A blockade of GABAergic inhibition increases the receptive field(RF) size of most somatosensory cortex (SI) and some ventrobasal thalamus (VB) neurons. The results suggest RF size of cuneate neurons may be modulated through GABAa and GABAb receptors, independent of firing frequency.

The research discussed here examines how normal healthy aging affects spatial suppressive mechanisms in a variety of visual tasks using both static and dynamic stimuli. Prior research has suggested that younger adults demonstrate a center-surround antagonistic pattern in which they show spatial summation at low contrast and spatial suppression at high contrast in brief motion direction discrimination tasks. Older adults have been shown to have reduced spatial suppression at high contrast and this is thought to be related to reduced GABAergic inhibition in the visual cortex. The results obtained from this program of research suggest that age-related changes in optical and neural visual mechanisms do not affect spatiotemporal mechanisms for static stimuli when the target is presented with the mask (embedded masking). However, when the mask appears immediately before (forward masking) or after (backward masking) the target, older adults require more contrast to detect the target (Chapter 2). In addition, spatial suppression is not reduced for older adults in a task with moving stimuli presented at long durations, even with increasing speed (Chapter 3). In Chapter 4, we used static stimuli presented at brief durations to induce a sudden motion onset and found that although there was no significant age difference in spatial suppression, there was a trend showing reduced levels of spatial suppression in older adults. These results taken together suggest that inhibitory neural mechanisms in the visual cortex may mediate spatial suppression for briefly presented stimuli only. / Thesis / Doctor of Philosophy (PhD)

In der Folge eines Status epilepticus entwickelt sich häufig eine chronische Epilepsie. In der vorliegenden Dissertation wurde die Fragestellung bearbeitet, ob ein Inhibitionsverlust im Gyrus dentatus Grundlage der Epileptogenese nach Status epilepticus ist. Ein selbst-erhaltender Status epilepticus (SSSE) wurde an erwachsenen Ratten durch elektrische Stimulation ausgelöst. Das Auftreten spontaner epileptischer Anfälle wurde im Verlauf von acht Wochen nach Status epilepticus zu drei Zeitpunkten (1, 4 und 8 Wochen) mittels Videoüberwachung erfasst. Zu denselben Zeitpunkten und vor Status epilepticus wurden elektrophysiologische Messungen im Gyrus dentatus durchgeführt. Die Aktivität der Prinzipalzellen des Gyrus dentatus unterliegt unter physiologischen Bedingungen einer ausgeprägten inhibitorischen Kontrolle. Durch Analyse von Doppelreizantworten wurden Veränderungen der Inhibition in dieser für die Epileptogenese relevanten Hirnstruktur beurteilt. Im Verlauf von acht Wochen nach SSSE entwickelte sich bei einem Großteil der Versuchstiere eine chronische Epilepsie. Zum spätesten Beobachtungszeitpunkt traten rekurrente spontane epileptische Anfälle bei 80 Prozent der Tiere auf. Die Inhibition im Gyrus dentatus war eine Woche nach Status epilepticus signifikant reduziert. Vier und acht Wochen nach SSSE zeigte sich eine zunehmende Wiederannäherung an die vor dem Status epilepticus erhobenen Messwerte, so dass von einem transienten Inhibitionsverlust im Gyrus dentatus nach Status epilepticus gesprochen werden kann. Zusammenfassend konnte in der Dissertation gezeigt werden, dass sich in der Folge eines Status epilepticus bei der Mehrzahl der Tiere eine chronische Epilepsie entwickelt. Der Inhibitionsverlust im Gyrus dentatus war zu einem Zeitpunkt am größten, da noch keine spontanen epileptischen Anfälle auftraten. Als sich bei den meisten Tieren eine chronische Epilepsie entwickelt hatte, war die Inhibition komplett wiederhergestellt. Daher ist ein Inhibitionsverlust im Gyrus dentatus nach einem Status epilepticus nicht der führende pathophysiologische Mechanismus für die Entwicklung einer chronischen Epilepsie. / Development of chronic epilepsy as a consequence of status epilepticus is a frequent clinical observation. The aim of this work was to test the hypothesis that epileptogenesis after status epilepticus depends on a loss of inhibitory function in the dentate gyrus. A self-sustaining status epilepticus (SSSE) was induced in rats by continuous electrical stimulation of the perforant path. The occurrence of spontaneous epileptic seizures was assessed by video monitoring 1, 4 and 8 weeks after SSSE. At the same time points and directly before SSSE, inhibition in the dentate gyrus was measured using a paired pulse paradigm. In this region, excitability of principal cells is under physiological conditions effectively controlled by the activity of inhibitory interneurons. In addition, the dentate gyrus is relevant for the process of epileptogenesis due to anatomical properties. In the time course after SSSE, the fraction of animals showing spontaneous epileptic seizures increased steadily reaching 80 % after eight weeks. One week after SSSE, inhibition in the dentate gyrus was significantly reduced. This loss proved to be transient, as inhibition recovered after 4 weeks and reached pre-status values after 8 weeks. In conclusion, the majority of animals developed chronic epilepsy as a consequence of status epilepticus. Loss of inhibition in the dentate gyrus was maximal while spontaneous seizures had not yet developed. Inhibition was normalized when most animals had become epileptic. Thus, loss of inhibition in the dentate gyrus following status epilepticus is not a decisive mechanism in the emergence of spontaneous seizures.

[Truncated abstract] Formation and consolidation of the retinotectal projection during optic nerve regeneration has been associated with two major interlinked processes. Initially, retinal ganglion cell (RGC) axons are guided by molecular guidance cues, such as the Eph receptor tyrosine kinases and their ligands, the ephrins, to their approximately correct location and form a coarse topographic map in the optic tecum. Such axon guidance occurs in the absence of neural activity and is considered to be activity-independent. The second process involves glutamatergic excitation, whereby correctly located connections are strengthened by correlated neural activity, whilst removing inappropriately located ones thereby sharpening the topography.The second process is considered to be activitydependent. Here, a number of experiments were undertaken to further examine the interrelationships of activity-dependent and independent processes with respect to functional outcomes. Two models of optic nerve regeneration were studied. In goldfish, following optic nerve crush, regeneration is successful. … In goldfish, guidance along the medio-lateral tectal axis may occur through preordering of axons prior to entering the tectum via the appropriate medial and lateral brachium, with EphA/ephrin-A then guiding axons over the rostral-caudal axis establishing gross topography. The increase in involvement of NMDA-mediated transmission during the period of activity-dependent refinement consolidated the role of this receptor in synapse plasticity. However what triggers NMDA-mediated activity to increase is still largely unresolved, although as the factors governing receptor trafficking during development and synaptic plasticity become better understood, these can be applied to the period of plasticity associated with regenerating axons. And finally, as GABAergic inhibition appears to suppress activity-dependent refinement, means of overcoming this inhibition through 4 such methods as visual training or pharmacological intervention may have significance for mammalian regeneration.

Les glucocorticoïdes (GC) sont des hormones stéroïdes synthétisées par les glandes surrénales. La production de ces GC est une des réponses de l’organisme pour rétablir l’homéostasie grâce à différentes actions comprenant des effets centraux sur le comportement et la douleur. C’est ce dernier qui a fait l’objet de mes travaux dans le cadre de cette thèse.Les afférences sensorielles primaires véhiculent les informations de la périphérie dans les cornes dorsales de la moelle épinière. Ces informations qui peuvent être nociceptives sont modulées par un réseau de neurones spinal avant d’être transmises et intégrées. Nous avons montré que les GC sont impliqués dans la maturation et le fonctionnement de la transmission inhibitrice faisant intervenir le neurotransmetteur GABA. Dans les cornes dorsales, cette inhibition est cruciale pour limiter les mécanismes de transmission de l’information nociceptive. / Glucocorticoids (GC) are steroid hormones synthesized in adrenals following HPA axis activation. GC production is a response of the organism to alleviate homeostasis perturbations through different actions. One of them involves central neuronal modulation of behavior and pain perception.Primary afferents convey peripheral sensory information in the dorsal horns of the spinal cord. This information can be nociceptive and are modulated by a spinal neuronal network before being transmitted and integrated. We showed that GC are implied in the maturation and functioning of the inhibitory transmission involving GABA neurotransmitter. In the dorsal horns this inhibitory transmission is of major importance, limiting the processing of nociceptive information.

Les épilepsies acquises se déclarent après un processus graduel appelé épileptogenèse. Bien que cliniquement silencieux, ce processus implique des modifications fonctionnelles observables notamment par électroencéphalographie. Cette thèse vise i) à identifier des marqueurs électrophysiologiques apparaissant au cours de l’épileptogenèse, et ii) à comprendre les modifications physiopathologiques sous-jacentes responsables de ces marqueurs et de leur évolution temporelle. Dans un premier temps, nous avons, dans un modèle d’épilepsie partielle chez la souris, monitoré des signaux électrophysiologiques intracérébraux pendant la mise en place de la maladie. Nous avons observé dans ces signaux expérimentaux, l’émergence d’événements transitoires pathologiques appelés pointes épileptiques. Nous avons développé des méthodes de traitement du signal pour détecter et caractériser automatiquement ces événements. Ainsi, nous avons pu mettre en évidence certains changements dans la forme des pointes épileptiques au cours de l’épileptogenèse ; en particulier l’apparition et l’augmentation d’une onde qui suit la pointe épileptique. Une hypothèse défendue dans ces travaux est que ces changements morphologiques peuvent constituer des marqueurs de l’épileptogenèse dans ce modèle animal. Dans un second temps, afin d’interpréter ces modifications électrophysiologiques en termes de processus neurophysiologiques sous-jacents, nous avons implémenté un modèle biomathématique, physiologiquement argumenté, capable de simuler des pointes épileptiques. Formellement, ce modèle est un système dynamique non linéaire qui reproduit les interactions synaptiques (excitatrices et inhibitrices) dans une population de neurones. Une analyse de sensibilité de ce modèle a permis de mettre en évidence le rôle critique de certains paramètres de connectivité dans la morphologie des pointes. Nos résultats montrent en effet, qu’une diminution de l’inhibition GABAergique entraîne un accroissement de l’onde dans les pointes épileptiques. À partir du modèle théorique, nous avons pu ainsi émettre des hypothèses sur les modifications opérant au cours du processus d’épileptogenèse. Ces hypothèses ont pu être en partie vérifiées expérimentalement en bloquant artificiellement l’inhibition GABAergique, dans le modèle in vivo chez la souris, et dans un modèle in vitro chez le rat. En conclusion, ce travail de thèse fournit, dans un modèle animal, un biomarqueur électrophysiologique de l’épileptogenèse et tente d’expliquer, grâce à une modélisation biomathématique, les processus neurophysiologiques sous-jacents qu’il reflète. / Acquired epilepsies occur after a process called epileptogenesis. Although clinically silent, this process involves some functional modifications which can be observed by electroencephalography. The objectives of this thesis are i) to identify electrophysiological markers occurring during epileptogenesis, and ii) to understand which underlying pathophysiological modifications are responsible for these markers and their evolution. Firstly, using an in vivo experimental mouse model of partial epilepsy, we have monitored intracranial electrophysiological signals during epileptogenesis. We observed the emergence of pathological transient events called epileptic spikes. We have developed signal processing methods in order to automatically detect and characterize these events. Hence, we observed and quantified morphological changes of epileptic spikes during epileptogenesis. In particular, we noticed the emergence and the increase of a wave which directly follows the spike component. In this work, we defend the hypothesis that these morphological modifications can constitute markers of the epileptogenesis process in this animal model of epilepsy. Secondly, in order to interpret these electrophysiological modifications in terms of underlying pathophysiological processes, we have implemented a computational model able to simulate epileptic spikes. This neural mass model is a neurophysiologically-plausible mesoscopic representation of synaptic interactions (excitation and inhibition) in the hippocampus. Based on a sensitivity analysis of model parameters, we were able to determine some connectivity parameters that play a key role in the morphology of simulated epileptic spikes. In particular, our results show that a diminution of GABAergic inhibition leads to an increase of the aforementioned wave. Thus, using this theoretical model, we defined some hypotheses about pathophysiological modifications occurring during the epileptogenesis process. One of these hypotheses has been confirmed in blocking GABAa receptors in the in vivo mouse model, as well as in an in vitro model (rat, organotypic slices). In summary, based on the shape features of epileptic spikes, we devised an electrophysiological biomarker of epileptogenesis observed in a mouse model but useful in Human studies as well. Moreover, a computational modeling approach has permitted to suggest which pathophysiological processes might underlie this biomarker.