Precise point-to-point connectivity is the basis of ordered maps of the visual field in the brain. One point in the visual field is represented at one locus in the dLGN and one locus in primary visual cortex. A fundamental problem in the development of most sensory systems is the creation of the topographic projections which underlie these maps. Mechanisms ranging from ordered ingrowth of fibres, through chemical guidance of axons to sculpting of the map from an early exuberant input have been proposed. However, we know little about how ordered maps are created beyond the first relay. What we do know is that a topological mismatch requires the exchange of neighbours in the geniculo-cortical projection and that manipulating the input to the primary relay can affect the geniculo-cortical topography. Taking advantage of the immaturity of the newborn hamster’s visual system, I studied the generation of an ordered map in primary visual cortex during the time of target innervation in normal and manipulated animals. I also investigated the patterning of neuronal activity prior to natural eye-opening. Paired injections of retrograde fluorescent tracers into visual cortex reveal that geniculate fibres are highly disordered at the time of invasion of the cortical plate. Topography in the geniculo-cortical projection emerges out of an unordered projection to area 17 in the first postnatal week. Furthermore, I show that manipulating the peripheral input can alter the topographic map which arises out of the early scatter. Removal of one eye at birth appears to slow the process of geniculo-cortical map formation ipsilateral to the remaining eye and at the end of the second postnatal week, a double projection between thalamus and cortex has formed. If retinal activity is blocked during this time, this double projection does not emerge. The results implicate retinal activity as the signal that induces the development of a different topographic order in the geniculo-cortical projection. It is generally believed that visual experience can influence development only after eye-opening. However, the final part of my thesis shows that neurons in the developing visual cortex of the ferret can not only be visually driven at least 10 days before natural eye-opening, but are also selective for differently oriented gratings presented <i>through the closed eye-lid</i>. Thus, visually-driven neuronal activity could influence development much earlier than previously assumed in many developmental studies.

Les hétérotopies nodulaires périventriculaires (HNP) sont des malformations du cortex cérébral caractérisées par la formation d’amas de neurones dans des parties inappropriées du cerveau. Elles peuvent être responsables d’une multitude de troubles tels qu’une hypotonie, un déficit intellectuel ou des épilepsies. Notre équipe a montré que le gène NEDD4L codant pour une E3 ubiquitine ligase était responsable d’HNP associées à des syndactilies. Des études cellulaires et une approche in utero nous ont permis de montrer une instabilité de la protéine mutante et des problèmes lors de la neurogénèse, le positionnement neuronal et la translocation terminale. Des études plus approfondies mettent en lumière le rôle critique de NEDD4L dans différentes voies de signalisation. En effet, alors que l’excès de protéine NEDD4L WT conduit à une dérégulation de DAB1 et de la voie mTORC1, l’instabilité des protéines mutantes conduit à une dérégulation des voies mTOC1 et AKT. L’ensemble de ces données permet de mieux comprendre le rôle critique de NEDD4L dans la régulation des voies mTOR et sa contribution dans le développement cortical. / Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to PNH associated with toes syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of wild type (WT) NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin based experiments, revealed differential deregulation of pathways involved. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1 and AKT activities. Altogether, these data provide insights to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

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Chez les plantes les protéines de la famille GRAS régissent un grand nombre de processus allant du développement racinaire à la transduction de signaux hormonaux. Deux protéines de cette famille de facteurs de transcription, SCR et SHR jouent un rôle essentiel dans le développement racinaire d’Arabidopsis thaliana en régulant la formation des tissus internes. Chez le riz, il existe deux co-orthologues putatifs pour ces deux gènes, OsSCR1, OsSCR2, OsSHR1 et OsSHR2. Nous avons caractérisé la fonction de trois membres de cette famille au cours du développement racinaire et aérien du riz. OsSHR1 et OsSHR2 sont impliqués dans la variation du nombre de couches de cortex et interfèrent aussi dans la formation des cellules bulliformes et du sclerenchyme dans les feuilles. OsSCR2 a un rôle majeur dans le contrôle du nombre de ramifications aériennes. Nos résultats ont aussi permis de démontrer qu’OsSCR2 et OsSHR2 ont des fonctions spécifiques au riz. / Summary to be coming

Le néocortex humain est particulièrement plissé. Des variations de plissement cortical ont été associées à certaines maladies neuro-développementales comme l’autisme ou la schizophrénie. Il est cependant difficile de savoir ce qu’impliquent ces différences de motif, au delà d’être des marqueurs de variations de la structure interne du cortex. Au cours du développement, les plis corticaux apparaissent chez l’humain pendant le dernier trimestre de gestation, simultanément avec le développement de sa connectivité. Aujourd’hui la communauté scientifique semble se retrouver sur des théories qui relient l’émergence des plis à l’organisation cytoarchitectonique et fonctionnelle du cortex. Nous avons développé une hypothèse de plissement prenant également en compte le stress mécanique engendré par la croissance des tissus ainsi que son rôle dans une possible rétro-action mécanique des plis sur l’organisation interne du cortex. Grâce à son développement en partie post-natal, le furet apparait comme un modèle animal idéal pour l’étude de l’organisation et du plissement cortical. A partir de données d’IRM structurales, nous avons segmenté et reconstruit en trois dimensions les surfaces piale et interne du cortex de 28 cerveaux de furets, afin de mener des analyses de surface et d’épaisseur corticale. Par une description anatomique précise du plissement du cortex du furet, basée sur l’étude de cartes de courbure, nous montrons la présence inattendue de plis déjà au 4ème jour après la naissance (P4). Par ailleurs, l’analyse longitudinale du plissement du cortex à partir d’algorithmes de recalage, suggère un gradient rostro-caudal dans la croissance de la surface corticale qui pourrait être impliqué dans la gyrification. En effet, les aires corticales les plus rostrales, plus grandes, et plus plissées à l’âge adulte, semblent croitre plus tôt et plus vite au cours du développement, en comparaison avec les régions caudales plus petites, et moins plissées chez l’adulte. L’analyse de l’épaisseur corticale révèle une corrélation entre l’épaisseur du cortex et la localisation des gyri et sulci. Cependant cette corrélation n’apparait qu’à partir du 8ème jour après la naissance, soit après la formation des plis à P4. L’ensemble de nos résultats suggère donc un possible effet mécanique du plissement du cortex sur son épaisseur, et donc potentiellement sur son organisation cytoarchitectonique et sa connectivité. / The human neocortex is highly folded. Its folding pattern has been associated with neurodevelopmental conditions, like autism or schizophrenia. It is still difficult, however, to understand what theses differences may imply, beyond being a marker of underlying variations in cortical organization. During development, folds appear during the last semester of gestation in human, synchronously with connective development. Nowadays, researchers recognize the existence of a relationship between the geometry of neocortical folds, and its cytoarchitectonic and functional organization. We have developed a hypothesis considering the role that mechanical stress can play in the determination of neocortical organization. The ferret appears as an ideal animal model to study the link between folding and cortical organization, as both processes in the ferret take place after birth. We segmented and reconstructed the pial and white matter cortical surfaces from 28 ferret brain structural MR images, and used them for surface and cortical thickness analysis. We highlight an unexpected significant presence of folds at postnatal day 4 (P4), on curvature maps of the pial surface. Besides, longitudinal analyses of the pial folding using meshes registration suggest the presence of a gradient in surface expansion that can be related to gyrification. The larger rostral areas — that turn to be more folded in adult brains — seem to expand earlier and faster than caudal regions with smaller surface area. In cortical thickness analysis, the correlation between pial surface curvature and thickness reveals a variation of cortical thickness in gyri and sulci. However, this correlation appears after postnatal day 8, thus after the emergence of folds around P4.Together, our results suggest a possible mechanical causal effect of folding on the thickening of the cortex and on its cytoarchitectonic and connective development.

Neuroscience research has been largely focused on neurons, while an equally important cell type, glia, was sidelined until recently. Astrocytes are star-shaped glial cells responsible for a variety of homeostatic processes of the central nervous system in addition to participating in synaptogenesis and neuronal signal transmission. A variety of immunohistochemical markers have been utilized to visualize these cells in the brain including glial fibrillary acidic protein (GFAP), vimentin, and aldehyde dehydrogenase 1 family member L1 (ALDH1L1). The current study makes use of a multiplex immunohistochemistry protocol developed in collaboration with General Electric to stain rhesus monkey brain tissue samples from the lateral prefrontal cortex (LPFC; n=5) and the primary visual cortex (V1; n=4) with a large number of markers, including GFAP, vimentin, and ALDH1L1 as well as neuronal, microglial, and oxidative stress markers. Using algorithms and manual cell classification, we were able to obtain neuronal and astrocytic counts and use these to estimate astrocyte-to-neuron ratios (ANRs) of the individual brain areas and laminae as well as assess the relative intensity of the markers of interest between areas. Among our findings there was higher ANRs in LPFC compared to V1 gray matter as well as in layer 1 compared to layer 2 in both areas studied. There is also a higher density of astrocytes in layer 1 potentially due to the recognized lack of neurons in this layer. We found significantly higher intensities of GFAP across all gray matter layers in V1 compared to LPFC as well as higher intensities for TSPO and Cleaved Caspase-3 in some V1 layers compared to their LPFC counterparts. This higher intensity of V1 reactive astrocyte markers are potentially due to the increased number of neurons these astrocytes need to support as demonstrated by the low ANR seen in V1 when compared to LPFC. In order to further our knowledge of normal astrocyte properties in these brain areas, it is imperative that we confirm our counts with stereologic studies and include oligodendrocyte markers in our multiplex staining protocol in order to better assess glial numbers within our sections. Additionally, morphological studies assessing rhesus monkey astrocytes identified with a variety of markers is important as we have shown that no one marker stains all astrocytes even though most astrocytes express more than one marker at a time.

The hippocampus is a brain region that can undergo tremendous plasticity in adulthood. The hippocampus is related to the formation of spatial memories in birds and mammals. In birds, plasticity in the hippocampus occurs when formation of such memories is directly relevant to survival or reproduction, such as for breeding or food caching. In reptiles, the homologues to the hippocampus are the dorsal and medial cortices (DC and MC). In several lizard, snake and turtle species, these structures have been related to spatial memory. Experimental investigations indicate that differences in DC volume are related to space use associated with differing foraging ecologies. Differences in MC volume have been associated with territory size-based mate acquisition strategies. Furthermore, territory size has previously been correlated with plasma testosterone (T) levels. Therefore, I hypothesized that neuroplasticity within the MC/DC is controlled by demands on spatial navigation and seasonal differences and that these changes may involve the action of T. During two experimental trials, male Western Fence Lizards (Sceloporus occidentalis) were placed into either large or small semi-natural enclosures and allowed to interact with a female and intruder males over the span of seven weeks. One trial was performed during the spring breeding season and the other during the summer non breeding season, to examine seasonal differences in plasticity. Blood samples were collected at initial time of capture and before sacrifice to measure plasma T. Immunostaining for doublecortin was used to determine the density of immature neurons in each region, and cresyl violet staining allowed for volume measurements of specific regions. MC cell layer neurogenesis was higher in lizards placed in large enclosures than those in small enclosures and higher in the summer than in the spring. DC volume was smaller in lizards held in large enclosures than those in small enclosures. The decreased DC volume seen lizards held in large enclosures may indicate a cost to the increased neurogenesis in the MC of lizards in the same enclosures. These results indicate a possible trade-off between DC volume and MC neurogenesis that allows for switching between the ability to solve novel spatial tasks using the DC while storing a cognitive map in the MC. During the spring, T had no relationship with MC volume, while during the summer this was negative, so effects of T on the MC may be seasonal.

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