Mark Dubach

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost?

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces, in both human and non-human primates, a syndrome very similar to idiopathic Parkinsons disease. The syndrome is associated with degeneration of the dopamine-containing neurons in the substantia nigra, many of which project to the neostriatum. The purpose of the present study was to quantify the regional distribution of midbrain dopamine neurons remaining after MPTP administration to the monkey (Macaca fascicularis) and to develop alternative procedures for maintaining the normal nutrition in MPTP-treated animals. Three monkeys were treated with MPTP and three served as controls. Representative sections were examined from rostral to caudal through the midbrain dopamine cell nuclei and the location of every tyrosine hydroxylase-containing cell was entered into a computer. Midbrain dopamine neuronal cell loss ranged from 36-78%, being most extensive in the two monkeys which exhibited the most severe parkinsonian syndrome. The greatest cell loss (46-93%) occurred in the substantia nigra pars compacta, or nucleus A9, and the loss was primarily in the ventral portion of the nucleus. Contrary to most previous reports, however, there was also a loss of cells in the ventral tegmental area (28-57%) and ventral reticular formation (33-87%), corresponding to nuclei A10 and A8, respectively. Since neuroanatomical tracing studies have shown that the dorsal and lateral portions of the striatum (areas showing the greatest dopamine depletion after MPTP) receive input from cells in the ventral A9 and from cells in the A8 and A10 areas, the present data suggest that MPTP preferentially destroys dopamine cells that project to the striatum (i.e. the mesostriatal cells).

Primate neostriatal neurons containing tyrosine hydroxylase: Immunohistochemical evidence

We have detected, in monkey caudate nucleus and putamen, neuronal cell bodies containing tyrosine hydroxylase-like immunoreactivity, as revealed by peroxidase-antiperoxidase immunohistochemistry. Many of these cells are distributed in an outer rim of 1-2 mm throughout the anterior-posterior extent of the neostriatum near its borders with the corona radiata; others are embedded in the adjacent white matter, especially near the ventral putamen and nucleus accumbens. Light and electron microscopy indicate that they are small (8-12 micron), bipolar cells with large nuclei. Such neostriatal neurons, containing tyrosine hydroxylase-like immunoreactivity, number in the tens of thousands.

The INIA19 Template and NeuroMaps Atlas for Primate Brain Image Parcellation and Spatial Normalization

The INIA19 is a new, high-quality template for imaging-based studies of non-human primate brains, created from high-resolution, T1-weighted magnetic resonance (MR) images of 19 rhesus macaque (Macaca mulatta) animals. Combined with the comprehensive cortical and sub-cortical label map of the NeuroMaps atlas, the INIA19 is equally suitable for studies requiring both spatial normalization and atlas label propagation. Population-averaged template images are provided for both the brain and the whole head, to allow alignment of the atlas with both skull-stripped and unstripped data, and thus to facilitate its use for skull stripping of new images. This article describes the construction of the template using freely available software tools, as well as the template itself, which is being made available to the scientific community (http://nitrc.org/projects/inia19/).

Development of a model of status epilepticus in pigtailed macaque infant monkeys.

Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline ‘cocktail’ was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans.

Transplant improves hemiparkinsonian syndrome in nonhuman primate: intracerebral injection, rotometry, tyrosine hydroxylase immunohistochemistry.

Publisher Summary This chapter describes the methods for creating a unilateral DA lesion by direct injection of neurotoxin into substantia nigra, and for collecting quantitative behavioral data using a rotometer, and using these methods to test the efficacy of fetal nigral cell-suspension transplants. The histopathological results reveal that there is no evidence of immune rejection of the grafts as judged by the absence of lymphocytes, neutrophils, or macrophages. The behavioral changes observed in the monkey are believed to be related to the transplant, but it is not known why the improvement occurred so soon after the transplant, or why it ended so quickly. It is impossible to state with any certainty that the excess dopamine (DA) cells on the lesioned and transplanted side represent surviving transplanted cells, which migrated from the original graft site toward the ventricle. However, it is possible that the lesion alone results in a transformation or induction of endogenous tyrosine hydroxylase-like immunoreactive (TH-LI) cells, but this question will require investigation of additional transplantation animals and lesion controls.

NeuroNames: An Ontology for the BrainInfo Portal to Neuroscience on the Web

BrainInfo (http://braininfo.org) is a growing portal to neuroscientific information on the Web. It is indexed by NeuroNames, an ontology designed to compensate for ambiguities in neuroanatomical nomenclature. The 20-year old ontology continues to evolve toward the ideal of recognizing all names of neuroanatomical entities and accommodating all structural concepts about which neuroscientists communicate, including multiple concepts of entities for which neuroanatomists have yet to determine the best or ‘true’ conceptualization. To make the definitions of structural concepts unambiguous and terminologically consistent we created a ‘default vocabulary’ of unique structure names selected from existing terminology. We selected standard names by criteria designed to maximize practicality for use in verbal communication as well as computerized knowledge management. The ontology of NeuroNames accommodates synonyms and homonyms of the standard terms in many languages. It defines complex structures as models composed of primary structures, which are defined in unambiguous operational terms. NeuroNames currently relates more than 16,000 names in eight languages to some 2,500 neuroanatomical concepts. The ontology is maintained in a relational database with three core tables: Names, Concepts and Models. BrainInfo uses NeuroNames to index information by structure, to interpret users’ queries and to clarify terminology on remote web pages. NeuroNames is a resource vocabulary of the NLM’s Unified Medical Language System (UMLS, 2011) and the basis for the brain regions component of NIFSTD (NeuroLex, 2011). The current version has been downloaded to hundreds of laboratories for indexing data and linking to BrainInfo, which attracts some 400 visitors/day, downloading 2,000 pages/day.

Topography of dyskinesias and torticollis evoked by inhibition of substantia nigra pars reticulata

GABAergic neurons of the substantia nigra pars reticulata (SNpr) and globus pallidus pars interna (GPi) constitute the output pathways of the basal ganglia. In monkeys, choreiform limb dyskinesias have been described after inhibition of the GPi, but not the SNpr. Given the anatomical and functional similarities between these structures, we hypothesized that choreiform dyskinesias could be evoked by inhibition of an appropriate region within the SNpr. The GABAA receptor agonist, muscimol, was infused into various sites within the SNpr and the adjacent STN of freely moving macaques. The effect of the GABAA antagonist, bicuculline (BIC), was also examined. Muscimol (MUS) in SNpr evoked the following: (1) choreiform dyskinesias of the contralateral arm and/or leg from central and lateral sites; (2) contralaterally directed torticollis from central and posterior sites; and (3) contraversive quadrupedal rotation from anterior and lateral sites. MUS infusions into the adjacent SN pars compacta or STN were without effect, ruling out a contribution of drug spread to adjacent structures. BIC in SNpr induced ipsiversive postures without choreiform dyskinesia or torticollis, whereas in the STN, it evoked ballistic movements. This is the first report of choreiform dyskinesia evoked by inhibition of the SNpr. This highly site‐specific effect was obtained from a restricted region within the SNpr distinct from that responsible for inducing torticollis. These results suggest that overactivity of different SNpr outputs mediates choreiform dyskinesia and torticollis. These abnormalities are symptoms of dystonia, Huntingtons disease, and iatrogenic dyskinesias, suggesting that these conditions may result, in part, from a loss of function in SNpr efferent projections.

Effects of acute and chronic alprazolam treatment on cerebral blood flow, memory, sedation, and plasma catecholamines

The effects of 0.014 mg/kg intravenous alprazolam administration on cerebral blood flow (CBF), memory, sedation, and plasma norepinephrine and epinephrine were determined in eight healthy males at baseline levels and following 1 week of daily oral alprazolam treatment. At baseline, intravenous alprazolam administration caused acute reductions in whole-brin CBF (25% to 30% decrease), memory, plasma epinephrine, and self-rated alertness. Following 1 week of alprazolam treatment, tolerance developed to the acute effects of intravenous alprazolam on CBF, memory, and plasma epinephrine. There were no consistent regional neuroanatomic differences in the CBF effects of acute alprazolam, or in the development of tolerance to these effects, and no correlations between the various measures of acute alprazolam efects on either test day.

Morphological Plasticity in an Infant Monkey Model of Temporal Lobe Epilepsy

Summary: Purpose/Methods: Seizures in early life are thought to contribute to the development of human temporal lobe epilepsy. To examine the consequences of early seizures, we elicited status epilepticus in immature, 5.5‐ to 7.0‐month‐old pigtailed macaques by unilateral microinfusion of bicuculline methiodide into the entorhinal cortex.

Techniques for improving stereotaxic accuracy in Macaca fascicularis

Sources of stereotaxic variability in long-tailed macaques (Macaca fascicularis) were examined by X-ray techniques. Accuracy in the vertical dimension can be improved significantly by measuring from the top of the brain rather than from the Frankfurt plane established by external bony landmarks. Even greater accuracy in both the vertical and anterior-posterior dimensions can be attained by rotating the cranium in the stereotaxic instrument to bring the intercommissural line, as defined by ventriculography, into a plane parallel to the horizontal stereotaxic plane, thus approximating the orientation of the brain as represented in both of the brain atlases currently available for this species. An adjustable eyebar spacer, which allows the cranium to be rotated in the stereotaxic instrument, is described.