Pas de résumé en français / The cortex can be viewed as a network of functional areas. A cortical area, composed ofneurons forming local connections, interacts with other areas via long distance connections.Each neuron receives multiple inputs and has to integrate the incoming signals. This integrativecapacity is the basis of the computational power of the brain. Our work concentrates onunderstanding the principles that govern the structure of the cortical network i.e. the allocationof neural resources as well as the anatomical segregation between processing steams. Usingretrograde tracer injections we extract two quantitative parameters: (i) the proportion ofSupragranular Labelled Neurons (SLN) identifies the feedforward (FF) or feedback (FB)operation between the source and target area; (ii) the Fraction of Labelled Neurons (FLN)identifies the magnitude of a connection pathway.We have made repeat injections in V1, V2, V4 to investigate the consistency of corticalpathways. This showed that (i) connection weights are consistent between animals; (ii) the listof areas projecting to each injection site is highly reproducible. We find that there are fixedFLN values for each pair of interconnected areas. The FLN values of all the afferent pathwaysto a given target span over a factor of 6 levels of log and although there is some overdispersiontheir variability is not larger than one single level of log meaning that there is a specificconnectivity profile for each area. Futermore the FLN follow a lognormal distribution. Inlognormals the mode is lower than the median and the mean i.e. the majority of pathways haveFLN weaker than the average FLN, meaning that strong projections are rare. If instead thedistribution of FLN was to follow a power law, then high FLN values would have been evenrarer. We found, a regularity in that the strongest input is invariably from within the injectedarea, second strongest are the inputs from areas sharing common borders with the target area.Sub-cortical inputs have a weak FLN, even when they are associated with an importantfunctional role such as the LGN → V1 pathway. We found that projection distance is inverselyrelated to the FLN value and an exponential distance rule operates that constrains short distanceprojections to high FLN and long distance projections to low FLN.We injected a total of 26 cortical areas homogenously distributed across the cortex. Thisrevealed 1232 projection pathways. Roughly 30% of pathways that we reveal have notpreviously been reported in the literature. Our ability to find new connections is due to theimproved tracing and brain segmentation techniques. We scan the whole brain at up to 80μmintervals to detect projection neurons, and this, as discussed in the text, is a major advantage toexisting studies. The weak long distance connections were shown to contract the characteristicpath-length of the graph (number of hops needed to go between any two areas).Our analysis of the graph showed that contrary to current belief the cortical inter-areal networkis dense (i.e. 58% of the connection that could exist do exist). At such a density, models basedon binary features such as small world cannot capture the specificity of the graph. Hence thecortex does not correspond small–world network, with sparse clustered graph possessingempowered by few critical projecitons that ensure short characteristic path-lengths. Furtheranalysis of pathway efficiency showed that the short distance connections of high magnitudeprovide large bandwidth for local connectivity and form a backbone of clustered functionallyrelated areas. This backbone is embedded in a sea of weak connections providing direct linksbetween cortical areas. We refer to this architecture as a tribal–network. We speculate that thesmall scale and high density that characterize the cortico-cortical network is facilitating theemergence of synchrony between cortical areas.

Au cours de cette thèse, j’ai cherché à comprendre comment trois structures impliquées dans la modulation des états vigilance agissaient sur la dynamique du réseau cortical. Les noyaux du thalamus non-spécifique sont impliqués dans le transfert d’informations contextuelles. À l’inverse, les noyaux spécifiques convoient des informations sensorielles vers le néocortex. Ces entrées sensorielles activent fortement les interneurones fast-spiking du cortex qui limite la durée de l’activation du réseau. À l’inverse, mes travaux montrent que les entrées contextuelles entraînent l’activation des interneurones lents, générant une activation prolongée du réseau cortical. D’autre part, je me suis intéressée à la couche VIb du néocortex dont les neurons sont sensibles à deux modulateurs des états de vigilance : l’orexine et à l’acétylcholine. J’ai pu montrer que la couche VIb projette principalement dans les couches corticales infragranulaires où elle pourrait être servir d’amplificateur dépendant de l’orexine des entrées du thalamus non-spécifique. Finalement, j’ai cherché à comprendre si la transmission nicotinique endogène était médiée par une synapse ou par transmission volumique. Pour cela, j’ai comparé les courants nicotinques reçus par les neurones des couches I et VI. Mes travaux mettent en évidence l’existence d’une synapse mixte comprenant des récepteurs α4β2 et α7 dans la couche I et d’une synapse simple comprenant uniquement α4β2 en couche VI. Ces synapses sont activées par la stimulation phasique des neurones cholinergiques. Néanmoins mes résultats suggèrent aussi l’existence de récepteurs α4β2 extra-synaptiques activés par la libération tonique des fibres cholinergiques. / During my PhD, I investigated how three structures involved in the modulation of arousal states act on the dynamic of the cortical network. Nuclei of the non-specific thalamus convey information on environmental and behavioral context, whereas specific nuclei relay sensory information to the neocortex. These sensory inputs activate strongly the fast-spiking interneurons of the neocortex that limits response duration of the network. Conversely, I showed that contextual inputs target mainly the slow adapting interneurons allowing a long-lasting activation of the cortical network. I have also been interesting in the layer VIb of the neocortex whose neurons are sensitive to orexin and acetylcholine, two main modulators of the arousal states. I showed that layer VIb projects mainly onto infragranular cortical layers where its activation should act as an orexin-dependent amplifier of the non-specific thalamic inputs. Finally, I tried to decipher whether the endogenous nicotinic transmission is mediated by a synapse or by volume transmission. To do that, I compared nicotinic currents received by layer I interneurons and layer VI pyramidal cells. I showed that nicotinic transmission is likely to be mediated by a mixed synapse comprising α4β2 and α7 receptors in layer I and a simple α4β2 containing synapse in layer VI. These synapses are activated by a phasic stimulation of the cholinergic fibers. However, my results also suggest that a tonic activation of these fibers recruits extra-synaptic α4β2 receptors in both layer I and VI neurons.

L’excès de synchronisation dans le réseau cortico-sous-cortical est une caractéristique majeure de la maladie de Parkinson. La stimulation cérébrale profonde (DBS) à haute fréquence (HF) des ganglions de la base modifie ces synchronies et améliore significativement les troubles moteurs. Il n’était pas encore connu si l’excès de synchronisation dans le cortex moteur primaire (M1) est présent avant les signes moteurs et si la modulation antidromique des réseaux corticaux via la stimulation HF de la voie hyperdirecte cortico-subthalamique suffit à le désynchroniser. Nous avons étudié la synchronisation des activités spontanées dans M1 de souris juvéniles PINK1 -/-, modèle génétique de Parkinson (PARK6) par imagerie calcique bi-photonique in vitro et l’avons comparée à celle de souris contrôle (P14-P16). Nous avons testé l’impact de la stimulation HF des fibres cortico-subthalamiques (région subthalamique) sur ces synchronies corticales. A un stade précoce, les réseaux M1 présentent un excès de synchronisation et, dans notre modèle de tranche, la DBS HF normalise le patron de synchronisation, plaidant pour un rôle primordial de la modulation antidromique de l’activité corticale via la voie hyperdirecte. En conclusion, nous proposons, grâce à ce modèle génétique progressif, que (1) des activités de réseau pathologiques sont présentes dans M1 bien avant les premiers signes moteurs et (2) que la modulation par voie antidromique de ces réseaux corticaux est un mécanisme essentiel d’action de la DBS HF. Ces résultats montrent qu’une pathologie dégénérative est détectable très tôt dans le développement (neuroarchéologie) mais ne s’exprimer somatiquement que tardivement. / The excess of synchronization of neuronal activities within the cortico-basal ganglia network is a hallmark of the pathophysiology of Parkinson’s disease. High frequency deep brain stimulation (DBS) applied to various basal ganglia nuclei dampens the synchronized activity in the whole network, and brings about a significant motor improvement. However it is not to date established whether an early presymptomatic abnormal pattern of synchronization is present in the primary motor cortex long before motor signs, nor whether its antidromic modulation via the hyperdirect cortico-subthalamic pathway is sufficient to remove its excess of synchronization. To answer these questions we studied the synchronization of spontaneous activities in the primary motor cortex of PINK-/- mice (genetic rodent model of Parkinson’s (PARK6), a progressive model) and compared it with age-matched control mice (P14-16 (wild-type)) by means of two-photon calcium imaging. Secondly, we analyzed in vitro the impact of the high frequency stimulation of cortico-subthalamic fibers on the pattern of synchronization of cortical networks. We show that, (1) at an early stage of development, there is an excess of synchronized activity in primary motor cortical networks and that, (2) antidromic modulation of cortical activity is a key mechanism to account for the normalization of hyper synchronized activity. These results show that a neurodegenerative adult pathology may begin early during development (neuroarcheology) though clinical signs appear late in adulthood. Moreover, antidromic invasion of a network seems to be a key mechanism of deep brain stimulation.