Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia.

The basal ganglia (BG) integrate inputs from diverse sensorimotor, limbic, and associative regions to guide action-selection and goal-directed behaviors. The entopeduncular nucleus (EP) is a major BG output nucleus and has been suggested to channel signals from distinct BG nuclei to target regions involved in diverse functions. Here we use single-cell transcriptional and molecular analyses to demonstrate that the EP contains at least three classes of projection neurons-glutamate/GABA co-releasing somatostatin neurons, glutamatergic parvalbumin neurons, and GABAergic parvalbumin neurons. These classes comprise functionally and anatomically distinct output pathways that differentially affect EP target regions, such as the lateral habenula (LHb) and thalamus. Furthermore, LHb- and thalamic-projecting EP neurons are differentially innervated by subclasses of striatal and pallidal neurons. Therefore, we identify previously unknown subdivisions within the EP and reveal the existence of cascading, molecularly distinct projections through striatum and globus pallidus to EP targets within epithalamus and thalamus.

Glutamatergic pallidothalamic projections and their implications in the pathophysiology of Parkinson's disease.

GABAergic projections emitted from the entopeduncular nucleus (ENT) and the substantia nigra pars reticulata (SNr) innervate different thalamic nuclei and they are known to be hyperactive after dopaminergic depletion. Here we show that isoform 2 of the vesicular glutamate transporter (VGLUT2) is expressed by neurons in the ENT nucleus but not in the SNr. Indeed, dual in situ hybridization demonstrated that the ENT nucleus contains two different subpopulations of projection neurons, one single-expressing GAD65/67 mRNAs and another one that co-expresses either of the GAD isoforms together with VGLUT2 mRNA. Unilateral dopaminergic depletion induced marked changes in pallidothalamic-projecting neuron gene expression, resulting in increased expression of GAD65/67 mRNAs together with a clear down-regulation of VGLUT2 mRNA expression. Our results indicate that the increased thalamic inhibition typical of dopamine depletion might be explained by a synergistic effect of increased GABA outflow coupled to decreased glutamate levels, both neurotransmitters coming from ENT neurons.

Identification and morphogenesis of the eminentia thalami in the zebrafish.

This study documents early zebrafish brain expression patterns (2-5 days postfertilization) of proliferating neural (PCNA) as well as early-determined (Pax6, Zash-1a, Zash-1b, neurogenin1, neuroD) and differentiating (Hu-proteins) neuronal cells. These patterns are used to outline the spatiotemporal local dynamics of secondary neurogenesis as well as neuronal migration and differentiation in the region of the eminentia thalami. The analysis presented not only allows identification for the first time of the eminentia thalami in the zebrafish model system (because it forms a neurogenin1/neuroD-guided locus of neurogenesis in contrast to adjacent preoptic region and ventral thalamus) but furthermore shows that the entopeduncular complex is a derivative of the embryonic zebrafish eminentia thalami, which has never been reported for a teleost before. An analysis of the relevant literature shows that the mammalian entopeduncular nucleus/avian paleostriatum primitivum/reptilian globus pallidus clearly are part of the basal ganglia (i.e., the pallidum). In amniote embryos, an anterior entopeduncular area is recognized at the base of the medial ganglionic eminence (i.e., the future pallidum; part of alar plate of prosomere 5), separate from the more posterior eminentia thalami (alar prosomere 4). There is a comparable periventricular eminentia thalami in (young and adult) amphibians and teleosts. However, the migrated anterior entopeduncular nucleus of anuran amphibians likely is homologous to part of the pallidum of other vertebrates and has no developmental relationship to the eminentia thalami. In contrast, the migrated teleostean entopeduncular complex does not correspond to a pallidal division but is indeed the adult derivative of the early-recognized eminentia thalami as shown in this study.