A Stereotaxic Template Atlas of the Macaque Brain for Digital Imaging and Quantitative Neuroanatomy

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112

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.

Section: Methodsmentioning

confidence: 99%

Dopaminergic Substantia Nigra Neurons Project Topographically Organized to the Subventricular Zone and Stimulate Precursor Cell Proliferation in Aged Primates

Freundlieb¹,

François²,

Tandé³

et al. 2006

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112

“…A scalp incision was made, a hole was drilled in the skull overlaying the pallidum, and the dura was reflected. Micropipettes (8 -10 m tip diameter) were backfilled with the 1% solution of CTb in 0.1 M PB, pH 6.0, and lowered stereotaxically into the GPi (15 mm anterior to ear bars; 7.0 mm lateral and 13.0 mm ventral to skull surface) (Martin and Bowden, 1996) in one hemisphere and into the GPe (16 mm anterior to ear bars; 9 mm lateral and 14 mm ventral to skull surface) (Martin and Bowden, 1996) in the other hemisphere of each animal. We injected 100 nl of CTb by air pressure with a Picospitzer (General Valve Corporation, Fairfield, NJ).…”

Section: Methodsmentioning

confidence: 99%

Phenotype of Striatofugal Medium Spiny Neurons in Parkinsonian and Dyskinetic Nonhuman Primates: A Call for a Reappraisal of the Functional Organization of the Basal Ganglia

Nadjar¹,

Brotchie²,

Guigoni³

et al. 2006

The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D 2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D 1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia. To identify striatal cells projecting to external (indirect) or internal (direct) segments of the globus pallidus, the retrograde tracer cholera toxin subunit B (CTb) was injected stereotaxically into the terminal areas. Using immunohistochemistry techniques, brain sections were double labeled for CTb and dopamine receptors, opioid peptides, or the substance P receptor (NK1). We also used HPLC-RIA to assess opioid levels throughout structures of the basal ganglia. Our results suggest that medium spiny neurons retain their phenotype because no variations were observed in any experimental condition. Therefore, it appears unlikely that dyskinesia is related to a phenotype modification of the striatal neurons. However, this study supports the concept of axonal collateralization of striatofugal cells that project to both globus pallidus pars externa and globus pallidus pars interna. Striatofugal pathways are not as segregated in the primate as previously considered.

“…The ventral anterior (VA) and ventral lateral (VL) nuclei are defined as thalamic targets of the motor loop. VA nuclei were measured on sections 4 mm anterior to anterior commissura (AC) where the STN is absent, and VL nuclei were measured on sections 6 mm to AC where the STN is present (Martin and Bowden, 1996). The mediodorsal nucleus (MD) is defined as thalamic output of the associative loop of the basal ganglia (Parent and Hazrati, 1995a).…”

Section: Methodsmentioning

confidence: 99%

Involvement of Sensorimotor, Limbic, and Associative Basal Ganglia Domains in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Guigoni

Li²,

Aubert³

et al. 2005

Dyskinesia represents a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson's disease. Such motor manifestations are attributed to pathological activity in the motor parts of basal ganglia. However, because consistent funneling of information takes place between the sensorimotor, limbic, and associative basal ganglia domains, we hypothesized that nonmotor domains play a role in these manifestations. Here we report the changes in 2-deoxyglucose (2-DG) accumulation in the sensorimotor, limbic, and associative domains of basal ganglia and thalamic nuclei of four groups of nonhuman primates: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa and exhibiting overt dyskinesia. Although nondyskinetic animals display a rather normalized metabolic activity, dyskinetic animals are distinguished by significant changes in 2-DG accumulation in limbic-and associative-related structures and not simply in sensorimotorrelated ones, suggesting that dyskinesia is linked to a pathological processing of limbic and cognitive information. We propose that these metabolic changes reflect the underlying neural mechanisms of not simply motor dyskinesias but also affective, motivational, and cognitive disorders associated with long-term exposure to L-dopa.