The motor nervous system is one of the main systems of the body and is our principle means ofbehavior. Some of the most debilitating and wide spread disorders are motor systempathologies. In particular the basal ganglia are complex networks of the brain that control someaspects of movement in all vertebrates. Although these networks have been extensively studied,lack of proper methods to study them on a system level has hindered the process ofunderstanding what they do and how they do it. In order to facilitate this process I have usedcomputational models as an approach that can faithfully take into account many aspects of ahigh dimensional multi faceted system.In order to minimize the complexity of the system, I first took agnathan fish and amphibians asmodeling animals. These animals have rather simple neuronal networks and have been wellstudied so that developing their biologically plausible models is more feasible. I developedmodels of sensory motor transformation centers that are capable of generating basic behaviorsof approach, avoidance and escape. The networks in these models used a similar layeredstructure having a sensory map in one layer and a motor map on other layers. The visualinformation was received as place coded information, but was converted into population codedand ultimately into rate coded signals usable for muscle contractions.In parallel to developing models of visuomotor centers, I developed a novel model of the basalganglia. The model suggests that a subsystem of the basal ganglia is in charge of resolvingconflicts between motor programs suggested by different motor centers in the nervous system.This subsystem that is composed of the subthalamic nucleus and pallidum is called thearbitration system. Another subsystem of the basal ganglia called the extension system which iscomposed of the striatum and pallidum can bias decisions made by an animal towards theactions leading to lower cost and higher outcome by learning to associate proper actions todifferent states. Such states are generally complex states and the novel hypothesis I developedsuggests that the extension system is capable of learning such complex states and linking themto appropriate actions. In this framework, striatal neurons play the role of conjunction (BooleanAND) neurons while pallidal neurons can be envisioned as disjunction (Boolean OR) neurons.In the next set of experiments I tried to take the idea of basal ganglia subsystems to a new levelby dividing the rodent arbitration system into two functional subunits. A rostral group of ratpallidal neurons form dense local inhibition among themselves and even send inhibitoryprojections to the caudal segment. The caudal segment does not project back to its rostralcounterpart, but both segments send inhibitory projections to the output nuclei of the rat basalganglia i.e. the entopeduncular nucleus and substantia nigra. The rostral subsystems is capableof precisely detecting one (or several) components of a rudimentary action and suppress othercomponents. The components that are reinforced are those which lead to rewarding stateswhereas those that are suppressed are those which do not. The hypothesis explains neuronalmechanisms involved in this process and suggests that this subsystem is a means of generatingsimple but precise movements (such as using a single digit) from innate crude actions that theanimal can perform even at birth (such as general movement of the whole limb). In this way, therostral subsystem may play important role in exploration based learning.In an attempt to more precisely describe the relation between the arbitration and extensionsystems, we investigated the effect of dynamic synapses between subthalamic, pallidal andstriatal neurons and output neurons of the basal ganglia. The results imply that output neuronsare sensitive to striatal bursts and pallidal irregular firing. They also suggest that few striatalneurons are enough to fully suppress output neurons. Finally the results show that the globuspallidus exerts its effect on output neurons by direct inhibition rather than indirect influence viathe subthalamic nucleus. / <p>QC 20131209</p>

Development of brain function is instructed by both genetically-determined processes (nature) and environmental stimuli (nurture). The relative importance of nature and nurture is a major question in developmental neurobiology. In this dissertation, I investigated the role of visual experience in the development and plasticity of the visual pathway. Each neuron that receives visual input responds to a specific area of the visual field- their receptive field (RF). Developmental refinement reduces RF size and underlies visual acuity, which is important for survival. By rearing Syrian hamsters (Mesocricetus auratus) in constant darkness (dark rearing, DR) from birth, I investigated the role of visual experience in RF refinement and plasticity. Previous work in this lab has shown that developmental refinement of RFs occurs in the absence of visual experience in the superior colliculus (SC), but that RFs unrefine and thus enlarge in adulthood during chronic DR. Using an in vivo electrophysiological approach, I show that, contrary to a widely held view, visual experience is not necessary for refinement of RFs in primary visual cortex (V1). In both SC and V1, RFs refine by postnatal day (P) 60, but enlarge by P90 with chronic DR. One week of visual experience was sufficient to prevent RF enlargement in SC and V1. How normal sensory experience prevents plasticity in mature circuits is not well understood. Using an in vitro electrophysiological approach, I demonstrated that GABAergic inhibition is reduced in DR SC, which in turn affects short-term (but not long-term) synaptic plasticity. The level of GABABR-mediated short-term synaptic depression (STD) that occurs during high-frequency afferent stimulation, such as occurs during vision, is reduced by DR. Using a computational model of RF size, I propose that, in addition to the effect of reduced inhibition, reduced STD of excitation could contribute to enlarged RFs. This work provides insight into mechanisms of development and plasticity of the nervous system. How plasticity is restricted in mature circuits is of fundamental importance in neuroscience and could instruct therapies to prevent maladaptive plasticity in disease and to enhance recovery of function in adults.

The purpose of this thesis was to determine the neuronal circuitry mediating U50,488-induced locomotion in preweanling rats. To this end, preweanling rats received bilateral electrolytic lesions of the ventromedial thalamus or superior colliculus and, two days later, the same rats received a challenge injection of U50,488. It was predicted that bilateral lesions of the ventromedial thalamus or superior colliculus would attenuate the U50,488-induced locomotor activity of 18-day-old rats.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23340号 / 生博第458号 / 新制||生||61(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 松田 道行, 教授 見学 美根子, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

As theoretical neuroscience has grown as a field, machine learning techniques have played an increasingly important role in the development and evaluation of theories of neural computation. Today, machine learning is used in a variety of neuroscientific contexts from statistical inference to neural network training to normative modeling. This dissertation introduces machine learning techniques for use across the various domains of theoretical neuroscience, and the application of these techniques to build theories of neural circuits. First, we introduce a variety of optimization techniques for normative modeling of neural activity, which were used to evaluate theories of primary motor cortex (M1) and supplementary motor area (SMA). Specifically, neural responses during a cycling task performed by monkeys displayed distinctive dynamical geometries, which motivated hypotheses of how these geometries conferred computational properties necessary for the robust production of cyclic movements. By using normative optimization techniques to predict neural responses encoding muscle activity while ascribing to an “untangled” geometry, we found that minimal tangling was an accurate model of M1. Analyses with trajectory constrained RNNs showed that such an organization of M1 neural activity confers noise robustness, and that minimally “divergent” trajectories in SMA enable the tracking of contextual factors. In the remainder of the dissertation, we focus on the introduction and application of deep generative modeling techniques for theoretical neuroscience. Specifically, both techniques employ recent advancements in approaches to deep generative modeling -- normalizing flows -- to capture complex parametric structure in neural models. The first technique, which is designed for statistical generative models, enables look-up inference in intractable exponential family models. The efficiency of this technique is demonstrated by inferring neural firing rates in a log-gaussian poisson model of spiking responses to drift gratings in primary visual cortex. The second technique is designed for statistical inference in mechanistic models, where the inferred parameter distribution is constrained to produce emergent properties of computation. Once fit, the deep generative model confers analytic tools for quantifying the parametric structure giving rise to emergent properties. This technique was used for novel scientific insight into the nature of neuron-type variability in primary visual cortex and of distinct connectivity regimes of rapid task switching in superior colliculus.

Certains troubles visuo-moteurs observés dès le stade précoce de la maladie de Parkinson (MP) pourraient être liés à une altération du fonctionnement d’une structure sous-corticale reliée aux ganglions de la base, le colliculus supérieur (CS). L’objectif de cette thèse a été d’explorer l’état fonctionnel du CS chez le patient parkinsonien nouvellement diagnostiqué (de novo) avant et après instauration du traitement dopaminergique, afin d’évaluer son potentiel de biomarqueur. Pour cela, un paradigme expérimental d’Imagerie par Résonance Magnétique fonctionnelle (IRMf) a été développé, permettant d’imager avec succès l’activité fonctionnelle du CS et également du corps genouillé latéral (CGL) et de l’aire visuelle primaire V1 et de moduler leur activité via l’emploi de stimulation visuelle jouant sur de très faibles niveaux de contraste (<10%). Un test de psychophysique a également été développé, permettant d’estimer la réponse perceptuelle au contraste. Nous avons dans un premier temps testé notre protocole expérimental auprès de sujets sains d’âge variable afin d’évaluer le fonctionnement de ces trois régions d’intérêt (ROIs) au cours du vieillissement normal et de différencier les effets liés à l’âge de ceux potentiellement liés à la pathologie (Etude 1). Une diminution statistiquement significative de la réponse BOLD au sein du CGL et de V1 avec l’âge a été observée, ces réponses corrélant de plus parfaitement avec les réponses perceptuelles estimées en psychophysique. Les voies magnocellulaire et parvocellulaire semblent jouer un rôle dans cette perte de sensibilité au contraste de luminance liée à l’âge. Nous avons dans un second temps testé notre protocole auprès de patients parkinsoniens de novo avant et après instauration du premier traitement dopaminergique afin d’évaluer les effets de la MP et du traitement sur le fonctionnement de nos ROIs (Etude 2). Une altération précoce du traitement du contraste a été observée au sein du CS et du CGL chez les patients parkinsoniens, non normalisée par l’instauration du traitement dopaminergique. Ces travaux de thèse ont ainsi mis en évidence un déficit fonctionnel du CS et du CGL survenant précocement durant l’évolution de la MP, confirmé par nos analyses de connectivité effective. Ces résultats pourraient favoriser l’identification de déficits liés à un dysfonctionnement sensoriel de ces structures tout comme le développement de tests paraclinique et clinique impliquant ce système pour un diagnostic plus précoce de la maladie. / Some visuo-motor impairments observed in the early stages of Parkinson’s disease (PD) might be related to a dysfunction of a subcortical structure connected to the basal ganglia, the superior colliculus (SC). The aim of this PhD thesis was to explore the functional state of the SC in newly diagnosed (de novo) PD patients before and after dopaminergic treatment intake, in order to evaluate the potential value of the SC functioning as a biomarker. To do this, we developed a functional Magnetic Resonance Imaging (fMRI) experimental protocol, which successfully imaged the SC and also the lateral geniculate nucleus (LGN) and primary visual area V1 functional activity and modulate their activity by using visual stimuli with low luminance contrast levels (<10%). Additionally, we estimated the perceptual response to contrast by using a psychophysical task. We tested in a first time this experimental protocol on healthy subjects with varying age in order to evaluate the effect of normal aging on the functioning of these regions of interest (ROIs) and to distinguish the effects related to age from those potentially related to the pathology (Study 1). A significant progressive decrease of the BOLD amplitude with age was observed in the LGN and V1. These data were consistent with the response functions obtained with the psychophysical task. These results indicate a significant luminance contrast sensitivity decline with age of both the magnocellular and parvocellular pathways. In a second time, we tested our protocol on de novo PD patients before and after the introduction of the first dopaminergic treatment in order to assess the effects of PD and treatment on the ROIs functioning (Study 2). Our results highlighted an early alteration of the contrast processing for the SC and LGN in PD patients, with no normalization after dopaminergic treatment introduction. These findings indicate a functional deficit of the SC and LGN that appears early in the disease course, in line with our effective connectivity analyses. These results could favor the identification of deficits linked to sensory dysfunction of these structures as well as the development of paraclinical and clinical tests involving this system for an early diagnosis of the disease.

La neuropathie optique glaucomateuse est une pathologie du système visuel entrainant une cécité irréversible qui affectera 80 millions de personnes en 2020. Le principal facteur de risque du glaucome est l'élévation de la pression intraoculaire qui mène à la mort progressive des cellules ganglionnaires de la rétine (CGR) du nerf optique jusqu'aux voies visuelles dans le cerveau. Il a été montré que le glaucome partageait des mécanismes neuro-inflammatoires communs avec les pathologies neurodégénératives. Nous avons émis l'hypothèse que ces mécanismes contribueraient à la progression du glaucome. L'objectif de ma thèse a été d'analyser les processus neuro-inflammatoires observés de la rétine jusqu'aux colliculus supérieurs sur un modèle expérimental d'hypertension oculaire unilatérale chez le rat obtenu après la cautérisation des veines épisclérales. Par des approches de biologie cellulaire et moléculaire, nous avons montré que ce modèle animal se caractérise par 1) une atteinte neuronale des CGR de l'oeil cautérisé; 2) l'augmentation de marqueurs pro-inflammatoires dans la rétine de l'oeil cautérisé, dans la rétine de l'oeil controlatéral, dans le nerf optique et dans les colliculus supérieurs et 3) la transmission de la neuro-inflammation à l'oeil controlatéral se fait majoritairement par les fibres des CGR qui projettent dans les deux colliculus supérieurs. Toutes ces données mettent en évidence le rôle complexe joué par le colliculus supérieur chez le rat dans la propagation de la neuro-inflammation induite par l'hypertension oculaire unilatérale. / Glaucoma is a visual system disorder leading to irreversible blindness and affecting 80 millions people worldwide by 2020. The major risk factor is elevated intraocular pressure leading to progressive retinal ganglion cell (RGC) death from the optic nerve (ON) to visual pathways in the brain. Glaucoma has been reported to share neuroinflammatory mechanisms with neurodegenerative disorders. We therefore hypothesize that mechanisms in central visual pathways may contribute to the spread of glaucoma disease. The aim of the present study was to analyze the neuroinflammation processes that occur from the pathological retina to the superior colliculi (SCs) in a rat model of unilateral ocular hypertension induced by episcleral vein cauterization. By molecular and cell biology methods, we have shown that this animal model is characterized by 1) neuronal damage of CGR from the cauterized eye; 2) the increase in proinflammatory markers in the retina of the cauterized eye, in the retina of the contralateral eye, in the optic nerve and in the superior colliculus and 3) transmission of neuroinflammation in contralateral eye is done mainly by CGR fibers that project into the two superior colliculus. All these data evidence the complex role played by the SCs, in rat, in the propagation of neuroinflammatory events induced by unilateral ocular hypertension.

<p dir="ltr">Localizing movements in the external space is crucial for animals to navigate safely, find food, avoid predators, and interact with their surroundings. Efficient localization during body movements requires the brain to distinguish between externally generated movements and self-generated ones. This involves integrating external stimulation with a continuous estimate of one's body position, to isolate external motion by suppressing sensations arising from self-motion.</p><p dir="ltr">To explore the neural mechanisms underlying object localization during active touch, we focused on the mouse superior colliculus (SC), which harbors multiple egocentric maps of sensorimotor space. Our studies revealed that SC neurons exhibit a rapidly adapting tactile response during externally generated touch. The response is significantly attenuated during self-generated touch, thus enhancing the ability to distinguish between external and self-induced tactile stimuli. Additionally, the direction of external motion is precisely encoded in the firing rates of these tactile-responsive neurons, indicating a specialized localization mechanism within the SC.</p><p dir="ltr">In scenarios devoid of external stimuli, SC neural activity accurately reflects the kinematics of self-motion, such as whisker position and locomotion speed, capturing past, present, and future body positions. Half of the neurons that encode self-motion also respond to external tactile stimuli. This dual functionality suggests that these neurons not only track self-motion but also engage in the processing of external tactile information. The magnitude of the external tactile response in these neurons is modulated by the state of self-motion upon touch. These results suggest that SC neurons integrate internal estimates of body movements with external tactile inputs to compute the egocentric distance of objects.</p>

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Chez plusieurs espèces, les neurones auditifs sensibles à la durée de la stimulation sont présents au niveau des collicules inférieurs. Toutefois, le décours temporel de leur développement fonctionnel est inconnu. Étant donné que le collicule supérieur est l’un des principaux relais sous-cortical impliqué dans l’intégration des stimuli audio-visuels, nous voulons déterminer si le collicule supérieur du rat contient de tels neurones et s’ils sont sensibles et sélectifs à différentes durées de stimulation auditive. De plus, l'originalité de cette étude est de déterminer les étapes de leur maturation fonctionnelle. Des enregistrements neuronaux unitaires et extra-cellulaires sont effectués dans le collicule supérieur de rats juvéniles (P15-P18, P21-P24, P27-P30) et adultes anesthésiés. La sensibilité à la durée est déterminée lors de la présentation de bruits gaussiens (2-10 dB SPL au-dessus du seuil) de durées variables (3-100 ms). Seulement un faible pourcentage des neurones du collicule supérieur est de type passe-bande (3-9% des neurones parmi les ratons et 20% chez les rats adultes). Une différence significative de la distribution entre les différents types de neurones auditifs sensibles à la durée est présente au cours du développement: les neurones de type passe-haut (63-75%) sont présents en majorité chez les groupes juvéniles alors que 43% des neurones sont de type insensible à la durée de la stimulation auditive chez les rats adultes. Ces résultats montrent qu’une population importante de neurones auditifs du collicule supérieur du rat est sensible à la durée des signaux sonores et qu’un développement fonctionnel important survient au cours du premier mois postnatal. / In many species, duration-sensitive neurons which could possibly analyse species-specific vocalizations are encountered in the inferior colliculus. However, their postnatal development is unknown. Since the superior colliculus is one of the most important subcortical relay implicated in the audiovisual integration, we sought to gain insight on whether the SC of the rat contains such neurons and, if so, whether they are sensitive and selective to duration. Furthermore, the originality of this study is to determine their fonctional maturation. Extracellular single-unit recordings were assessed in the deep layers of the superior colliculus of anesthetized rats throughout postnatal days (P15 – P18, P21 – P24, P27 – P30) and at adulthood. Gaussian noises of different durations (3-100 ms) were presented in free-field in pseudo-random order (2 – 10 dB SPL above threshold). Only few neurons are band-pass: about 3 – 9% across the different age groups (P15 – P30) and 20 % in adults. Thus, in terms of categories of duration-sensitive neurons profiles, a significant difference was evident across postnatal development: long-pass (63-75%) neurons were mostly encountered in the different groups of pups relative to all-pass (43%) in adult rats. These results demonstrate that a large population of neurons in the superior colliculus of the rat is sensitive to noise durations and that important development changes occur during postnatal maturation.