We have previously shown that the arcuate organization of cell fates within the ventral midbrain critically depends upon the morphogen, Sonic Hedgehog (SHH), which is secreted from a signaling center located along the ventral midline, called the floor plate (FP). Thus, it is ultimately the specification of the FP that is responsible for the patterning and specification of ventral midbrain cell fates. Interestingly, we have found that the chick midbrain FP can be divided into medial (MFP) and lateral (LFP) regions on the basis of gene expression, mode of induction and function. Overexpression of SHH alone is sufficient to recapitulate the entire pattern of ventral cell fates, although remarkably it cannot induce MFP, consistent with the observation that the MFP is refractory to any perturbations of HH signaling. In contrast, overexpression of the winged-helix transcription factor FOXA2/HNF3[beta]robustly induced the MFP fate throughout ventral midbrain while blocking its activity resulted in the absence of the MFP. Thus, by analyzing the differences between SHH and FOXA2 blockade and overexpression, we were able to attribute functions to each the LFP and the MFP. Notably, we observed that FOXA2 overexpression caused a bending of the midbrain neurepithelium that resembled the endogenous median hinge-point observed during neurulation. Additionally, FOXA2 misexpression led to a robust induction of DA progenitors and neurons that was never observed after SHH expression alone. In contrast, we found that all other ventral cell types required HH signaling directly, at a distance and early on in the development of the midbrain when its tissue size is relatively small. Additionally, HH blockade resulted in increased cell-scatter of the arcuate territories and in the disruption of the regional boundaries between the ventral midbrain and adjacent tissue. Thus, we bring new insight into the mechanism by which midbrain FP is specified and ascribe functional roles to its subregions. We propose that while the MFP regulates the production of dopaminergic progenitors and the changes in cellshape required for bending and shaping the neural tube, the LFP appears to be largely responsible for cell survival and the formation of a spatially coherent pattern of midbrain cell fates. / text

La voie dopaminergique mésolimbique qui prend son origine dans le mésencéphale ventral et qui projette vers des régions rostrales du système limbique fait partie du substrat nerveux qui contrôle la récompense et les comportements motivés. Il a été suggéré qu’un signal de récompense est produit lorsque le patron de décharge des neurones dopaminergiques passe d’un mode tonique à un mode phasique, une transition qui est initiée par l’action du glutamate aux récepteurs N-Méthyl-D-aspartate (NMDA). Étant donné qu’une altération du système de récompense est souvent associée à des anomalies cliniques telles que l’addiction compulsive et à des troubles émotionnels tels que l’anhédonie, nous avons étudié le rôle des récepteurs NMDA dans la récompense induite par la stimulation électrique intracérébrale. Puisque les récepteurs NMDA sont composés de sous-unités distinctes, GluN1, GluN2 et GluN3, nous avons étudié le rôle de deux sous-unités qui sont présentes dans le mésencéphale ventral : GluN2A et GluN2B. Les résultats montrent que des injections mésencéphaliques de R-CPP et de PPPA, des antagonistes préférentiels aux sous-unités GluN2A/B, ont produit une augmentation dose-dépendante de l’effet de récompense, un effet qui était, à certains temps après les injections, accompagné d’une augmentation du nombre de réponses maximales. Ces effets n’ont pas été observés après l’injection d’une large gamme de doses de Ro04-5595, un antagoniste des sous-unités GluN2B. Ces résultats suggèrent que le glutamate mésencéphalique exerce une modulation négative sur le circuit de récompense, un effet dû à son action au niveau des récepteurs NMDA composés des sous-unités GluN2A. / The mesolimbic dopaminergic pathway, originating from the ventral midbrain and projecting to rostral limbic structures, is part of a neural substrate that controls reward and incentive behaviors. It has been suggested that the rewarding effect is produced by a tonic to phasic shift in dopamine cell firing and a transduction process initiated by the action of glutamate at the N-Methyl-D-aspartate (NMDA) receptors. Given that an alteration in reward signaling is often associated with clinical symptoms of compulsive addictive behaviors and emotional disturbances such as anhedonia, we investigated the role of NMDA receptors in reward induced by intracranial electrical stimulation. Since NMDA receptors are composed of distinct subunits, GluN1, GluN2 and GluN3, we investigated the role of the main GluN2 subunits that are expressed in the ventral midbrain, GluN2A and GluN2B. Results show that ventral midbrain injections of R-CPP or PPPA, preferential GluN2A/2B antagonists, produce a dose-orderly enhancement of reward, an effect that was, at some time after the injection, accompanied by an increase in maximum response rates. These effects were not observed following ventral midbrain injections of a wide range of doses of the selective GluN2B antagonist, Ro-04-5595. These findings suggest that ventral midbrain glutamate exerts a negative modulation on reward induced by electrical stimulation of the posterior mesencephalon, an effect most likely mediated by NMDA receptors composed of GluN2A subunits.

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