We investigated whether there is neurogenesis in the striatum of aged monkeys, and whether dopamine (DA) depletion induces the genesis of new DA neurons in this structure. Six aged macaques received repeated intraperitoneal injections of bromodeoxyuridine (BrdU) over a 3 week period to label dividing cells. Three macaques were injected in parallel with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to decrease dopaminergic innervation of the striatum. The brains were analysed 3 weeks after the last BrdU injection. In MPTP-treated aged macaques, the number of tyrosine hydroxylase (TH) immunoreactive (ir) striatal neurons increased 2.3-fold compared with controls. These TH-ir striatal cells did not express dopamine beta hydroxylase (DBH) but the dopamine transporter (DAT), suggesting that they are functional DA neurons. They were also negative for calbindin (CB), neuropeptide Y (NPY) and parvalbumin (PV), and a small proportion expressed calretinin (CR). This suggests that these cells stained for TH are interneurons. All these cells also co-expressed glutamic acid decarboxylase (GAD). They thus resemble the small, aspiny, GABAergic interneurons. None of the BrdU-labelled cells in the striatum expressed the neuronal markers neuronal nuclei (NeuN), or GAD or TH, and none of TH-ir cells incorporated BrdU. These data indicate that neurogenesis did not occur in the striatum of aged macaques. The new striatal TH-ir neurons observed after DA depletion was therefore derived from pre-existing GABAergic interneurons. Understanding of the molecular signals mediating this phenotypic shift might help in developing novel and elegant strategies for a cell-based therapy for Parkinson's disease that would avoid many of the drawbacks of cell transplantation.

The subventricular zone of the adult primate brain contains neural stem cells that can produce new neurons. Endogenous neurogenesis might therefore be used to replace lost neurons in neurodegenerative diseases. This would require, however, a precise understanding of the molecular regulation of stem cell proliferation and differentiation in vivo. Several regulatory factors, including dopamine, have been identified in rodents, but none in primates. We have, therefore, studied the origin and function of the dopaminergic innervation of the subventricular zone in nonhuman primates. Tracing experiments in three macaques revealed a topographically organized projection from the substantia nigra pars compacta (SNpc), but not the adjacent retrorubral field, to the subventricular zone: the anteromedial SNpc projects to the anteroventral subventricular zone, the posterolateral SNpc to the posterodorsal subventricular zone. Double immunolabeling for tyrosine hydroxylase and BrdU (5-bromo-2Јdeoxyuridine) incorporated into the DNA of proliferating cells showed that dopaminergic fibers approach proliferating cells in the subventricular zone. We investigated the effect of this nigro-subventricular projection on cell proliferation in six aged macaques, because the rate of neurogenesis differs between young adult and aged primates and because neurodegenerative diseases mainly affect aged humans. Three macaques were treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to decrease dopaminergic innervation of the subventricular zone. A significant decrease in the number of PCNA ϩ (proliferating cell nuclear antigen-positive) proliferating cells (Ϫ44%) and PSA-NCAM ϩ (polysialylated neural cell adhesion moleculepositive) neuroblasts (Ϫ59%) was found in the denervated regions of the subventricular zone, suggesting that an intact dopaminergic nigro-subventricular innervation is crucial for sustained neurogenesis in aged primates.

Current theoretical positions assume that action-related word meanings are established by functional connections between perisylvian language areas and the motor cortex (MC) according to Hebb's associative learning principle. To test this assumption, we probed the functional relevance of the left MC for learning of a novel action word vocabulary by disturbing neural plasticity in the MC with transcranial direct current stimulation (tDCS). In combination with tDCS, subjects learned a novel vocabulary of 76 concrete, body-related actions by means of an associative learning paradigm. Compared with a control condition with "sham" stimulation, cathodal tDCS reduced success rates in vocabulary acquisition, as shown by tests of novel action word translation into the native language. The analysis of learning behavior revealed a specific effect of cathodal tDCS on the ability to associatively couple actions with novel words. In contrast, we did not find these effects in control experiments, when tDCS was applied to the prefrontal cortex or when subjects learned object-related words. The present study lends direct evidence to the proposition that the left MC is causally involved in the acquisition of novel action-related words.

Parkinson's disease is a neurodegenerative disorder characterized by a progressive neuronal loss affecting preferentially the dopaminergic neurons of the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has provided the proof of principle that a cell replacement therapy can ameliorate clinical symptoms in affected patients. Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain. Such stem cells have been identified in so called neurogenic brain areas, where neurogenesis is constitutively ongoing, but also in primarily non-neurogenic areas, such as the midbrain and the striatum, where neurogenesis does not occur under normal physiological conditions. We review here presently published evidence to evaluate the concept that endogenous neural stem cells may have the potential to be instrumentalized for a non-invasive cell replacement therapy with autologous neurons to repair the damaged nigrostriatal dopaminergic projection in Parkinson's disease.

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Despite a growing number of studies, the neurophysiology of adult vocabulary acquisition is still poorly understood. One reason is that paradigms that can easily be combined with neuroscientfic methods are rare. Here, we tested the efficiency of two paradigms for vocabulary (re-) acquisition, and compared the learning of novel words for actions and objects. Cortical networks involved in adult native-language word processing are widespread, with differences postulated between words for objects and actions. Words and what they stand for are supposed to be grounded in perceptual and sensorimotor brain circuits depending on their meaning. If there are specific brain representations for different word categories, we hypothesized behavioural differences in the learning of action-related and object-related words. Paradigm A, with the learning of novel words for body-related actions spread out over a number of days, revealed fast learning of these new action words, and stable retention up to 4 weeks after training. The single-session Paradigm B employed objects and actions. Performance during acquisition did not differ between action-related and object-related words (time*word category: p = 0.01), but the translation rate was clearly better for object-related (79%) than for action-related words (53%, p = 0.002). Both paradigms yielded robust associative learning of novel action-related words, as previously demonstrated for object-related words. Translation success differed for action- and object-related words, which may indicate different neural mechanisms. The paradigms tested here are well suited to investigate such differences with neuroscientific means. Given the stable retention and minimal requirements for conscious effort, these learning paradigms are promising for vocabulary re-learning in brain-lesioned people. In combination with neuroimaging, neuro-stimulation or pharmacological intervention, they may well advance the understanding of language learning to optimize therapeutic strategies.

Brain-derived neurotrophic factor (BDNF) has been suggested to play a major role in plasticity, neurogenesis and learning in the adult brain. The BDNF gene contains a common val66met polymorphism associated with decreased activity-dependent excretion of BDNF and a potential influence on behaviour, more specifically, on motor learning. The objective of this study was to determine the influence of the BDNF val66met polymorphism on short-term implicit associative learning and whether its influence is cognitive domain-specific (motor vs. language). A sample of 38 young healthy participants was genotyped, screened for background and neuropsychological differences, and tested with two associative implicit learning paradigms in two different cognitive domains, i.e., motor and vocabulary learning. Subjects performed the serial reaction time task (SRTT) to determine implicit motor learning and a recently established associative vocabulary learning task (AVL) for implicit learning of action and object words. To determine the influence of the BDNF polymorphism on domain-specific implicit learning, behavioural improvements in the two tasks were compared between val/val (n = 22) and met carriers (val/met: n = 15 and met/met: n = 1). There was no evidence for an impact of the BDNF val66met polymorphism on the behavioural outcome in implicit short-term learning paradigms in young healthy subjects. Whether this polymorphism plays a relevant role in long-term training paradigms or in subjects with impaired neuronal plasticity or reduced learning capacity, such as aged individuals, demented patients or patients with brain lesions, has to be determined in future studies.

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