Le neurone est une cellule hautement spécialisée qui permet, par des impulsions électriques appelées potentiel d’action (PA) d’assurer la communication neuronale de manière rapide et efficace vers les autres neurones du cerveau. L’axone occupe une place privilégiée dans la genèse du PA. En effet, une région spécialisée de l’axone appelé segment initial de l’axone (SIA) concentre les protéines canaux qui sont à l’origine du PA, les canaux sodium.Le sujet de cette thèse a pour objet d’identifier les facteurs géométriques et électriques contrôlant le seuil du PA. Par une approche essentiellement électrophysiologique couplée à la modélisation, nous identifions ici pour la première fois l’importance de la résistance axiale de l’axone, des canaux sodium et de certains canaux potassium dans le seuil du PA mesuré au corps cellulaire. Cette étude devrait permettre d’affiner et de valider les modèles de seuil du PA en apportant une meilleure compréhension de l’excitabilité neuronale. / The neuron is a highly specialized cell which permits, thanks to electrical impulsion called action potential (AP), to ensure the neuronal communication in a quick and efficient manner towards the other neurons of the brain. The axon takes a privileged place in AP genesis. Indeed, a specified region of the axon, called the axon initial segment (AIS) concentrates channel proteins that are at the origin of the AP, the sodium channels.The subject of this thesis aims to identify the geometrical and electrical factors controlling the threshold of AP. Essentially using an electrophysiological approach coupled with modeling, we identify for the first time here the importance of the axial resistance of the axon, the sodium channels, and some of the potassium channels in the threshold of AP measured in the cell body. This study should permit to refine and validate models of AP threshold by bringing a better understanding of neuronal excitability.

In dieser Arbeit wird die Selbstorganisation in Halbleiterlasern mit ultrakurzer optischer Rueckkopplung untersucht. Es wurden eine Vielzahl neuer nichtlinearer dynamischer Szenarien experimentell praepariert und untersucht, wobei die Steuerung der relevanten Rueckkopplungsparameter ueber Injektionsstroeme erfolgt. Zwei verschiedene Typen von selbsterhaltenden Intensitaetspulsationen wurden abhaengig von der Phase und der Staerke der Rueckkopplung gefunden. Ein Pulsationstyp entsteht in einer Hopf-Bifurkation aus gedaempften Relaxationsoszillationen. Beim zweiten Pulsationstyp handelt es sich um Schwebungs-Oszillationen zweier verschiedener konkurrierender Moden der Gesamtkavitaet. Diese Ergebnisse repraesentieren experimentelle Beweise fuer theoretische Vorhersagen. Die Koexistenz von Schwebungsoszillationen und Relaxationsoszillationen fuehrt zum uebergang von regulaeren Pulsationen in chaotische Emission ueber eine quasiperiodische Route zum Chaos. Ein ploetzlicher Untergang des Chaos deutet auf ein Boundary-Crisis-Szenario hin. Die Existenz chaotischer Saettel, die transienten chaotischen Dynamiken nach einer Boundary Crisis zugrunde liegen und die Erregung von chaotischen Transienten ist eng verwandt mit konventioneller Erregbarkeit, wird experimentell verifiziert. Es wird der Einfluss externen Gaussschen Rauschens nahe von sub- und superkritischen Hopf-Bifurkationen untersucht. Rausch-induzierte Schwingungen tauchen als verrauschte Vorlaeufer in Form von lorentzfoermigen Spitzen im Powerspektrum auf. Der Kohaerenzfaktor, definiert durch das Produkt aus Hoehe der Spitze und Qualitaetsfaktor, zeigt fuer beide Typen von Hopf-Bifurkationen ein nichtmonotones Verhalten. Damit wird Kohaerenzresonanz experimentell demonstriert. Die Messungen zeigen neben diesen uebereinstimmungen auch qualitative Unterschiede zwischen den beiden Faellen. Die experimentellen Ergebnisse werden mittels eines allgemeinen Modells fuer rauschgetriebene Bewegungen in der Naehe von Bifurkationen untersucht. / In this work, self-organization in semiconductor lasers with ultra-short optical feedback is investigated. Exploiting dc currents to tune the relevant feedback parameters, we have experimentally prepared and studied a number of novel nonlinear dynamical scenarios. Two different types of self-sustaining intensity-pulsations are detected depending on strength and phase of the feedback. One type of pulsations is emerging in a Hopf-bifurcation from relaxation oscillations. The second type of pulsations is a beating of distinct compound-cavity modes. It is also born in a Hopf bifurcation. These findings represent experimental evidence for theoretical predictions. Coexistence of mode beating and relaxation oscillations gives rise to the break-up of regular pulsations into chaotic emission via a quasi-periodic route to chaos. The sudden destruction of chaos is indicative of a boundary crisis scenario. The existence of chaotic saddles underlying transient chaotic dynamics which appears behind boundary crisis is experimentally verified. It is experimentally demonstrated that an excitation of chaotic transients is closely related to a conventional excitability. The influence of external Gaussian noise close to the onset of sub- and super-critical Hopf bifurcations is studied. Noise-induced oscillations appear as a noisy precursor with Lorentzian shape peak in the power spectrum. The coherence factor defined by the product of height and quality factor exhibits non-monotonic behavior with a distinct maximum at a certain noise intensity for both types of Hopf bifurcations, demonstrating coherence resonance. Besides these similarities, the measurements reveal also qualitative differences between the two cases. Whereas the width of the noise induced peak increases monotonically with noise intensity for the supercritical bifurcation, it traverses a pronounced minimum in the subcritical case. The experimental findings are examined in terms of general model for the noise driven motion close to bifurcations.

Im Fokus dieser Untersuchung steht der Einfluss von Fluktuationen auf gekoppelte erregbare Systeme. Wir betrachten numerisch die stationäre Wahrscheinlichkeitsverteilung und den -fluss für ein einzelnes FitzHugh--Nagumo (FHN) System mit Rauschen. Abhängig von der Rauschintensität treten unterschiedliche Kombinationen von Extrema in der Verteilung auf. In einer Kombination finden wir Reminiszenzen an Kohärente Resonanz. Zur Untersuchung von gekoppelten Ensembles erregbarer Systeme nutzen wir eine Methode die auf der Dynamik der zentralen Momente der zugehörigen Verteilungen basiert. Wir leiten einen allgemeinen Ausdruck für ein System mit N Variablen her und diskutieren die Qualität verschiedener Näherungsmethoden. Rauschen kann die Dynamik eines ursprünglich nicht erregbaren Systems derart verändern, dass dieses Erregbarkeit zeigt. Dies demonstrieren wir durch Verallgemeinerung eines bekannten Modells für rauschinduzierte Phasenübergänge. Mit Hilfe der Momentenmethode erhalten wir das Bifurkationsdiagramm. Es zeigt Regionen rauschinduzierter Oszillationen und auch rauschinduzierter Erregbarkeit. Wenn wir additives Rauschen auf ein global gekoppeltes Ensemble mit FHN Kinetik anwenden, beobachten wir ein kompliziertes Übergangsregime hin zu Oszillationen des Mittelwerts. Neben Periodenverdopplung, Chaos und anderen Dynamiken finden wir ein plötzliches starkes Ansteigen der Ausdehnung eines chaotischen Attraktors. Dieses Phänomen ist bei Grenzzyklen als Canard Explosion bekannt. Wir demonstrieren die Möglichkeit von Musterbildung mit Hilfe von dichotomen Fluktuationen an Hand eines lokal gekoppelten Systems mit FHN Kinetik. Abhängig von räumlichen und zeitlichen Korrelationen tritt die Formation von Structure Patterns durch unterschiedliche Mechanismen und in unterschiedlichen Parameterregionen auf. / The focus of this study is on the influence of fluctuations on coupled excitable systems. We examine numerically the stationary probability distribution and the flux for an individual FitzHugh--Nagumo (FHN) system with noise. Depending on noise intensity different combinations of extrema of the distribution occur. In one combination we find reminiscences of coherence resonance. For the investigation of coupled ensembles of excitable systems we use a method based on the central moment dynamics of the corresponding probability distribution. We derive a general expression for a system with N variables and discuss the quality of different approximation techniques. Noise can alter dynamics that are formerly not excitable in a way that it becomes excitable. We demonstrate this using a generalization of a well known model for noise-induced phase transitions. With the help of the moment dynamics we obtain the phase diagram. It shows regions of noise induced oscillations and noise-induced excitability. When applying additive noise to a globally coupled ensemble with FHN kinetics a complicated transition regime towards oscillations of the mean is observed. Besides period-doubling, chaos, and other regimes we find a quick increase of the size of a chaotic attractor. This phenomenon is known from limit cycle oscillations as Canard explosion. We demonstrate the possibility of pattern formation with the help of dichotomous fluctuations using a system with nearest neighbor coupling obeying FHN kinetics. Depending on the spatial and temporal correlations we find structure pattern formation via different mechanisms in different parameter regions.

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.

Excitabilité et structures localisées sont des phénomènes universels qui ont été observés dans une grande variété de systèmes. Chacun des deux phénomènes a des propriétés intéressante pour des applications potentielles, surtout dans l'optique. L'excitabilité est la propriété intrinsèque du neurone, elle décrit sa réponse à une stimulation: pour des stimulations en-dessous d'un certain seuil, le neurone reste dans son état de repos mais quand la stimulation dépasse ce seuil, il émet une impulsion dont la taille ne dépend pas de la force de la stimulation. Les structures localisées dans les systèmes optiques sont des pics de surintensité qui coexistent avec un fond homogène sur la section transversale spatialement étendue d'une cavité laser. Dans cette thèse nous avons étudié l'apparition de ces deux phénomènes non-linéaires dans des microcavités à semi-conducteur, pour lesquelles les applications dans le traitement tout-optique de l'information sont prometteuse. En outre, nous avons étudié la possibilité de trouver un nouveau phénomène à l'intersection entre les deux: les structures localisées excitables. D'une part nous avons étudié les propriétés des structures localisées qui se forment dans un laser à solitons. Celui-ci est constitué par deux laser à semiconducteur à cavité verticale (VCSEL) mutuellement couplées dans une configuration de laser avec absorbant saturable (LSA). Nous observons l'émissions aléatoire et localisée d'impulsions que nous affirmons être la première évidence expérimentale de structures localisées excitables. D'autre part nous avons démontré le comportement excitable d'un laser avec signal injecté par la possibilité de contrôler les impulsions excitable grâce à une perturbation externe appropriée. Nous avons également réalisé des simulations numériques qui montrent l'existence des structures localisées excitables dans un modèle de VCSEL avec absorbant saturable. / Excitability and localized structures are universal phenomena, observed in various systems. Both possess interesting properties for potential applications, especially in optics. Excitability is the intrinsic property of the neuron defining its response to an external stimulus: for a sub-threshold stimulus the neuron stays quiescent; for a super-threshold stimulus, it emits a well-calibrated pulse independent on the strength of the stimulus. Localized structures in optics are bright intensity peaks coexisting with a homogeneous low intensity background. They appear in the transverse section of spatially-extended laser resonators. We study the occurrence of these nonlinear phenomena in semiconductor microcavities since the applications in all-optical processing of information are promising. Moreover we investigate the possibility of a novel kind of localized structure which stands at the intersection of these two phenomena: the excitable localized structures. On the one hand we study the properties of localized structures arising from a cavity soliton laser composed of two mutually coupled broad-area VCSELs in a LSA (Laser with Saturable Absorber) configuration . We report on the observation of a random and localized emission of pulses which we claim to be the first experimental evidence of noise-triggered excitable localized structures whose excitability is induced by inhomogeneities and drift. On the other hand we demonstrate the excitability in an optically injected laser by showing the control of excitable pulses by means of an external perturbation. We also perform numerical simulations which reveal the existence of excitable localized structures in a model of broad area VCSEL with saturable absorber.

Les cellules chromaffines des glandes surrénales sont des cellules neuroendocrines excitables impliquées dans la sécrétion de catécholamines. En réponse à un stress, ces hormones, parmi les premières à être libérées exercent de multiples actions sur leurs organes-cibles, contribuant à la réponse adaptive de l'organisme. Ainsi, élucider la physiopathologie du stress est un enjeu de santé publique et mieux connaître les mécanismes permettant au tissu médullosurrénalien d'optimiser la sécrétion de catécholamines aux besoins de l'organisme est un défi à relever.La sécrétion des catécholamines est liée à l'activité électrique des cellules chromaffines et élucider les mécanismes cellulaires qui en contrôlent l'excitabilité est d'intérêt. L'activité électrique de ces cellules est régulée par le nerf splanchnique ainsi que par des conductances ioniques intrinsèques. Dans ce contexte, les conductances opérant autour du potentiel de repos jouent un rôle majeur dans le déclenchement des potentiels d'action. C'est en particulier le cas du canal NALCN (sodium leak channel), récemment décrit comme régulant le potentiel de repos des neurones. C'est pourquoi nous avons orienté nos travaux vers la caractérisation du rôle de NALCN dans l'excitabilité des cellules chromaffines, dans des tranches de glandes surrénales de souris. L'enregistrement du potentiel de membrane révèle qu'environ 62% des cellules chromaffines présentent des potentiels d'action spontanés et que le profil de décharge suit un mode régulier ou un mode en bouffées. Des enregistrements plus longs révèlent qu'une même cellule présente alternativement ces 2 modes de décharge. Un changement de potentiel de quelques mV autour du potentiel de repos favorise un mode, indiquant que les courants ioniques actifs autour du potentiel de repos sont des composantes cruciales de l'excitabilité cellulaire. NALCN est-il un de ces courants?Pour commencer, nous avons observé, par hybridation in situ, la présence du transcrit codant NALCN dans les cellules chromaffines chez la souris (coll Dr. Ventéo, INM, Montpellier). Nous avons alors cherché à déterminer si NALCN est impliqué dans l'activité électrique des cellules chromaffines. Nous avons utilisé un protocole de diminution de la concentration extracellulaire de Na+, classiquement utilisé pour l'étude électrophysiologique de NALCN. La diminution du Na+ extracellulaire induit une hyperpolarisation et un arrêt des potentiels d'action. Cet effet n'est pas bloqué par la TTX. En potentiel imposé, la diminution du Na+ réduit le courant de maintien, elle n'est ni bloquée par la TTX ni par le Cs+. La courbe courant/potentiel du courant sensible à la réduction du Na+ révèle un courant linéaire entre -130 et -50 mV et un potentiel d'inversion en accord avec la contribution de plusieurs espèces ioniques. Ce courant présente une perméabilité majeure au Na+ vs K+. Ainsi, ces résultats décrivent une conductance ionique partageant des propriétés biophysiques et pharmacologiques similaires à celles de NALCN.Afin de poursuivre dans cette direction, nous avons initié des travaux ambitieux visant à éteindre l'expression du gène codant NALCN dans les cellules chromaffines, au travers d'une stratégie d'injection de virus in vivo. Une construction codant pour un shRNA dirigé contre NALCN, a été injectée dans la glande surrénale gauche. Les résultats sont très encourageants, montrant i) la présence, dans les glandes injectées, de cellules chromaffines transduites et ii) une diminution significative de l'expression de NALCN dans les glandes injectées avec le ShRNA-anti NALCN. Cette approche de transduction virale mérite d'être poursuivie.En conclusion, et même si les résultats actuels ne permettent pas d'affirmer avec certitude que NALCN contribue à l'excitabilité des cellules chromaffines, ce travail de thèse apporte néanmoins une contribution majeure à l'étude de l'excitabilité de ces cellules et ouvre des perspectives attractives quant au rôle de NALCN. / Adrenal chromaffin cells are excitable neuroendocrine cells involved in the secretion of catecholamines. Once delivered into the blood circulation, these hormones exert multiple actions, leading to physiological adjustments enabling the organism to cope with stress. Deciphering the physiology/pathology of stress is a major public health issue, especially in the field of the mechanisms that lead to optimal catecholamine secretion.The electrical activity of chromaffin cells critically shapes the catecholamine secretory pattern. Elucidating the mechanisms regulating the firing discharge is therefore of interest. In situ, chromaffin cell excitability is regulated by both the splanchnic nerve inputs and the intrinsic ion conductances expressed in cells. Regarding this, the conductances operating near the resting membrane potential are crucial in the cell competence to spontaneously fire. In particular, the background current flowing through the sodium leak channel NALCN has been recently reported to tune the resting potential of neuronal cells. This finding prompted us to investigate the possible contribution of NALCN to chromaffin cell excitability in mouse acute adrenal slices. The first part of my thesis was aimed at investigating chromaffin cell electrical firing pattern. Whole-cell recordings indicate that about 62% of mouse chromaffin cell spontaneously fire and exhibit two discharge patterns, a regular firing mode and a bursting mode. Long-lasting recordings of spontaneous electrical activity reveal that the two firing modes can occur in the same cells. When the membrane potential is challenged around the resting value, the firing pattern alternate between the two modes, indicating that currents operating around the resting membrane potential are key components in regulating cell excitability. Is NALN one of these currents?To answer this question, we first unveiled, by in situ hybridization, the presence of the transcript encoding NALCN in mouse chromaffin cells (coll with Dr. Ventéo, INM, Montpellier). Second, we performed electrophysiological experiments using protocols and pharmacological agents commonly used to study NALCN currents. Decreasing external NaCl leads to a robust membrane hyperpolarization, abrogating action potentials. This effect is not blocked by TTX. In voltage-clamp conditions, external Na+ reduction leads to a decrease in the holding current. This effect is not blocked by Cs+. Depolarizing voltage ramps unveil that the current blocked by lowering external Na+ blocks is linear between -130 and -50 mV, and displays a reversal potential arguing for a non-selective conductance. The ionic permeability is dominant for Na+ over K+. Collectively, our results describe a voltage-independent and non-selective cationic conductance operating near the resting potential of mouse chromaffin cells. Its electrophysiological and pharmacological properties recapitulate two NALCN attributes.In the third part, we developed an ambitious approach aiming at silencing NALCN expression specifically in chromaffin cells in vivo. Viral vectors encoding anti-NALCN shRNA under the control of the tyrosine hydroxylase promoter, as well as appropriate positive and negative viral constructs, were injected in the left gland. As promising results, transduced cells were detected in the injected glands only and a significant decrease in NALCN expression was observed in glands injected with the anti-NALCN shRNA. As such, the data collected from in vivo manipulation of NALCN expression are encouraging and this approach deserves to be pursued.This thesis describes a Na+-sensitive current operating near the resting membrane potential of mouse chromaffin cells, sharing biophysical and pharmacological properties with NALCN. Even though further experiments are needed to ascertain that NALCN supports this conductance, our work contributes to a better knowledge of chromaffin cell excitability.

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.

The lipid kinase PI3K plays key roles in cellular responses to activation of receptor tyrosine kinases or G protein coupled receptors such as the metabotropic glutamate receptor (mGluR). Activation of the PI3K catalytic subunit p110 occurs when the PI3K regulatory subunit p85 binds to phosphotyrosine residues present in upstream activating proteins. In addition, Ras is uniquely capable of activating PI3K in a p85-independent manner by binding to p110 at amino acids distinct from those recognized by p85. Because Ras, like p85, is activated by phosphotyrosines in upstream activators, it can be difficult to determine if particular PI3K-dependent processes require p85 or Ras. Here we ask if PI3K requires Ras activity for either of two different PI3K-regulated processes within Drosophila larval motor neurons. To address this question, we determined the effects on each process of transgenes and chromosomal mutations that decrease Ras activity, or mutations that eliminate the ability of PI3K to respond to activated Ras. We found that PI3K requires Ras activity to decrease motor neuron excitability, an effect mediated by ligand activation of the single Drosophila mGluR DmGIuRA. In contrast, the ability of PI3K to increase synaptic bouton number is Ras independent. These results suggest that distinct regulatory mechanisms underlie the effects of PI3K on distinct phenotypic outputs. We additionally found that the glutamate-activation of DmGIuRA initiates ERK signaling; however the signaling intermediates linking DmGIuRA to this kinase cascade are unknown.

Movement training modulates the excitability in several cortical and subcortical areas. Compared to training with a single arm, movement training with both arms yields a greater increase in motor related cortical regions. A short-term session of bimanual training (BMT) enhances cortical activity of motor preparation and execution areas in both hemispheres. The underlying neural mechanisms for this increased activation with BMT are unclear, but may involve interhemispheric connections between homologous primary motor cortex (M1) representations and input from motor preparatory areas (i.e. dorsal premotor cortex (PMd)). Also, it is unclear how selective up-regulation or down-regulation of specific motor-related areas may contribute to changes in M1 excitability when combined with BMT. The work in this thesis investigated modulation of M1 excitability in terms of in-phase versus anti-phase BMT (Study #1), potentially up-regulating the left dorsal premotor cortex (lPMd) via iTBS before BMT (Study #2), theoretically down-regulating contralateral (right) M1 homologous representation before BMT (Study #3), and finally the potential intracortical and interhemispheric cortical adaptations in M1 bilaterally due to the same interventions as Study #2 (Study #4). For Study #1, it was hypothesized that in-phase BMT would lead to an increased excitability in M1. For Studies #2-4, it was hypothesized that modulation of motor-related areas would cause an increase in the excitability of left M1, and this modulation would be greater when combined with BMT. Study #1 found that in-phase, and not anti-phase BMT, lead to increase M1 excitability. Study #2 found that iTBS to lPMd followed by BMT caused a unique increase in M1 excitability, in terms of increased spatial extent and global MEP amplitude. Study #3 found that the combination of cTBS to right M1 with BMT caused greater excitability enhancements than either intervention alone. Finally, Study #4 found distinct modulations of cortical excitability within and across M1 bilaterally due to BMT, iTBS to lPMd and the combination of these interventions that involved long-interval inhibitory circuitry asymmetrically. Overall, this current work found that the modulation of remote cortical areas to M1 (i.e. lPMd and contralateral M1) in combination with movement training led to unique, and at times greater, excitability enhancements of M1 which could be advantageous in enhancing short-term plasticity in damaged M1.

Parallèlement aux adaptations cardiovasculaires et neuromusculaires, les exercices mono-articulaires ou locomoteurs peuvent induire des changements neuroplastiques de muscles impliqués ou non dans l’exercice. Si l’effet de paramètres de l’exercice, comme l’intensité ou la durée, sur les changements neuroplastiques ont déjà été étudiés, l’effet du mode de contraction musculaire reste, quant à lui, moins connu. L’objectif de cette thèse a été d’évaluer les effets du mode de contraction musculaire sur les changements neuroplastiques consécutifs à un exercice locomoteur ou mono-articulaire. La première étude a montré que l’augmentation de l’excitabilité corticospinale d’un muscle non-impliqué dans l’exercice (muscle de la main), observée suite à un exercice de marche/ course, n’était pas modulée par le mode de contraction des muscles extenseurs du genou. En revanche, une modulation spécifique des réseaux intracorticaux par le mode de contraction impliqué lors d’un exercice a été mise en évidence par l’application d’un protocole de stimulation associative jumelée. Des observations similaires ont été faites dans une seconde étude investiguant les changements corticospinaux observés au niveau des muscles extenseurs du genou impliqués dans des exercices mono-articulaires fatigants, effectués dans un mode de contraction concentrique ou excentrique. Une troisième étude a montré que pour un exercice de marche/ course réalisé à même fréquence cardiaque en montée, à plat ou en descente, la modalité en descente induisait une fatigue musculaire des extenseurs du genou plus importante, avec des altérations contractiles plus marquée. La quatrième étude a montré que seule la modalité en descente induisait une augmentation de l’excitabilité corticospinale, et une réduction de l’inhibition corticale des muscles extenseurs du genou. Les travaux de cette thèse proposent que le mode de contraction musculaire lors d’un exercice n’est, en lui-même, pas un facteur prépondérant des changements neuroplastiques observés pour des muscles impliqués dans l’exercice. Ces changements neuroplastiques seraient au contraire dépendant de la magnitude de la fatigue neuromusculaire induite, elle-même dépendante du mode de contraction musculaire. / Along with cardiovascular and neuromuscular changes, mono-articular and locomotor exercises may induced neuroplastic changes from muscles involved, or non-involved, in the exercise. If the effect of exercise intensity or duration on neuroplastic changes has been previously investigated, the effect of the mode of muscle contraction remains unclear. The aim of this thesis was to investigate the effects of the mode of muscle contraction on neuroplastic changes induced a locomotor or a single-joint exercise. The first study showed that the increase in the corticospinal excitability of a non-exercised hand muscle, observed after a walking/ running exercise, was not modulated by the knee extensors mode of muscle contraction. However, a specific modulation of the intracortical networks by the mode of muscle contraction was evidenced using a paired-associative stimulation protocol. Similar findings were made in a second study that investigated corticospinal changes in the knee extensors following a fatiguing single-joint exercise, performed in either a concentric or an eccentric mode of muscle contraction. A third study showed that for a walking/ running exercise performed at the same heart rate in either a inline, a level or a decline condition, the latter condition induced a greater magnitude of neuromuscular fatigue of the knee extensors, with greater contractile impairments. The fourth study reported that only a decline exercise induced an increase in the corticospinal excitability, and a reduction of the cortical inhibition of the knee extensors. Altogether, findings from this thesis suggest that the mode of muscle contraction during an exercise is not, per se, a main factor responsible for neuroplastic changes observed in exercised muscles. Rather, these changes may depend upon the magnitude of neuromuscular fatigue induced, which could depend upon the mode of muscle contraction involved during exercise.