronal internal systems, in different time scales, creating properties like adaptation, latency and bursting, resulting in different roles that neurons may have in the network. This dissertation contains a study of six reduced compartmental conductance-based models of neurons found in the primary visual cortex of mammals under the dynamical systems and sensitivity analysis viewpoints. These models correspond to six eletrophysiological classes of cortical neurons and this dissertation offers a contribution to the understanding of the dynamical-systems principles underlying such classification.

Basische Helix-Loop-Helix (bHLH)-Proteine bilden eine diverse Gruppe evolutionär gut konservierter Transkriptionsfaktoren. Viele transaktivierende bHLH-Proteine werden zelltyp- oder gewebespezifisch exprimiert und fungieren als wichtige Schlüsselregulatoren zellulärer Determinations- und Differenzierungsprozesse. Die eng verwandten neuronalen bHLH-Gene Neurod1, Neurod2 und Neurod6 werden in differenzierenden Pyramidenneuronen des sich entwickelnden zerebralen Kortex exprimiert und stehen schon lange im Verdacht, deren Reifung zu steuern. In der Vergangenheit wurde jedes der drei Gene in Mäusen inaktiviert. Untersuchungen an den einfach-defizienten Tieren konnten jedoch keine wichtigen Funktionen in embryonalen Pyramidenneuronen identifizieren. Da die Aminosäuresequenzen und die Expressionsmuster der Faktoren sehr ähnlich sind, wurde angenommen, dass sie sich redundante Funktionalität teilen. Um dies zu überprüfen, habe ich Neurod2/6-doppel-defiziente Tiere gezüchtet und unter besonderer Berücksichtigung der Differenzierung von Pyramidenneuronen und der Konnektivität des zerebralen Kortex analysiert: Die Experimente zeigen, dass Neurod2 und Neurod6 tatsächlich mehrere bisher unbekannte gemeinsame Funktionen haben, wobei jeder Faktor für den Verlust des jeweils anderen kompensieren kann. Zumindest eines der beiden Gene ist notwendig für (1) die Kontrolle der radialen Migration eines Teils der Pyramidenneurone, (2) die frühe Regionalisierung des zerebralen Kortex und (3) die Bildung kortikaler Projektionen vom Neokortex zum Striatum, zum Thalamus und zur kontralateralen Hemisphäre. Callosale Axone bilden in Neurod2/6-doppel-defizienten Mäusen Faserbündel die tangential in den medialen Kortex einwachsen, aber noch vor Erreichen des ipsilateralen Cingulums und vor dem Kontakt mit der Mittellinie stoppen und defaszikulieren. Es resultiert eine neue Variante der callosalen Agenesie, die nahelegt, dass es bisher nicht identifizierte Wachstumssignale im medialen Kortex gibt. Die Expression von Neurod1, welche sich normalerweise auf die Subventrikularzone beschränkt, persistiert in radial migrierenden Pyramidenneuronen der Intermediärzone und der Kortikalplatte von Neurod2/6-doppel-defizienten Mäusen. Diese ektopische Neurod1-Expression kann dort den Verlust von Neurod2 und Neurod6 kompensieren. In einem weiteren Schritt habe ich konditionale Neurod1/2/6-tripel-defiziente Mäuse gezüchtet. In diesen Tieren wird das Neurod1-Gen durch selektive genetische Rekombination in all jenen Zellen, die über Neurod6-Promoteraktivität verfügen, irreversibel entfernt: Wie erwartet, teilt sich Neurod1 weitere gemeinsame Funktionen mit Neurod2 und Neurod6. Zumindest eines der drei Gene ist notwendig für die Differenzierung hippokampaler Pyramidenzellen und die Hemmung des programmierten Zelltods der unreifen Neuronen des Cornu Ammonis. Während die gemeinsame Inaktivierung von Neurod1/2/6 zur Aplasie des Hippocampus führt, überlebt ein Großteil der neokortikalen Pyramidenzellen. Die terminale neuronale Differenzierung ist jedoch auch im Neokortex gestört und die neokortikale Konnektivität sehr stark reduziert. Diese Arbeit zeigt, dass die Transkriptionsfaktoren der NeuroD-Familie gemeinsam die Differenzierung, das Überleben, die Migration und das axonale Wachstum von pyramidalen Neuronen des sich entwickelnden zerebralen Kortex steuern. Während der Embryonalentwicklung ergeben sich folgende, teils überschneidende Funktionen der NeuroD-Gene: Die Differenzierung und das Überleben von hippocampalen Körnerzellen ist abhängig von Neurod1. Die frühen Schritte der Differenzierung von hippocampalen Pyramidenneuronen und deren Überleben sind eine Funktion von wahlweise Neurod1, Neurod2 oder Neurod6. Spätere neuronale Differenzierungsschritte, die Regionalisierung des Neokortex und das gezielte Wachstum wichtiger neokortikaler Faserzüge basieren auf Funktionen von Neurod2 oder Neurod6, aber nicht von Neurod1. Der postnatale Umbau des somatosensorischen Kortex und die funktionale Integration thalamischer Afferenzen wurden bereits als strikt Neurod2-abhängig beschrieben.

Abstract This thesis is a study of the odour responses of insect olfactory (or odorant) receptor neurons (ORN) of blowfly (Calliphora vicina), mosquito (Aedes communis), fruitflies (Drosophila melanogaster and D. virilis) and large pine weevil (Hylobius abietis). A power-law dependence (similar to Stevens' law in psychophysics) was obtained for the action potential rate of ORN responses vs. odour concentration in measurements with metal microelectrodes from blowfly ORNs and an analysis system was developed for the extracellularily recorded action potentials (or nerve pulses). Odour exposure sequences were used to study action potential rates quantitatively as a function of odour concentration in air exposure. For an odour exposure sequence, a known initial amount of the odour compound in a filter paper inside a Pasteur pipette at the beginning of repeated exposures caused a gradual dilution of the odour concentration in the exposure sequence. The concentration at each exposure was calculated according to the discrete multiple headspace extraction and dilution (DMHED) method. The estimated odour concentration was assumed to obey in the method an exponential law with respect to the exposure number in the sequence. Despite that many uncontrollable parameters remain for measuring quantitatively the characteristics of the ORNs, the results obtained, e.g., sensitivity, specificity, adaptability, and the power-law realation are both biologically and technically very interesting. A time-to-voltage converter (TVC) was utilized for the response analysis in determining action potential intervals originating from a single ORN. A precision analysis of TVC was also performed. With the mosquito (Aedes communis), fruitflies (Drosophila melanogaster and D. virilis) and large pine weevil (Hylobius abietis) antennae were tested for inhibitory and excitatory effects to find out repellents and attractants. Human sweat was found to cause strong stimulus exposure in the responses of the mosquito ORNs and Neutroil® caused inhibitory responses in pine weevil ORNs, respectively. The power-law exponents for blowfly ORNs were about 0.19 in the case of 1-hexanol (HX), 0.065 in the case of 1,4-diaminobutane (14DAB) and 0.32 in the case of butyric acid (BA). The corresponding Stevens' law exponent values 0.39 and 0.33 have been reported for HX and BA, respectively, by Patte et al. (1975).

Abstract Artificial Life is an interdisciplinary scientific and engineering enterprise investigating the fundamental properties of living systems through the simulation and synthesis of life-like processes in artificial media. One of the avenues of investigation is autonomous robots and agents. Mimicking of the growth and adaptation of a biological neural circuit in an artificial medium is a challenging task owing to our limited knowledge of the complex process taking place in a living organism. By combining several developmental mechanisms, including the chemical, mechanical, genetic, and electrical, researchers have succeeded in developing networks with interesting topology, morphology, and function within Artificial Computational Chemistry. However, most of these approaches still fail to create neural circuits able to solve real problems in perception and robot control. In this thesis a phenomenological developmental model called a Stochastic Evolutionary Neuron Migration Process (SENMP) is proposed. Employing a spatial encoding scheme with lateral interaction of neurons for artificial neural networks, which represent candidate solutions within a neural network ensemble, neurons of the ensemble form problem-specific spatial patterns with the desired dynamics as they migrate under the selective pressure. The approach is applied to gain new insights into development, adaptation and plasticity in neural networks and to evolve purposeful behaviors for mobile robots. In addition, the approach is used to study the relationship of spatial patterns, composed of interacting entities, and their dynamics. The feasibility and advantages of the approach are demonstrated by evolving neural controllers for solving a non-Markovian double pole balancing problem and by evolving controllers that exhibit navigation behavior for simulated and real mobile robots in complex environments. Preliminary results regarding the behavior of the adapting neural network ensemble are also shown and, particularly, a phenomenon exhibiting Hebbian-like dynamics. This thesis is a step toward a long range goal that aims to create an intelligent robot that is capable of learning complex skills and adapts rapidly to environmental changes.

No description available.

Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established paradigm it was also found that in almost all cases the S(+) enantiomer was the more potent.

This thesis deals about using models of neural networks like alternative of time series model based on Box-Jenkins methodology. The work is divided into two parts according to the model construction method. Each of the parts contains a theory that explains the individual processes and the progress of the model construction. This is followed by two experiments demonstrating the difference in approach to the design of a given model and creating a forecast by estimated values. for the following year. The last part expertly evaluates the quality of the predictions and considers the use of neural networks against prediction models as an alternative to Box-Jenkins methodology based models

L'agrégation des canaux sodium (Nav) aux nœuds de Ranvier est une étape importante pour la propagation électrique saltatoire rapide le long des axones myélinisés. L'assemblage des nœuds dépend d'interactions neurones-cellules gliales myélinisantes, les oligodendrocytes dans le système nerveux central (SNC) et les cellules de Schwann dans le système nerveux périphérique (SNP). Bien décrits dans le SNP, les mécanismes cellulaires et moléculaires restent à caractériser dans le SNC. Lors de ma thèse, je me suis focalisé sur les étapes précoces d'assemblage des nœuds dans le SNC. Ce travail montre que des agrégats de protéines nodales (ou pré-nœuds) sont formés le long des axones de neurones GABAergiques avant la myélinisation dans des cultures neurones-glies d'hippocampe et également au cours du développement chez les rongeurs. La formation de pré-nœuds dépend de protéines sécrétées par les oligodendrocytes et de la protéine axonale d'échafaudage, ankyrineG. En outre, la transition des isoformes de Nav le long des axones est régulée par la présence des cellules gliales. Enfin, les pré-nœuds permettent d'accélérer la vitesse de conduction de l'influx nerveux par un facteur 1,5, indépendamment de la myélinisation et du calibre axonal. Globalement, ces résultats renforcent notre connaissance des mécanismes d'assemblage des nœuds de Ranvier dans le SNC et suggèrent une fonction développementale de l'agrégation nodale avant le début de la myélinisation. Si la vitesse de conduction a été décrite comme liée aux propriétés isolantes de la gaine de myéline, les résultats de cette thèse apportent un concept novateur de régulation de la conduction axonale en l'absence de myéline. / The clustering of sodium channels (Nav) at the nodes of Ranvier is an important step in permitting rapid saltatory conduction along myelinated axons. Nodal assembly is neuron-glia dependent, mediated by myelinating oligodendrocytes of the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). While the mechanisms of nodal assembly are currently best characterized in the PNS, cellular and molecular mechanisms underlying their assembly in the CNS are only partially understood. In the core of my PhD dissertation, I focused on the early developmental steps of nodal protein clustering in the CNS and show that clusters of nodal proteins, called prenodes, are detected before myelination along GABAergic axons in hippocampal neuron-glia cultures and also in the developing rodent hippocampus. Prenodal clustering requires extrinsic oligodendroglial secreted proteinaceous factors, and also the intrinsic axonal cytoskeletal scaffolding protein ankyrinG. Furthermore, the transition of sodium channels isoforms is tightly regulated along GABAergic axons during development, but this transition is lost in the absence of the physical presence of glial cells. Lastly, prenodes increase axonal conduction by a factor of 1.5x, independently of myelination and axonal caliber. Taken together, these results further our understanding of CNS nodes of Ranvier assembly mechanisms and the developmental function of nodal clustering prior to myelin ensheathment. While conduction velocity along axons has long been thought to mostly rely on the insulating properties of myelin, these results may shed light on a new concept of axonal conduction in the absence of myelination.

Spinal Muscular Atrophy (SMA) is a neuronal degenerative disease caused by the mutation or loss of the Survival Motor Neuron (SMN) gene. The cause for the specific motor neuron susceptibility in SMA has not been identified. The high axonal transport/localization demand on motor neurons may be one potentially disrupted function, more specific to these cells. We therefore used a large-scale immunoprecipitation (IP) experiment, to identify potential interactors of SMN involved in neuronal transport and localization of mRNA targets. We identified KH-type splicing regulatory protein (KSRP), a multifunctional RNA-binding protein that has been implicated in transcriptional regulation, neuro-specific alternative splicing, and mRNA decay. KSRP is closely related to chick zipcode-binding protein 2 and rat MARTA1, proteins involved in neuronal transport/localization of beta-actin and microtubule-associated protein 2 mRNAs, respectively. We demonstrated that KSRP is arginine methylated, a novel SMN interactor (specifically with the SMN Tudor domain; and not with SMA causing mutants). We also found this protein to be misregulated in the absence of SMN, resulting in increased mRNA stability of KSRP mRNA target, p21cip/waf1. A role for SMN as an axonal chaperone of methylated RBPs could thus be key in SMA pathophysiology.