A interação entre agentes inteligentes na disputa por recursos necessários à sobrevivência é um fato onipresente na luta pela vida. Este tipo de interação é estudado e formalizado matematicamente pela teoria dos jogos. Na literatura experimental encontramos vários estudos envolvendo primatas humanos e não humanos em tarefas de jogos estratégicos, mas, até o momento, não foi desenvolvido nenhum modelo deste comportamento com roedores. Estudos do comportamento animal mostram que estes aprendem e aprimoram este tipo de estratégias através de aprendizagem por reforço. O elemento central dos modelos computacionais de aprendizado por reforço é o sinal de violação de expectativa, que sinaliza o quanto um resultado difere, para mais ou para menos, do esperado. Este sinal é utilizado pelo agente para atualização dos valores e, assim, da probabilidade de escolha das opções. A pesquisa neurofisiológica tem consistentemente demonstrado que o sinal fásico emitido pelo sistema dopaminérgico conforma-se muito de perto às características do sinal descrito pela teoria computacional. Dessa maneira, os objetivos do presente estudo são pesquisar (1) se roedores são capazes de jogar um jogo estratégico simples e se a evolução do seu desempenho é consistente com o aprendizado por reforço e (2) se os efeitos de agonistas e antagonistas dopaminérgicos na estratégia de jogo são consistentes com a teoria segundo a qual o sinal dopaminérgico fásico desempenha função central na atualização constante da estratégia de jogo. Nossos resultados demonstram que, neste jogo estratégico, roedores efetivamente são capazes de um desempenho muito próximo do normativo, que seu desempenho é consistente com o aprendizado por reforço e, finalmente, que o sistema dopaminérgico está envolvido no processo de atualização da estratégia. / Intelligent agents competing for the resources necessary for survival is a universal factor in the struggle for life. This type of interaction has been studied and mathematically formalized by game theory. In scientific literature we have come across several studies involving human and non-human primates carrying out strategic game tasks; however, until now, no model for such behavior has been developed for rodents. Animal behavior studies have shown that animals learn and develop strategies through reinforcement learning. A central element of computational models of reinforcement learning is the reward-prediction error signal, which indicates how much a result differs, either positively or negatively, from the expected result. This signal is used by the agent to update the values of its options, and so their probability of being chosen. Neurophysiologic research has consistently shown that the phasic signal emitted by the dopamine system conforms very closely to the characteristics of the signal described by computational theory. The purposes of this study are: (1) to discover whether rodents are capable of playing a simple strategic game and whether the evolution of their performance is consistent with reinforcement learning; and (2) whether the effects of dopamine agonists and antagonists on game strategy are consistent with the theory that phasic dopamine signals have a primary role in the constant update of game strategy. Our results prove that, in this strategic game, rodents are effectively capable of finding a strategy that is very close to the normative one, that their performance is consistent with reinforcement learning and, finally, that the dopamine system is involved in the process of strategic updating.

The compound m-chlorophenylpiperazine (m-CPP) is used clinically to manipulate serotonergic function, though its precise mechanisms of actions are not well understood. m-CPP alters synaptic transmission and neuronal function in vertebrates by non-selective agonistic actions on 5-HT1 and 5-HT2 receptors. In this study, we demonstrated that m-CPP did not appear to act through a 5-HT receptor in depressing neuronal function in the invertebrates (crayfish and Drosophila). Instead, m-CPP likely decreased sodium influx through voltage-gated sodium channels present in motor and primary sensory neurons. Intracellular axonal recordings showed that m-CPP reduced the amplitude of the action potentials in crayfish motor neurons. Quantal analysis of excitatory postsynaptic currents, recorded at neuromuscular junctions (NMJ) of crayfish and Drosophila, indicated a reduction in the number of presynaptic vesicular events, which produced a decrease in mean quantal content. m-CPP also decreased activity in primary sensory neurons in the crayfish. In contrast, serotonin produces an increase in synaptic strength at the crayfish NMJ and an increase in activity of sensory neurons; it produces no effect at the Drosophila NMJ. In the rat spinal cord, m-CPP enhances the occurrence of spontaneous excitatory postsynaptic potentials with no alteration in evoked currents.

Disruptions of the memory systems in the brain are linked to the manifestation of many neuropsychiatric diseases such as Alzheimer’s disease, depression, and post-traumatic stress disorder. The limited efficacy of current treatments necessities the development of more effective therapies. Neuromodulation has proven effective in a variety of neurological diseases and could be an attractive solution for memory disorders. However, the application of neuromodulation requires a more detailed understanding of the network dynamics associated with memory formation and recall. In this work, we applied a combination of optical and computational tools in the development of a novel strategy for the modulation of memories, and have expanded its application for interrogation of the hippocampal circuitry underlying memory processing in mice. First, we developed a closed-loop optogenetic stimulation platform to activate neurons implicated in memory processing (engram neurons) with a high temporal resolution. We applied this platform to modulate the activity of engram neurons and assess memory processing with respect to synchronous network activity. The results of our investigation support the proposal that encoding new information and recalling stored memories occur during distinct epochs of hippocampal network-wide oscillations. Having established the high efficacy of the modulation of engram neurons’ activity in a closed-loop fashion, we sought to combine it with two-photon imaging to enable high spatial resolution interrogation of hippocampal circuitry. We developed a behavioral apparatus for head-fixed engram modulation and the assessment of memory recall in immobile animals. Moreover, through the optimization of dual color two-photon imaging, we improved the ability to monitor activity of neurons in the subfields of the hippocampus with cellular specificity. The platform created here will be applied to investigate the effects of engram reactivation on downstream projections targets with high spatial and cell subtype specificity. Following these lines of investigations will enhance our understanding of memory modulation and could lead to novel neuromodulation treatments for neurological disorders associated with memory malfunctioning.

Understanding the complex information transfer process of our nervous system is one of the most urgent needs in the biomedical community. Neuromodulation is a technique that can artificially influence or modulate the activity of the target neurons. It's an inevitable tool in both the neuroscience study but also the clinical treatment of neurological diseases. The conventional method for neural modulation is the electrical stimulation using implantable electrodes. However, its intrinsic current leakage problem is an obstacle for further improving its performance in clinical scenarios because of the finite spatial resolution and recording artifacts. In general, an ideal method should be able to modulate neural activities with a high spatial, temporal and functionality specificity but without biocompatibility and reliability issues even in long term. Photoacoustic stimulation is an emerging light-mediated, non-genetic neural modulation method with high spatiotemporal resolution. Multiple devices have been designed in the past few years. But there are still several gaps to be filled to further expand its applications. One is the material mismatch, and another is that more function is needed, for example the capability of simultaneous recording. My research focused on the design and development of two new types of photoacoustic materials to expand the use of photoacoustic stimulation. A soft hydrogel film and a multifunctional fiber-based emitter for photoacoustic neuromodulation have been developed in my Ph.D. research. The study on these materials increased our knowledge to photoacoustic neurostimulation, also help us to investigate the effect of photoacoustic neuromodulation in the treatment of neurological and neurodegenerative diseases.

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Les récepteurs ionotropiques AMPA (AMPAR) activés par le glutamate sont les principaux acteurs de la transmission synaptique excitatrice rapide du cerveau. Ils jouent également un rôle crucial dans les processus de plasticité synaptique, reconnus pour être à la base des fonctions cognitives. Les récepteurs canaux P2X sont activés par l'adénosine-5'-triphosphate (ATP) extracellulaire libéré par les neurones ou les cellules gliales. Ils sont exprimés dans le cerveau en périphérie des synapses glutamatergiques, où ils participent à l’excitabilité neuronale et modulent la transmission synaptique ainsi que la plasticité synaptique. Bien que la signalisation purinergique ait de multiples effets sur la transmission et la plasticité synaptique, la fonction des récepteurs P2X au niveau des synapses du cerveau reste à établir. Ici, nous montrons dans les neurones d'hippocampe en culture que l'activation des récepteurs P2X postsynaptiques par l'ATP exogène ou via la libération d'ATP endogène par les cellules gliales diminue l'amplitude des courants miniatures et évoqués des AMPAR postsynaptiques. En utilisant des approches d’électrophysiologie, de biochimie et d'imagerie en temps réel, nous démontrons que l'afflux de calcium passant par les canaux P2X déclenche l’internalisation des AMPAR par un mécanisme d’endocytose clathrine et dynamine dépendante. Cette diminution de surface altère par conséquent la transmission synaptique médiée par les AMPAR. Nous avons aussi démontré par des approches moléculaires et pharmacologiques la cascade de signalisation engagée dans l’altération du trafic des AMPAR de surface après activation des récepteurs P2X. Cette inhibition par les récepteurs P2X, serait dépendante de l’activation de kinases et des phosphatases qui régulent le niveau de phosphorylation des AMPAR. Nos travaux de recherche suggèrent ainsi, que les récepteurs postsynaptiques P2X jouent un rôle essentiel dans la régulation de l'expression de surface des AMPAR et régulent ainsi la force et la plasticité synaptique. / Ionotropic AMPA receptors (AMPAR) activated by glutamate are the main actors of the fast excitatory synaptic transmission in the brain. They also play a crucial role in the process of synaptic plasticity that are widely recognized to be the basis cognitive functions. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular adenosine-5’-triphosphate (ATP) released by neurons or glia. P2X receptors are located et the periphery of glutamatergic synapses and although purinergic signaling has multiple effects on synaptic transmission and plasticity, the function of P2X receptors at brain synapses remains to be established.Here, we show in cultured hippocampal neurons that activation of postsynaptic P2X receptors by exogenous ATP or glial release of endogenous ATP decreases the amplitude of miniature excitatory postsynaptic currents and AMPA-evoked currents. Using a combination of electrophysiology, surface or internalization assays and real time imaging, we demonstrate that the calcium influx through the ATP-gated channels triggers AMPA receptor internalization through clathrin-mediated dynamin-dependent endocytosis leading to reduced surface AMPA receptors and therefore, altered AMPA-mediated current. We also identified by molecular and pharmacological approaches the signaling cascade involved in the P2X-mediated alteration of surface AMPAR trafficking. P2X-mediated AMPAR internalization is dependent on the activation of kinases CamKII and phosphatases which regulate the phosphorylation level of AMPARs. Our finding indicates that postsynaptic P2X receptors play a critical role in regulating the surface expression of AMPAR and thereby regulate the synaptic strength.

Les systèmes neuromodulateurs jouent un rôle essentiel dans la mise en place et dansla régulation des réseaux moteurs spinaux afin d’adapter finement le rythme et le patronlocomoteur aux contraintes internes et externes de l’organisme. Il a été montré que desaltérations du fonctionnement de ces systèmes étaient impliquées dans de nombreusespathologies neurologiques. La sclérose latérale amyotrophique (SLA) est une maladieneurodégénérative caractérisée par la perte des neurones moteurs corticaux et spinaux. Bienque les symptômes de la SLA n’apparaissent qu’à l’âge adulte, de plus en plus d’élémentsamènent à penser que des modifications précoces des réseaux locomoteurs spinaux ont lieudès les stades précoces du développement chez un modèle animal de la SLA, la souris SOD1.C’est dans ce cadre général que nous avons émis l’hypothèse que des altérations précoces dessystèmes neuromodulateurs pourraient intervenir dans la physiopathologie de la SLA. Dansun premier temps, nous avons comparé la modulation monoaminergique des réseaux moteursspinaux en réalisant des enregistrements extracellulaires de l’activité locomotrice générée parla préparation de moelle épinière isolée chez la souris nouveau-née sauvage et SOD1. Nousnous sommes ensuite attachés en combinant des enregistrements électrophysiologiques extraetintracellulaires avec des techniques d’immunohistochimie et de biologie cellulaire à décrirela mise en place et l’évolution avec l’âge des synapses cholinergiques reçues par lesmotoneurones en provenance d’interneurones de la lamina X : les boutons en C. Enfin, nousavons initié une approche (1) comportementale sur le long terme de l’activité motrice dessouris SOD1 et (2) des capacités plastiques des synapses glutamatergiques reçues par lesmotoneurones en culture. L’ensemble de ces travaux, nous a permis de mettre en évidence desaltérations précoces et évolutives des principaux systèmes neuromodulateurs spinaux:cholinergique, dopaminergique et noradrénergique chez les animaux SOD1. Nos résultatsmontrent pour la première fois (1) qu’une dynamique complexe des récepteurs M2 sous lesboutons en C existe et que celle-ci est perturbée chez les souris SOD1 et (2) que lesmotoneurones ne sont pas les seuls neurones à dégénérer dans la moelle de ces animaux maisque les neurones cholinergiques de la lamina X situés dans les segments lombaires L2 sontaussi la cible de processus neurodégénératifs. / Neuromodulatory systems play a crucial role in the establishment and regulation ofspinal motor networks to finely adjust the locomotor rhythm and pattern to the internal andexternal constraints. It is now well admitted that alterations in neuromodulatory functions areinvolved in diverse neurologic disorders. Amyotrophic lateral sclerosis is a neurodegenerativedisease characterized by the specific loss of cortical and spinal motor neurons. A growingbody of evidence now suggests that although ALS syndromes occur in adulthood, alterationscan be detected as early as at the embryonic stages in the spinal cord of the rodent model ofALS, the SOD1 mouse. In this context, we hypothesized that early alterations in the spinalneuromodulatory systems may be involved in the pathophysiology of ALS. To answer thisquestion, in a first step, we compared the monoaminergic modulation of spinal network byrecording extracellularly the fictive locomotion produced in the in vitro spinal cordpreparation form newborn wild-type and SOD1 mice. By combining extra- intracellularrecordings with immunohistochemical and cellular biology technics, we aimed, in a secondstep, to investigate the cholinergic synapses arising onto motoneurons and their neuronalsource, the lamina X interneurons as a function of the mouse age. Finally, we initiated (1) aninnovative behavioural study of mouse motor habits and (2) an analysis of the synapticplasticity of glutamatergic synapses imping on motoneurons in culture. Altogether, our datademonstrated early and progressive changes of the major spinal neuromodulatory systems:cholinergic, dopaminergic and noradrenergic. Our data show for the first time that: (1) M2receptors undergo a complex dynamic under C-bouton that is completely disturbed in SOD1motoneurons and (2) motoneurons are not the only cellular subtype to degenerate in SOD1mice. Indeed, we found evidence that neurodegenerative processes also target lamina Xcholinergic interneurons in the SOD1 spinal cord.

Pour pouvoir être autonomes dans un environnement complexe, les humains comme les systèmes artificiels doivent posséder un apprentissage souple et capable de s’adapter au changement. Dans cette thèse, nous nous intéressons à comment cette autonomie peut être obtenue par interactions entre les différents systèmes d’apprentissage de notre cerveau. Pour cela, nous modélisons dans une approche inspirée de la biologie le comportement de certaines des parties du cerveau impliquées dans les apprentissages répondant et opérant, et observons comment leurs interactions permettent un apprentissage flexible dans des tâches impliquant des changements comme l’extinction et le reversal. / In a complex environment, humans and artificials systems need a flexible learning system to adapt themselves to situations which can change. In this thesis, we study how autonomy can be the result of interactions between the different learning systems of our brain. In particular, in a biologically inspired approach, we model different parts of the brain involved in respondant and operant conditioning, et show how their interactions can promote flexible learning in tasks in which situation can change, like extinction or reversal.

La neuromodulation de circuits olfactifs par l'acétylcholine (ACh) joue un rôle important dans la discrimination et l'apprentissage d’odeur. Le traitement précoce des signaux chimiosensoriels se produit dans deux régions fonctionnellement et anatomiquement distinctes, les principaux et accessoires bulbes olfactifs (MOB et AOB), qui reçoivent entrée cholinergique significative du cerveau antérieur basal. Ici, nous explorons la régulation des circuits de l’AOB et la MOB par ACh, et comment cette modulation influence le comportement à médiation olfactifs. De manière surprenante, malgré la présence d'un circuit conservé, l'activation des récepteurs muscariniques de l'ACh révèle des différences marquées dans la modulation cholinergique des neurones de sortie: l’excitation de l’AOB et l'inhibition de la MOB. Les cellules granulaires (GCs), le neurone intrinsèque le plus abondant dans l'OB, présentaient également une réponse muscarinique complexe. Alors que les GCs de l’AOB ont été excitées, les GCs de la MOB présentaient une action muscarinique double, une hyperpolarisation et une augmentation de l'excitabilité non couvert par la dépolarisation cellulaire. Par ailleurs, l’ACh a eu un effet différent sur la relation d'entrée / sortie des MCs dans l’AOB et la MOB, montrant un effet net sur le gain en les MCs de la MOB, mais pas dans l'AOB. Fait intéressant, malgré les différences frappantes dans les actions neuromodulateurs sur les neurones de sortie, l'inhibition de la libération d'ACh chemogenetic produit des perturbations similaires dans les comportements olfactifs médiés par ces deux régions. La diminution de l’ACh dans l'OB a perturbé la discrimination naturelle des odeurs liées moléculairement et l'enquête naturelle des odeurs associées à des comportements sociaux. Ainsi, la neuromodulation distincte par l’ACh dans ces circuits pourrait déclencher des solutions différentes générales pour le traitement des odeurs et les médiateurs chimiques, ainsi que les comportements olfactifs diverses qu'ils déclenchent. / Neuromodulation of olfactory circuits by acetylcholine (ACh) plays an important role in odor discrimination and learning. Early processing of chemosensory signals occurs in two functionally and anatomically distinct regions, the main and accessory olfactory bulbs (MOB and AOB), which receive significant cholinergic input from the basal forebrain. Here we explore the regulation of AOB and MOB circuits by ACh, and how this modulation influences olfactory mediated behaviors. Surprisingly, despite the presence of a conserved circuit, activation of muscarinic ACh receptors revealed marked differences in cholinergic modulation of output neurons: excitation in the AOB and inhibition in the MOB. Granule cells (GCs), the most abundant intrinsic neuron in the OB, also exhibited a complex muscarinic response. While GCs in the AOB were excited, MOB GCs exhibited a dual muscarinic action, a hyperpolarization and an increase in excitability uncovered by cell depolarization. Furthermore, ACh had a different effect on the input/output relationship of MCs in the AOB and MOB, showing a net effect on gain in MCs of the MOB, but not in the AOB. Interestingly, despite the striking differences in neuromodulatory actions on output neurons, chemogenetic inhibition of ACh release produced similar perturbations in olfactory behaviors mediated by these two regions. Decreasing ACh in the OB disrupted the natural discrimination of molecularly related odors and the natural investigation of odors associated with social behaviors. Thus, the distinct neuromodulation by ACh in these circuits could underlie different solutions to the processing of general odors and semiochemicals, and the diverse olfactory behaviors they trigger.

Chez les patients hémiparétiques chroniques, la tDCS a été testée sur diverses tâches du membre inférieur, montrant des résultats intéressants, mais parfois contradictoires. Cependant, les effets de la tDCS sur la fonction motrice volontaire (extension de genou) et semi-automatique (locomotion) chez des patients hémiparétiques ne sont pas encore totalement connus. L’objet de ce travail était d’évaluer contre placébo les effets de la tDCS en polarité anodale sur les fonctions motrices volontaires et semi-automatiques, chez des patients hémiparétiques. L’étude comporte deux parties : la première a pour but d’évaluer l’effet contre placébo de la tDCS bilatérale sur la force volontaire maximale du quadriceps parétique par isocinétisme, la seconde a pour objectif d’étudier les effets contre placébo des effets de la tDCS unilatérale sur la marche par analyse tridimensionnelle du mouvement. Les résultats ont montré une absence d’effet de la tDCS sur les deux types de mouvements étudiés. De plus, la tDCS n’a pas eu d’effet sur la spasticité du quadriceps ni sur la performance aux tests fonctionnels des patients hémiparétiques. Cela suggère qu’il n’y a pas d’intérêt à l’utilisation de la tDCS bilatérale pour améliorer une performance motrice maximale (l’extension de genou) ni de la tDCS unilatérale pour améliorer un mouvement semi-automatique (la locomotion) chez les patients hémiparétiques chroniques. Les perspectives envisagées sont de reconduire ces expérimentations chez un groupe homogène de patients hémiparétiques en phase aigüe ou subaigüe afin de potentialiser les phénomènes plastiques post-lésionnels. Ceci permettra de renforcer ou non l’intérêt de l’utilisation de la tDCS chez les patients hémiparétiques afin d’améliorer leurs performances motrices. / In chronic hemiparetic patients, the use of tDCS has been tested on various lower limb tasks, showing interesting but sometimes contradictory results. However, the effects of tDCS on voluntary (knee extension) and semi-automatic (locomotion) motor function in hemiparetic patients are not yet fully known. The purpose of this work was to quantify the effects of tDCS in anodal polarity on the voluntary and semi-automatic motor functions in placebo-controlled studies. The study is divided into two parts: the first aims to evaluate the effect against placebo of bilateral tDCS on the maximal voluntary force of the paretic quadriceps by isokinetic assessment, the second aims to study the effects against placebo of unilateral tDCS on the gait of chronic hemiparetic patients, assessed by three-dimensional gait analysis. The results showed an absence of effect of tDCS on the two types of movements studied. In addition, tDCS had no effect on quadriceps spasticity or functional test performance in hemiparetic patients. This suggests that there is no interest in using bilateral tDCS to improve maximal motor performance (knee extension) or unilateral tDCS to improve semi-automatic movement (locomotion) in chronic hemiparetic patients. The envisaged perspectives are to continue these experiments in a homogeneous group of hemiparetic patients in acute or subacute stroke patients in order to potentiate the post-lesional plastic phenomena. This will strengthen or not the interest of the use of tDCS in hemiparetic patients to improve their motor performance.