Neurological and psychiatric disorders reveal that the basal ganglia subserve diverse functional domains, including movement, reward, and cognitive disorders (e.g., Parkinson's disease, addiction, schizophrenia). Monkey anatomical studies show that the striatum, the input structure of the basal ganglia, receives projections from nearly the entire cerebral cortex with a broad topography of motor, limbic, and association zones. However, until recently, non-invasive methods have not been available to conduct the complete mapping of the cortex to the striatum in humans. The development of functional connectivity magnetic resonance imaging (fcMRI) now allows the identification of functional connections in humans. The present dissertation reports two studies that first create a complete map of corticostriatal connectivity and then more closely examine striatal connectivity with association networks underlying cognition.

Understanding the specificity of homeobox genes has been hampered by the lack of verified direct transcriptional targets. The Dlx family of homeobox genes is expressed in the ganglionic eminences of the developing forebrain. Dlx1/Dlx2 double knockout (DKO) mice die at birth. Phenotypic analyses demonstrate abnormal development of the basal telencephalon, including defects in neuronal differentiation in the basal ganglia, reduced expression of GABA in the basal telencephalon, and loss of migration of GABAergic inhibitory interneurons to the neocortex. The mechanisms underlying DLX protein regulation of differentiation and migration of GABAergic interneurons are poorly defined. We have successfully applied chromatin immunoprecipitation to identify potential direct transcriptional targets of DLX homeoproteins from embryonic tissues in vivo. Reporter gene assays demonstrated the transcriptional significance of the binding of DLX proteins to different downstream regulatory elements, which were confirmed in vitro by electrophoretic mobility shift assay and site-directed mutagenesis. The functional significance of DLX mediated transcriptional regulation of these targets was further elaborated through several series of loss-of-function assays including gene expression in Dlx1/2 knockout embryonic forebrain tissues, as well as siRNA or Lentiviral mediated shRNA knockdown experiments with primary forebrain cultures. Quantitative analysis of the regulatory effect of Dlx genes on various forebrain markers of differentiation and migration was performed using in situ hybridization, high-performance liquid chromatography coupled with cell counting. Neuronal migration was assessed by forebrain explants and diI labelling of migratory cells from ganglionic eminence to neocortex. We have demonstrated that DLX1 and DLX2 can transcriptionally activate (Gad1, Gad2) or repress (Nrp2) different downstream targets. In the Dlx1/2 DKO, reduction of GABA expression and failure of GABAergic interneurons to migrate to the neocortex is partly due to loss or aberrant expression of these DLX downstream targets. In the triple Dlx1/2; Nrp2KO, partial restoration of tangential migration of GABAergic interneurons from basal ganglia to the neocortex was successfully established signifying the importance of DLX regulation of Semaphorin-Neuropilin signalling during forebrain development.

Afin d'analyser le rôle de la plasticité striatale dans la perception temporelle, nous avons réalisé une étude comportementale et électrophysiologique d'un modèle rat transgénique de la maladie de Huntington impliquant la dégénérescence progressive du striatum. Pour ce faire, nous avons élaboré une étude longitudinale (4-15 mois) du suivi de la maladie de Huntington au niveau moteur, motivationnel et temporel, et une étude présymptomatique (4-5 mois) de l'estimation temporelle et électrophysiologique in vivo de la voie préfronto-striatale. Nous avons détecté un dysfonctionnement de la perception temporelle et de la plasticité synaptique de manière présymptomatique, suggérant une corrélation entre ces deux dysfonctionnements. En symptomatique, le comportement temporel discriminatif est plus fortement altéré, corrélat d'une dégénérescence du striatum.

Understanding the specificity of homeobox genes has been hampered by the lack of verified direct transcriptional targets. The Dlx family of homeobox genes is expressed in the ganglionic eminences of the developing forebrain. Dlx1/Dlx2 double knockout (DKO) mice die at birth. Phenotypic analyses demonstrate abnormal development of the basal telencephalon, including defects in neuronal differentiation in the basal ganglia, reduced expression of GABA in the basal telencephalon, and loss of migration of GABAergic inhibitory interneurons to the neocortex. The mechanisms underlying DLX protein regulation of differentiation and migration of GABAergic interneurons are poorly defined. We have successfully applied chromatin immunoprecipitation to identify potential direct transcriptional targets of DLX homeoproteins from embryonic tissues in vivo. Reporter gene assays demonstrated the transcriptional significance of the binding of DLX proteins to different downstream regulatory elements, which were confirmed in vitro by electrophoretic mobility shift assay and site-directed mutagenesis. The functional significance of DLX mediated transcriptional regulation of these targets was further elaborated through several series of loss-of-function assays including gene expression in Dlx1/2 knockout embryonic forebrain tissues, as well as siRNA or Lentiviral mediated shRNA knockdown experiments with primary forebrain cultures. Quantitative analysis of the regulatory effect of Dlx genes on various forebrain markers of differentiation and migration was performed using in situ hybridization, high-performance liquid chromatography coupled with cell counting. Neuronal migration was assessed by forebrain explants and diI labelling of migratory cells from ganglionic eminence to neocortex. We have demonstrated that DLX1 and DLX2 can transcriptionally activate (Gad1, Gad2) or repress (Nrp2) different downstream targets. In the Dlx1/2 DKO, reduction of GABA expression and failure of GABAergic interneurons to migrate to the neocortex is partly due to loss or aberrant expression of these DLX downstream targets. In the triple Dlx1/2; Nrp2KO, partial restoration of tangential migration of GABAergic interneurons from basal ganglia to the neocortex was successfully established signifying the importance of DLX regulation of Semaphorin-Neuropilin signalling during forebrain development.

L'acide rétinoïque (AR), la forme active de la vitamine A, est une molécule essentielle au cours du développement et dans le cerveau adulte. La signalisation par l'AR implique deux familles de récepteurs nucléaires: les récepteurs de l'AR (Rar α, β et γ) et les récepteurs des "rexinoïdes" (Rxr α, β et γ) et les enzymes de la famille rétinaldéhyde déshydrogénases, les Raldhs (Raldh1, 2, 3). Rarβ et/ou Raldh1 montrent des profils d'expression spatio-temporelle spécifiques dans le striatum et la substance noire pars compacta (SNc), les structures appartenant au système dopaminergique nigro-striée, ce qui suggère que l'AR pourrait jouer un rôle important dans le développement et les fonctions post-natales du ce système. Dans ce travail, je montre que l'ablation de Rarβ conduit à un déficit de la neurogenèse de neurones épineux moyens (MSN) GABAergiques dans le striatum. Le nombre de neurones exprimant les récepteurs dopaminergiques D1 et D2, qui définissent les populations distinctes des MSN, sont réduit chez les souris Rarβ-/-. Ces déficits cellulaires conduisent à la signalisation dopaminergique perturbée et une coordination motrice réduite chez les souris Rarβ-/-. L'ablation de Raldhl, l'enzyme de synthèse de l'AR présent dans le striatum postnatal, conduit à des déficits cellulaires et comportementaux similaires aux souris Rarβ-/-. Ces résultats montrent que l'AR produit en conditions physiologiques par Raldh1 est essentiel au maintien des MSN. Enfin, j'ai trouvé que l'ablation de Raldh1, qui est également connu comme le marqueur spécifique le plus précoce des neurones dopaminergiques dans le mésencéphale embryonnaire, conduit à des anomalies du développement dans le SNc.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.