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The ketogenic diet is high fat, low carbohidrate and protein. This kind of diet is used to treatment of a lot of disease, especially epilepsy, because their ability to interfere on body metabolism and cerebral excitability. This work contains two articles. The first one is a review of the molecular and cellular mechanisms of action of the ketogenic diet on the reduction of cerebral electrical activity to improve the seizures. The second one is an experimental study which aims to analyze the interference of two kinds of ketogenic diet on the cerebral excitability. One of diets used was the classical ketogenic diet, composed by long chain triglycerides with polyunsaturated fatty acids, soy oil, widely used to treatment of epilepsy; the other one was composed by triglycerides of the enantic acid, seven molecules of carbon, the triheptanoin, which is metabolized faster and well accepted by the organism, used to clinical treatment of disorders of pyruvate carboxilase enzyme and long chain fatty acid oxidation. In order to analyze the cerebral electric activity we used the Spreading Depression feature. The Spreading Depression is a phenomenon that occurs in the nervous system and when trigged at cerebral cortex leads to a reduction of neuronal activity which spreads slowly, with velocity of 2-5 mm/min, to all regions of the cerebral cortex. A burst of neuronal electrical activity similar to that found in epileptic EEG occurs during the initial phase of spreading depression. Because theirs characteristics this phenomenon had been widely used to study brain functionality. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A dieta cetogênica é caracterizada por altos níveis de lipídios e baixos níveis de proteínas e de carboidratos. Devido à sua grande interferência no metabolismo corporal, em especial na excitabilidade cerebral, este tipo de dieta tem sido utilizado para o tratamento de diversas doenças, em destaque a epilepsia. Este trabalho é composto por dois artigos. O primeiro artigo é uma revisão dos mecanismos moleculares e celulares pelos quais a dieta cetogênica poderia interferir no metabolismo cerebral causando uma redução da atividade elétrica cerebral, e assim, uma melhora das crises convulsivas. O segundo artigo trata da análise da influência de dois tipos de dietas cetogênicas na excitabilidade cerebral em ratos. Uma das dietas utilizadas foi a dieta cetogênica clássica, composta por triacilgliceróis com ácidos graxos poliinsaturados de cadeia longa, o óleo de soja, mais utilizada para tratamento clínico da epilepsia; o segundo tipo de dieta utilizado é constituído por triacilgliceróis derivados do ácido graxo enântico, a trienantina, mais rapidamente metabolizada pelo organismo e bem tolerada pelo mesmo, clinicamente utilizada para tratamento de deficiência da enzima piruvato carboxilase e deficiência na oxidação de ácidos graxos de cadeia longa. Para análise da atividade elétrica cerebral utilizou-se o modelo da Depressão Alastrante. A Depressão Alastrante é um fenômeno que ocorre no tecido nervoso e quando deflagrada no córtex cerebral, causa uma redução da atividade elétrica cortical que se propaga lentamente, com velocidade de 2-5 mm/min, por todas as regiões do córtex cerebral, e em cuja fase inicial encontrase um surto de atividade elétrica neuronal semelhante às ondas cerebrais características da epilepsia. Devido às suas características esse fenômeno tem sido amplamente utilizado para estudo da funcionalidade cerebral.

L’évolution du Syndrome Douloureux Régional Complexe (SDRC) peut aboutir à un état de douleur chronique invalidant et difficile à traiter. Parmi les stratégies thérapeutiques utilisables, la kétamine, administrée sur 5 jours à des doses infra-anesthésiques, a une place de choix. Cependant, il s'agit d'un traitement invasif et dont le mécanisme d'action antalgique n'est pas connu. Notre travail a porté sur deux aspects du traitement du SDRC par la kétamine: la prédiction de l’efficacité thérapeutique et la compréhension des mécanismes d'action. Dans un premier temps, chez 105 patients SDRC, nous avons évalué l'intérêt de la scintigraphie osseuse au Technétium 99 réalisée avant le traitement pour prédire l’efficacité thérapeutique de la kétamine. Cette efficacité était corrélée à l’augmentation relative de l'activité inflammatoire et du remodelage osseux objectivée par scintigraphie. Dans une deuxième étude, portant sur l’évaluation de l’excitabilité corticale par stimulation magnétique transcrânienne et incluant 19 patients SDRC, nous avons observé que la kétamine réprimait fortement et de façon bilatérale la facilitation intracorticale, paramètre de transmission glutamatergique, et en revanche restaurait l’inhibition intracorticale correspondant au côté douloureux, paramètre gabaergique qui était très altéré avant le traitement. L'effet antalgique de la kétamine était corrélé à cette restauration d'inhibition ainsi qu'à la réduction de la facilitation correspondant au côté sain. Ainsi, la kétamine semble jouer un rôle dans la balance d'influences gabaergiques et glutamatergiques transcalleuses. Ce travail a permis de caractériser de nouveaux mécanismes physiopathologiques ainsi qu’une nouvelle justification de l’efficacité thérapeutique de la kétamine dans le SDRC. / Regional Complex Pain Syndrome (CRPS) can result in a chronic pain condition that is disabling and difficult to treat. Among the therapeutic strategies that can be used, ketamine, administered over 5 days at infra-anesthetic doses, has a place of choice. However, it is an invasive treatment and the mechanism of analgesic action is not known. Our work focused on two aspects of the treatment of CRPS by ketamine: predicting therapeutic efficacy and understanding mechanisms of action. Initially, in 105 CRPS patients, we assessed the benefit of pre-treatment Technetium 99 bone scintigraphy to predict the therapeutic efficacy of ketamine. This efficacy was correlated with the relative increase in inflammatory activity and bone remodeling detected by scintigraphy. In a second study, evaluating cortical excitability by transcranial magnetic stimulation and including 19 CRPS patients, we observed that ketamine strongly and bilaterally repressed intracortical facilitation, a glutamatergic transmission parameter, and on the other hand restored the intracortical inhibition corresponding to the pain side, a gabaergic parameter which was very altered before the treatment. The analgesic effect of ketamine was correlated with this restoration of inhibition as well as the reduction of the facilitation corresponding to the healthy side. Thus, ketamine seems to play a role in the balance of gabaergic and glutamatergic transcallosal influences. This work allowed new physiopathological mechanisms to be characterized as well as a new justification of the therapeutic efficacy of the ketamine in the CRPS.

INTRODUÇÃO: o estresse, causa importante de ansiedade, provoca ativação do eixo HPA, liberando hormônios glicocorticoides e adrenalina, e neurotransmissores, como a norepinefrina. Consequentemente, ocorrem mudanças morfológicas e biomoleculares em diversas regiões do SNC, destacando-se o complexo basolateral da amígdala, além de alterações comportamentais. OBJETIVOS: investigar, por meio de administrações (ip) de atenolol e metirapona, possíveis influências periféricas dos receptores de NE (&#946;1) e GR no BLA de ratos na ansiedade tardia. Analisar também a via de sinalização intracelular ERK-MEK-CREB e a excitabilidade de neurônios da região. RESULTADOS: verificamos aumento do estado do tipo ansioso após 10 dias do estresse, efeito não visto com tratamento com atenolol (ip). Além disso, o estresse provocou aumento de EGR1 (p<0.05), dado indicador de maior taxa de atividade de neurônios do BLA, efeito não encontrado nos animais tratados com atenolol. Além disso, não encontramos alterações na fosforilação de ERK e na espressão de CREB. CONCLUSÃO: a sinalização adrenérgica/noradrenérgica periférica pode ter relevante função na modulação do comportamento do tipo ansioso tardio (10 dias) induzido por um único estresse de contenção. / INTRODUCTION: stress, an important cause of anxiety, triggers HPA activation, releasing epinephrine and glucocorticoids (GCs) hormones and neurotransmitters such as norepinephrine (NE). As result, morphological and biomolecular changes occurs in several regions of CNS, majorly in the amygdala basolateral complex, in addition to behaviors alterations. OBJECTIFS: to investigate, using atenolol and metyrapone administration (ip), the influence of NE receptors (&#946;1) and GR, respectively, in the BLA of rats in the restraint stress-induced long-lasting anxiety. In addition, also investigate the participation of ERK-MEK-CREB signaling and neuronal BLA excitability in such paradigm. RESULTS: we showed that restraint stress (2h) induced anxiety-like behavior 10 days after stress, and the pre-treatment with atenolol blunted such effect. In addition, we observed that restraint stress increased the expression of EGR1 (p<0.05) in the BLA of stressed rats, which was also blunted by atenolol administration, suggesting a higher activity in BLA neurons. We found no modulation in ERK and CREB activation in restraint stress-induced long-lasting anxiety rats. CONCLUSION: we conclude that the peripheral adrenergic/noradrenergic signaling may have a relevant function in long-lasting anxiety-like behavior (10 days) induced by a single episode of restraint stress.

Dans cette thèse, je reporte les résultats d'études développées durant ces trois dernières années à l'Institut Non-Linéaire de Nice. Premièrement, je présente des résultats sur l'application de perturbation à un système excitable, obtenus à partir d'un simple laser à signal injecté. L'excitabilité, qui vient dans ce cas de la proximité d'une bifurcation noeudselle sur un cercle, et est définit comme une réponse tout-ou-rien à une perturbation. La réponse excitable, présente pour des perturbations supérieures à un certain seuil, correspond au décrochage des deux lasers pour une période. Le déclenchement de tels réponses excitable, dont la forme ne dépend pas de la perturbation (type, amplitude), est démontré par l'application de perturbation. Dans un deuxième temps, j'analyse l'influence de la connexion entre un neurone et son propre axone. Expérimentalement nous ajoutons un miroir de rétroaction fabriquant ainsi un laser injecté et réinjecté. Sous certaines conditions, la précédente réponse excitable se régénère dans la cavité externe, exhibant une propriété de mémorisation, où l'information est codée dans la phase du faisceau. Analytiquement, cela correspond à l'addition d'un terme de retard linéaire qui joue le rôle d'un "quasi-espace" permettant la coexistence de plusieurs "réponse excitable", et leur interprétation en terme de solitons topologique de Sine-Gordon. L'application de perturbations appropriées peut mener au contrôle de l'information présente. De nombreux comportements ont ainsi été observés et reproduits numériquement avec des modèles appropriés, comme les collisions, le groupement, la diffusion, l'accrochage à une modulation périodique, ... / In this thesis, I report the results of studies performed during these last three years at Institut Non Linéaire de Nice. First, I present results on perturbing a neuron-like excitable system build from a simple laser with an injected signal experiment. Excitability, that comes in this case from the proximity of a Saddle-node bifurcation, is defined as an all or-nothing response to an external perturbation. The excitable response, that arises from perturbation larger than a certain threshold, corresponds to the unlocking between the two lasers for one period. Triggering of such excitable responses, that shape do not dependent on the perturbation (kind, strength), is demonstrated applying perturbations. In a second part, I analyze the influence of the connection between one of this neuron and its own axon. Experimentally we add a feedback mirror building a laser submitted to injection and feedback. Under certain conditions, the previous excitable response is found to regenerate in the external cavity, exhibiting a memory behavior where the information is coded in the time spiking pattern. Analytically, this corresponds to the addition of a linear delay term that acts as a space-like coordinate allowing the storage of many "excitable responses", and their interpretation in terms of Sine-Gordon topological solitons. Application of appropriate perturbations could lead to the control of "information" present. Many interesting behaviors of this new structures are observed and analyzed numerically with appropriate models, like collisions, clustering, particle-like diffusion, locking to periodic additional forcing...

This thesis describes a series of experiments in human observers using neurophysiological and behavioural approaches to investigate the effects of varying haptic stimuli, attentional demand and age on motor control and perception during haptic sensing (i.e., using the hand to seek sensory information by touch). In Experiments I-IV, transcranial magnetic stimulation (TMS) was used to explore changes in corticomotor excitability when participants were actively engaged in haptic sensing tasks. These studies showed that corticospinal excitability, as reflected in motor evoked potential (MEP) amplitude, was greatly enhanced when participants were engaged in different forms of haptic sensing. Interestingly, this extra corticomotor facilitation was absent when participants performed finger movements without haptic sensing or when attention was diverted away from haptic input by a concurrent cognitive task (Exp I). This provided strong evidence that the observed corticomotor facilitation was likely central in origin and related to haptic attention. Neuroimaging has shown activation of the parieto-frontal network likely subserves this aspect of haptic perception. Further, this haptic-specific corticomotor facilitation was finely modulated depending on whether participants focused attention on identifying material (texture) as opposed to geometric properties of scanned surfaces (Exp II). With regards to aging effects, haptic-related corticomotor facilitation was associated with higher recognition accuracy in seniors (Exp III). In line with this, seniors exhibited similar levels of haptic-related corticomotor facilitation to young adults when task demands were adjusted for age (Exp IV). Interestingly, both young and senior adults also showed substantial corticomotor facilitation in the ‘resting’ hand when the ipsilateral hand was engaged in haptic sensing (Exp IV). Simply touching the stimulus without being required to identify its properties (no attentional task demands) produced no extra corticomotor facilitation in either hand or age group, attesting again to the specificity of the effects with regards to haptic attention. In Experiments V-VI, the ability to recognise 2-D letters by touch was investigated using kinematic and psychophysical measures. In Experiment V, we characterized how age affected contact forces deployed at the fingertip. This investigation showed that older adults exhibited lower normal force and increased letter-to-letter variability in normal force when compared to young adults. This difference in contact force likely contributed to longer contact times and lower recognition accuracy in older adults, suggesting a central contribution to age-related declines in haptic perception. Consistent with this interpretation, Experiment VI showed that haptic letter recognition in older adults was characterized not only by lower recognition accuracy but also by substantial increases in response times and specific patterns of confusion between letters. All in all, these investigations highlight the critical interaction of central factors such as attentional demand with aging effects on motor and perceptual aspects of haptic sensing. Of particular significance is the clear demonstration that corticomotor excitability is greatly enhanced when a haptic sensing component (i.e., attending to specific haptic features) is added to simple finger movements performed at minimal voluntary effort levels (typically <15 % of the maximal effort). These observations underline the therapeutic potential of active sensory training strategies based on haptic sensing tasks for the re-education of motor and perceptual deficits in hand function (e.g., subsequent to a stroke). The importance of adjusting attentional demands and stimuli is highlighted, particularly with regards to special considerations in the aging population.

В работе изучаются три нелинейных модели, предложенных Альбертом Голдбетером для описания ферментативной реакции в живой клетке. Математически эти нелинейные модели интересны своей быстро-медленной динамикой, автоколебаниями канардового типа, крайней неоднородностью детерминированных фазовых портретов, большой вариабельностью и сосуществованием динамических режимов. В этих условиях даже небольшие случайные возмущения существенно изменяют динамику системы и индуцируют такие феномены, как стохастическая возбудимость, мультимодальность, фантомный аттрактор и переходы от порядка к хаосу. Проведенное исследование данных моделей дает понимание основных механизмов этих явлений с помощью методов численного и статистического анализа, а также теоретического подхода, основанного на функции стохастической чувствительности и методе доверительных областей. / The work examines three nonlinear models proposed by Albert Goldbeter to describe the enzymatic reaction in a living cell. Mathematically, these nonlinear models are interesting for their slow-fast dynamics, canard-type self-oscillations, extreme inhomogeneity of deterministic phase portraits, great variability and coexistence of dynamic modes. Under these conditions, even small random perturbations significantly change the dynamics of the system and induce such phenomena as stochastic excitability, multimodality, phantom attractor, and transitions from order to chaos. The study of these models provides an understanding of the main mechanisms of these phenomena using methods of numerical and statistical analysis, as well as a theoretical approach based on the stochastic sensitivity function and the method of confidence domains.

Essentiel à la survie, le stress est une expérience connue de tous les organismes. Son excès, tout comme son manque, peut cependant induire des conséquences néfastes pour la santé. Ainsi, un stress aigu peut engendrer des déficits au niveau des fonctions cognitives via l’activation de récepteurs aux glucocorticoïdes (GRs). L’activation de ces-derniers peut perturber les fonctions neuronales et induire des altérations du comportement et même de la physiologie neuronale. À ce jour, très peu d’information est disponible quant aux effets précis de l’activation des GRs sur la plasticité et la fonction synaptique; d’autant moins lorsque les différences sexuelles sont prises en compte. De plus, la manière dont la signalisation GR dans les types de cellules non- neuronales contribue au dysfonctionnement synaptique associé au stress reste encore moins claire. Ainsi, notre but était de caractériser les effets du stress aigu sur la fonction synaptique de l’hippocampe chez les souris mâles et femelles afin de mettre en évidence le rôle de la signalisation aux glucocorticoïde au sein des cellules non-neuronales. À cet effet, des souris ont été soumises à un test de nage forcée (acute swim stress), puis des tranches d’hippocampe ont été préparées in-vitro pour l’étude électrophysiologique. Les souris mâles ont exprimé une réponse neuroendocrine plus prononcée au stress aigu, alors que cette dernière est demeurée absente chez les femelles. Dans cet ordre d’idées, les déficits de potentialisation à long-terme (LTP) obtenus en réponse au stress ont aussi été observés exclusivement chez les mâles. Finalement, les enregistrements électrophysiologiques en cellule-attachée ont montré qu’un stress aigu augmente l’excitabilité intrinsèque dans CA1 chez les deux sexes, mais que des modifications aux afférences excitatrices de CA1 sont observés seulement chez les mâles. / Stress is a global experience across all organisms, and although important for our survival, stress can have detrimental effects on brain health. More specifically, acute stress induces an intense deficit in cognitive function via the activation of glucocorticoid receptors (GRs). The activation of GRs can modify neuronal function and structure to promote lasting changes in behaviour and physiology. Despite this, the effects and precise mechanisms of stress and GR activation on synaptic function and plasticity in male and female mice remain unclear. Furthermore, how GR signalling in non-neuronal cell types contributes to the synaptic dysfunction associated with stress remains even less clear. Thus, we aimed to conduct a detailed characterization of the effects of acute stress on hippocampal synaptic function in male and female mice and highlight the role of GR signalling in non-neuronal cell types in governing these effects. To accomplish this, mice were subjected to an acute swim stress and hippocampal brain slices were prepared for in-vitro electrophysiology. We found that male mice have a pronounced neuroendocrine response to acute stress, accompanied by an increase in astrocyte GR signalling. However, these changes were absent in female mice. In line with this, we have also found that stress-induced impairments of hippocampal long-term potentiation (LTP) are specific to males. Finally, whole-cell patch clamp recordings demonstrate that acute stress increases the intrinsic excitability of CA1 neurons in male and female mice; however, only male mice have changes in the excitatory inputs of CA1 neurons. Overall, our results demonstrate a sexually dimorphic response to an acute swim stress.

Résumé : L’interaction entre la douleur et le système moteur est bien connue en clinique et en réadaptation. Il est sans surprise que la douleur est un phénomène considérablement invalidant, affectant la qualité de vie de ceux et celles qui en souffrent. Toutefois, les bases neurophysiologiques qui sous-tendent cette interaction demeurent, encore aujourd’hui, mal comprises. Le but de la présente étude était de mieux comprendre les mécanismes corticaux impliqués dans l’interaction entre la douleur et le système moteur. Pour ce faire, une douleur expérimentale a été induite à l’aide d’une crème à base de capsaïcine au niveau de l’avant-bras gauche des participants. L'effet de la douleur sur la force des projections corticospinales ainsi que sur l’activité cérébrale a été mesuré à l’aide de la stimulation magnétique transcrânienne (TMS) et de l’électroencéphalographie (EEG), respectivement. L’analyse des données EEG a permis de révéler qu'en présence de douleur aiguë, il y a une augmentation de l’activité cérébrale au niveau du cuneus central (fréquence têta), du cortex dorsolatéral préfrontal gauche (fréquence alpha) ainsi que du cuneus gauche et de l'insula droite (toutes deux fréquence bêta), lorsque comparée à la condition initiale (sans douleur). Également, les analyses démontrent une augmentation de l'activité du cortex moteur primaire droit en présence de douleur, mais seulement chez les participants qui présentaient simultanément une diminution de leur force de projections corticales (mesurée avec la TMS t=4,45, p<0,05). Ces participants ont également montré une plus grande connectivité entre M1 et le cuneus que les participants dont la douleur n’a pas affecté la force des projections corticospinales (t=3,58, p<0,05). Ces résultats suggèrent qu’une douleur expérimentale induit, chez certains individus, une altération au niveau des forces de projections corticomotrices. Les connexions entre M1 et le cuneus seraient possiblement impliquées dans la survenue de ces changements corticomoteurs. / Abstract : The interaction between pain and the motor system is well-known in clinic. For instance, it is well documented that pain significantly complicates the rehabilitation of the patients. The aim of the present study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Nineteen healthy adults participated in the study. The effect of pain (induced with a capsaicin cream) on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. For EEG, 15 non-overlapping, 2-seconds artifacts were randomly selected for each participant. Intracranial source current density and functional connectivity was determined using sLORETA software. When participants experienced experimentally-induced inflammatory pain, their resting state brain activity increased significantly in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and both left cuneus and right insula (beta frequency; all ts >3.66; all ps<0.01). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a simultaneous reduction in the strength of the corticospinal projections (quantified using the recruitment curves obtained with TMS; t=4.45, p<0.05). These participants further showed greater beta motor-cuneus connectivity than participants for whom pain did not affect M1 somatotopy (t=3.58, p<0.05). These results suggest that pain-evoked increases in M1 beta power are intimately tied to alterations in corticospinal system. Moreover, we provide evidence that beta motor-cuneus connectivity is related to the corticomotor alterations induced by pain.

Les mécanismes cellulaires et moléculaires qui sous-tendent la mémoire et l’apprentissage chez les mammifères sont incomplètement compris. Le rythme thêta de l’hippocampe constitue l’état « en ligne » de cette structure qui est cruciale pour la mémoire déclarative. Dans la région CA1 de l’hippocampe, les interneurones inhibiteurs LM/RAD démontrent des oscillations de potentiel membranaire (OPM) intrinsèques qui pourraient se révéler importantes pour la génération du rythme thêta. Des travaux préliminaires ont suggéré que le courant K+ I(A) pourrait être impliqué dans la génération de ces oscillations. Néanmoins, peu de choses sont connues au sujet de l’identité des sous-unités protéiques principales et auxiliaires qui soutiennent le courant I(A) ainsi que l’ampleur de la contribution fonctionnelle de ce courant K+ dans les interneurones. Ainsi, cette thèse de doctorat démontre que le courant I(A) soutient la génération des OPM dans les interneurones LM/RAD et que des protéines Kv4.3 forment des canaux qui contribuent à ce courant. De plus, elle approfondit les connaissances sur les mécanismes qui régissent les interactions entre les sous-unités principales de canaux Kv4.3 et les protéines accessoires KChIP1. Finalement, elle révèle que la protéine KChIP1 module le courant I(A)-Kv4.3 natif et la fréquence de décharge des potentiels d’action dans les interneurones. Nos travaux contribuent à l’avancement des connaissances dans le domaine de la modulation de l’excitabilité des interneurones inhibiteurs de l’hippocampe et permettent ainsi de mieux saisir les mécanismes qui soutiennent la fonction de l’hippocampe et possiblement la mémoire chez les mammifères. / Cellular and molecular mechanisms underlying learning and memory in mammals are incompletely understood. The theta rhythm in the hippocampus constitutes the « on-line » state of this structure which is crucial for declarative memory. In the CA1 hippocampal area, LM/RAD inhibitory interneurons exhibit intrinsic membrane potential oscillations (MPOs) that could be important for the generation of theta rhythm. Preliminary work suggested that K+ current I(A) could be involved in the generation of these oscillations. Nevertheless, little is known about the identity of the principal and auxiliary protein subunits underlying I(A) current and the extent of the functional contribution of this K+ current in hippocampal interneurons. Thus, this Ph.D. thesis shows that I(A) current underlies MPO generation in LM/RAD interneurons and that Kv4.3 proteins form channels that contribute to this current. Also, it deepens the knowledge on the mechanism controlling the interactions between Kv4.3 channel-forming principal subunits and KChIP1 auxiliary proteins. Finally, it reveals that KChIP1 modulates native I(A)-Kv4.3 current and the action potential discharge frequency in interneurons. Our work takes part in advancing the knowledge on the field of modulation of excitability in hippocampal inhibitory interneurons and allows a better understanding of the mechanisms underlying the function of the hippocampus and possibly memory in mammals.