The objective of this thesis is to evaluate the possibility of creating a tool capable of predicting commodity prices. Along with other business strategies, tools and markets analyses for financial and capital markets, this tool should help make the best estimate of future developments on the observed markets. The main market, on which this work is focused, is the agricultural commodities market, namely corn and its related markets. The fundamental basis upon which the arguments in this thesis are built, is the use of artificial intelligence, particularly neural networks. The whole application is presented using a graphical user interface that allows even those with little or no understanding of this field to delve deeper into the interesting area - using modern computer systems to support trading activities.

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La composition chimique des aliments est perçue par les bourgeons du goût et transmise au cerveau postérieur par des nerfs viscérosensoriels particuliers, les nerfs du goût. L’intégrité de ces nerfs est essentielle au maintien des bourgeons du goût chez les animaux adultes. Cependant, leur rôle dans l’ontogénie des bourgeons, chez l’embryon et aux premiers stades postnataux, est controversé and reste non résolu. Dans cette étude, j’ai établi de façon définitive que la formation embryonnaire des bourgeons du goût dépend des nerfs gustatifs chez la souris, unifiant ainsi les mécanismes de maintien/régénération et d’ontogénie de ces organes. En parallèle, j’ai réexaminé la possibilité (jusque-là exclue par d’autres auteurs) d’un rôle du facteur de transcription Foxg1 dans la formation des ganglions sensoriels épibranchiaux. J’ai découvert que Foxg1 est un déterminant des neurones gustatifs dans le ganglion géniculé. Ce nouveau rôle, de pair avec ceux décrits précédemment dans l’épithélium olfactif, la placode otique et la rétine, révèle une cohérence physiologique remarquable des fonctions de Foxg1 (en dehors de son rôle bien établi dans le cortex) en tant que facteur de transcription maître des neurones impliqués dans les « sens spéciaux » : vision, ouïe, odorat et goût. / Taste information is received by taste buds and transmitted to the hindbrain by special visceral sensory nerves, the taste nerves. The integrity of taste nerves is essential for the maintenance of taste buds in adult animals. However, a role for taste nerves in the ontogeny of taste buds, in the embryo and at early postnatal stages, has been controversial and is still unresolved. In this study, I establish in a definitive manner that embryonic taste bud formation is nerve-dependent in mouse, thus unifying mechanistically the maintenance/regeneration and ontogeny of these organs. Parallel to this work, I re-examined the possibility (previously excluded by other authors) of a role for the transcription factor Foxg1 in epibranchial ganglion formation. I find that Foxg1 is essential for the differentiation of gustatory neurons in the geniculate ganglion. This novel role, together with previously described ones in the olfactory epithelium, otic placode and retina, unveils a striking physiological coherence of the functions of Foxg1 (outside its well established one in the cortex), as a master transcription factor for neurons involved in “special senses”: vision, hearing, smell and taste.

To quantify the concurrent transduction capabilities of spatially distributed intrinsic cardiac neurons, the activities generated by atrial vs. ventricular intrinsic cardiac neurons were recorded simultaneously in 12 anesthetized dogs at baseline and during alterations in the cardiac milieu. Few (3%) identified atrial and ventricular neurons (2 of 72 characterized neurons) responded solely to regional mechanical deformation, doing so in a tightly coupled fashion (cross-correlation coefficient r = 0.63). The remaining (97%) atrial and ventricular neurons transduced multimodal stimuli to display stochastic behavior. Specifically, ventricular chemosensory inputs modified these populations such that they generated no short-term coherence among their activities (cross-correlation coefficient r = 0.21 ± 0.07). Regional ventricular ischemia activated most atrial and ventricular neurons in a noncoupled fashion. Nicotinic activation of atrial neurons enhanced ventricular neuronal activity. Acute decentralization of the intrinsic cardiac nervous system obtunded its neuron responsiveness to cardiac sensory stimuli. Most atrial and ventricular intrinsic cardiac neurons generate concurrent stochastic activity that is predicated primarily upon their cardiac chemotransduction. As a consequence, they display relative independent short-term (beat-to-beat) control over regional cardiac indexes. Over longer time scales, their functional interdependence is manifest as the result of interganglionic interconnections and descending inputs.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20247号 / 医博第4206号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 鈴木 茂彦, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood-brain barrier to destroy 90-99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a 'treatment liability' of this model, yet other animal models have liability issues of a serious nature-the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain-which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD.

Presented in this work is the investigation and successful illustration of a coupled model of the human nerve fiber. SPICE netlist code was utilized to describe the electrical properties of the human nervous membrane in tandem with COMSOL Multiphysics, a finite element analysis software tool. The initial research concentrated on the utilization of the Hodgkin-Huxley electrical circuit representation of the nerve fiber membrane. Further development of the project identified the need for a linear circuit model that more closely resembled the McNeal linearization model augmented by the work of Szlavik which better facilitated the coupling of both SPICE and COMSOL programs. Related literature was investigated and applied to validate the model. This combination of analysis tools allowed for the presentation of a consistent model and revealed that a coupled model produced not only a qualitatively comparable, but also a quantitatively comparable result to studies presented in the literature. All potential profiles produced during the simulation were compared against the literature in order to meet the purpose of presenting an advanced computational model of human neural recruitment and excitation. It was demonstrated through this process that the correct usage of neuron models within a two dimensional conductive space did allow for the approximate modeling of human neural electrical characteristics.

This work focuses on modeling a demyelinated Hodgkin and Huxley (HH) neuron with Simulated Program with Integrated Circuit Emphasis (SPICE) platform. Demyelinating disorders affect over 350,000 people in the U.S and understanding the demyelination process at the cellular level is necessary to find safe ways to treat the diseases [9]. Utilizing a previous SPICE model of an electrically small cell neuron developed by Szlavik [32], an extended core conductor myelinated neuron was produced in this work. The myelinated neuron developed has seven active Nodes of Ranvier (nodes) separated by a myelin sheath. The myelin sheath can be successfully modeled with a resistive and capacitive network known as internodes. Both the Nodes of Ranvier and internode equivalent circuits were implemented in P-SPICE sub-circuit library files. Properties of the neuron can be changed in the library files to simulate neurons of different electrical or geometric properties. Using the P-SPICE code developed in this work, a myelinated neuron’s action potential was simulated and the action potential at each node was recorded. The action potential at each node was uniform in amplitude and pulse width. The conduction velocity of the action potential was calculated to be 57.15 m/s. Demyelination can be modeled by decreasing the capacitance and increasing the resistance of the myelin [34]. Two demyelinated neuron models were simulated in this work. The first model had one internode segment demyelinated, and the second model was of three consecutive internode segments. The resulting conduction velocity was calculated for both simulations. For one and three internode segment demyelinated the conduction velocity was slowed to 44.15 m/s, and 27.15 m/s respectively. This model successfully showed that an HH neuron implemented in SPICE could show the effects of demyelination on conduction velocity The goal of this work is to develop a demyelinated neuron so that treatments for Multiple Sclerosis (MS) and other demyelinated neurons could be simulated to test various treatments’ effectiveness. A current treatment for MS is ion channel blockers. Future work would be to use this model to test current ion channel blocker therapy and to validate if such therapies alleviate conduction slowing.

As Moore's law nears its limit, a new form of signal processing is needed. Neuromorphic computing has used inspiration from biology to produce a new form of signal processing by mimicking biological neural networks using electrical components. Neuromorphic computing requires less signal preprocessing than digital systems since it can encode signals directly using analog temporal encoders from Spiking Neural Networks (SNNs). These encoders receive an analog signal as an input and generate a spike or spike trains as their output. The proposed temporal encoders use latency and Inter-Spike Interval (ISI) encoding and are expected to produce a highly sensitive hardware implementation of time encoding to preprocess signals for dynamic neural processors. Two ISI and two latency encoders were designed using Integrate-and-Fire (IF) and Leaky Integrate-and-Fire (LIF) neurons and optimized to produce low area designs. The IF and LIF neurons were designed using the Global Foundries 180nm CMOS process and achieved an area of 186µm2 and 182µm2, respectively. All four encoders have a sampling frequency of 50kHz. The latency encoders achieved an average energy consumption per spike of 277nJ and 316pJ for the IF-based and LIF-based latency encoders, respectively. The ISI encoders achieved an average energy consumption per spike of 1.07uJ and 901nJ for the IF-based and LIF-based ISI encoders, respectively. Power consumption is proportional to the number of neurons employed in the encoder and the potential to reduce power consumption through layout-level simulations is presented. The LIF neuron is able to use a smaller membrane capacitance to achieve similar operability as the IF neuron and consumes less area despite having more components. This demonstrates that capacitor sizes are the main limitations of a small size in spiking neurons for SNNs. An overview of the design and layout process of the two presented neurons is discussed with tips for overcoming problems encountered. The proposed designs can result in a fast neuromorphic process by employing a frequency higher than 10kHz and by providing a hardware implementation that is efficient in multiple sectors like machine learning, medical implementations, or security systems since hardware is safer from hacks. / Master of Science / As Moore's law nears its limit, a new form of signal processing is needed. Moore's law anticipated that transistor sizes will decrease exponentially as the years pass but CMOS technology is reaching physical limitations which could mean an end to Moore's prediction. Neuromorphic computing has used inspiration from biology to produce a new form of signal processing by mimicking biological neural networks using electrical components. Biological neural networks communicate through interconnected neurons that transmit signals through synapses. Neuromorphic computing uses a subdivision of Artificial Neural Networks (ANNs) called Spiking Neural Networks (SNNs) to encode input signals into voltage spikes to mimic biological neurons. Neuromorphic computing reduces the preprocessing step needed to process data in the digital domain since it can encode signals directly using analog temporal encoders from SNNs. These encoders receive an analog signal as an input and generate a spike or spike trains as their output. The proposed temporal encoders use latency and Inter-Spike Interval (ISI) encoding and are expected to produce a highly sensitive hardware implementation of time encoding to preprocess signals for dynamic neural processors. Two ISI and two latency encoders were designed using Integrate-and-Fire (IF) and Leaky Integrate-and-Fire (LIF) neurons and optimized to produce low area designs. All four encoders have a sampling frequency of 50kHz. The latency encoders achieved an average energy consumption per spike of 277nJ and 316pJ for the IF-based and LIF-based latency encoders, respectively. The ISI encoders achieved an average energy consumption per spike of 1.07uJ and 901nJ for the IF-based and LIF-based ISI encoders, respectively. Power consumption is proportional to the number of neurons employed in the encoder and the potential to reduce power consumption through layout-level simulations is presented. The LIF neuron is able to use a smaller membrane capacitance to achieve similar operability which consumes less area despite having more components than the IF neuron. This demonstrates that capacitor sizes are the main limitations of small size in neurons for spiking neural networks. An overview of the design and layout process of the two presented neurons is discussed with tips for overcoming problems encountered. The proposed designs can result in a fast neuromorphic process by employing a frequency higher than 10kHz and by providing a hardware implementation that is efficient in multiple sectors like machine learning, medical implementations, or security systems since hardware is safer from hacks.

Les circuits nerveux s'organisent autour des grands axes de polarité du corps. Au cours du développement, la navigation ainsi que l'arrangement spatial des projections au sein de leurs territoires cibles sont contrôlés par de nombreux facteurs de guidage. Pendant ma thèse je me suis intéressée à deux modèles de formation des circuits neuronaux présentant une polarité dans l'axe droite-gauche. Le premier concerne la mise en place des projections des interneurones commissuraux de la moelle épinière, un modèle de navigation orientée et le second, porte sur l'innervation des motoneurones phréniques, un modèle d'organisation asymétrique dans le territoire cible. Les mouvements comme la marche, la course ou la nage font intervenir des circuits neuronaux particuliers dédiés à la coordination des deux côtés du corps. Ces circuits sont formés majoritairement par les projections des interneurones commissuraux de la moelle épinière. Au cours du développement, ces interneurones élaborent un axone qui traverse la ligne médiane partageant les deux moitiés du système nerveux central pour se connecter aux motoneurones ou à d'autres interneurones de l'hémi-moelle opposée. De nombreux travaux ont porté sur les mécanismes de traversée de la ligne médiane et ont mis en évidence un rôle fondamental de facteurs de guidage comme la Nétrine, les Slit et les Sémaphorines. Ces molécules sont secrétées par les cellules de la plaque du plancher (PP) environnant la ligne médiane ventrale. Lors de leur traversée les axones commissuraux sont tout d'abord attirés par les signaux attractifs secrétés par les cellules de la PP. Une fois que les axones ont traversé la ligne médiane, ils perdent leur sensibilité aux facteurs attractifs et développent des nouvelles sensibilités pour des facteurs répulsifs qui les guident hors de la PP. Une étude menée par mon équipe a permis de montrer que les axones commissuraux acquièrent une réponse à la Sémaphorine3B seulement après avoir traversé la ligne médiane. Dans cette étude, l'équipe a montré que pendant la phase qui précède la traversée de la PP, une protéase, la Calpaine-1, dégrade la Plexine-A1, le corécepteur de Sema3B (Nawabi et al., 2010). L'inhibition de cette voie pendant la traversée de la PP conduit à la stabilisation de la PlexineA1 à la surface du cône de croissance et la formation d'un complexe récepteur de Sema3B fonctionnel composé de la Plexine-A1 et de la sous-unité de liaison de Sema3B, la Neuropiline2. La suppression de l'activité Calpaine est contrôlée par des signaux de la PP dont la nature n'était pas connue. Au cours de ma thèse j'ai identifié et caractérisé les contributions fonctionnelles de deux signaux de la PP qui sont responsables de la suppression de l'activité Calpaine et la sensibilisation des axones à Sema3B après la traversée. Ces résultats ont permis d'élargir les fonctions du facteur neurotrophique gdnf, et d'apporter de nouveaux éléments sur les voies de contrôle de la signalisation Sémaphorine, les processus de traversée et les modulations post-traductionnelles des récepteurs Plexines. Dans un deuxième projet, je me suis intéressée aux asymétries droite-gauche du système nerveux, par l'étude d'un nouvel exemple de circuit neuronal asymétrique : l'innervation motrice du diaphragme. Le diaphragme est un muscle indispensable à la respiration, il est composé d'une région centrale tendineuse et de deux muscles latéraux. Ces muscles sont innervés par un groupe particulier de motoneurones provenant de la moelle épinière cervicale, qui forment les nerfs phréniques droits (D) et gauches (G). Malgré une position centrale dans l'organisme et une morphologie apparente symétrique, nous avons découvert que le diaphragme présente une asymétrie musculaire ainsi qu'une asymétrie nerveuse. Etonnamment les motoneurones phréniques établissent un motif de connexion typique et différent sur les muscles droit et gauche du diaphragme [etc...] / The nervous circuits have stereotype positions within the major body axes. During development, axonal navigation and special positioning of the axon tracts in the target territories are regulated by many axon guidance factors. During my thesis I have been interested in two models of neuronal circuit formation that present a leftright polarity. The first one concerns the formation of the spinal commissural neurons projections, a model of oriented navigation along the left-right axis and the second one is the innervation of the phrenic motoneurons, a novel model of left-right asymmetric innervation pattern. Rhythmic locomotor movements like walking, running or swimming require neuronal circuits ensuring left-right coordination. Central components of these circuits are commissural neurons of the spinal cord. During development theses neurons are projecting axons across the midline that divides the nervous system in two parts, which connect the contralateral side of the spinal cord. Extensive work focused on the mechanisms controlling midline crossing. These study revealed a fundamental role of guidance factors secreted by floor plate cells at the ventral midline such as Netrins, Slits and Semaphorins. They also revealed that before crossing, axons are attracted towards the floor plate, and navigating by the floor plate they lose responsiveness to these attractive factors and develop a new sensitivity to repulsive cues that drive them out of the floor plate. In a previous study, my team showed that commissural axons gain response to Sema3B only after floor plate crossing (Nawabi et al., 2010). Before crossing, Plexin-A1 the Sema3B receptor is processed by a protease: the Calpain1. During crossing suppression of this pathway enable Plexin-A1 expression at growth cone surface, leading to sensitization to Sema3B. The suppression of Calpain activity was found controlled by floor plate signals, which remained unknown. During my thesis I have identified and characterized the functional contribution of two floor plate signals that are responsible for the inhibition of Calpain activity and axon sensitization to Sema3B after midline crossing: the neurotrophic factor gdnf and the cell adhesion molecule NrCAM. My results bring new elements on the control of midline crossing processes, Semaphorin signaling, and post-translational modifications of the Plexins receptors. In my second project, I have been interested in left-right asymmetries of the nervous system through the study of a new model of left-right asymmetry: the diaphragm innervation. The diaphragm is a muscle essential for breathing, it is composed of one central tendinous region and two lateral muscles. These muscles are innervated by a subset of cervical spinal cord motoneurons which forms the left and right phrenic nerves. Despite its central disposition in the organism and its apparent symmetry, we noticed that the diaphragm presents nervous and muscular asymmetries. Surprisingly phrenic motoneurons present typical and different nerve patterns on the left and right diaphragm muscles. Diverse left-right characteristic have been documented in the brain but none concerned yet the spinal cord or peripheral projections. My thesis work has been dedicated to the identification of the mechanisms that control the asymmetry of the diaphragm innervation. My work showed that this asymmetry is set up very early during development via a molecular pathway that is known to control the visceral organ asymmetry. This work opens numerous perspectives and brings new information on the molecular diversity of spinal neurons that could shed a new light on the mechanisms of motoneuron physiopathology