Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

Displacement of the PET ligand18F-MPPF by the electrically evoked serotonin release in the rat hippocampus

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Pre-synaptic glutamate-induced activation of DA release in the striatum after partial nigral lesion.

International audienceThe present experiments aimed at understanding the functional link between dopamine (DA) and glutamate (GLU) during the compensatory processes taking place after partial DA denervation. Lesion of the lateral part of substantia nigra in rats using 6-hydroxydopamine resulted in DA denervation of the lateral region of the ipsilateral caudate/putamen complex (CPc) whereas the medial CPc was spared. In vivo voltammetry revealed a large increase of extracellular dopamine (DA(ext)) in the medial CPc both ipsilateral and contralateral to the lesion. In addition, in vivo microdialysis and HPLC-ED revealed a concomitant increase of extracellular glutamate (GLU(ext)) in the ipsilateral medial CPc. Post-lesion chronic treatment with the putative neuroprotectors amantadine, memantine, and riluzole counteracted the tonic increases of DA(ext) and GLU(ext), revealing a possible role of GLU neurotransmission in the DA over-expression. Finally, acute low doses of GBR12909 had no effect on the DA(ext) in sham- operated animals, but dramatically increased DA(ext) in lesioned animals. The data suggest that a partial unilateral nigral lesion induces a bilateral increase of DA turn-over in the non-denervated striata through GLU afferences to the DA terminals

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss

Primate brain template image and reference atlas creation for voxel-based functional analysis of PET in Macaca fascicularis

International audienceNeuroimaging studies are increasingly performed on non-human primates, including Macaca fascicularis. The analysis of functional imaging studies requires a corresponding anatomical image in order to identify brain structures. In the specific case of positron emission tomography (PET), anatomical correspondence is also required for quantification and modeling of interactions between the PET ligand and its pharmacological receptors. For voxel-based statistical parametric mapping, a reference frame (template) is needed to perform spatial normalization of individual brains. In this work we introduce a specific brain template and its associated atlas, with the purpose of enabling accurate, robust and reliable normalization and anatomical labeling of Macaca fascicularis brain images. Methods: Seven animals were included for template creation. For each, three high-resolution (0.6 mm 3) 3D T1 MRI scans were acquired and averaged for noise reduction. The atlas was created from the MRI of one subject by labeling 38 brain structures in three dimensions, following a precise manual delineation protocol. Regions included cortex, sub-cortical nuclei, brainstem, white matter and cerebrospinal fluid. The chosen MRI was then used as the target for an automatic iterative procedure of template creation: each MRI was subjected to automatic brain extraction, coregistered to the target with rigid-body transformations and resampled. Coregistered MRIs were averaged. The average brain was then coregistered to the original brain target to compensate for misalignment bias. The resulting image constituted the first template, and was used as the target for the next iteration. Iterations continued until each parameter of the coregistration of the ith template to the original target was below 0.3 mm and 1 arc degree. The final template was tested for accuracy, robustness and reproducibility as follows: accuracy was assessed by visually inspecting the normalized brain on the template, with positioning inspection of the brain structures of the atlas projected on individual MRI with the reverse normalization transform. Robustness was tested by normalizing a new set of MRIs coming from other individuals to the template. Reproducibility was tested on four of the seven monkeys which were also submitted to PET acquisitions with various tracers ([ 11 C] raclopride, [ 18 F]-dopa, [ 18 F]MPPF, [ 11 C]pe2i, and [ 11 C]DASB), with test-retest scans. Time-activity curves were extracted from manually delineated regions of interest (ROI), from automated delineated ROIs of the atlas on normalized data, and from atlases propagated to S174 NRM2010 abstracts-Poster presentation

Derivation and cloning of a novel rhesus embryonic stem cell line stably expressing tau-green fluorescent protein.

International audienceEmbryonic stem cells (ESC) have the ability of indefinite self-renewal and multilineage differentiation, and they carry great potential in cell-based therapies. The rhesus macaque is the most relevant preclinical model for assessing the benefit, safety, and efficacy of ESC-based transplantations in the treatment of neurodegenerative diseases. In the case of neural cell grafting, tracing both the neurons and their axonal projections in vivo is essential for studying the integration of the grafted cells in the host brain. Tau-Green fluorescent protein (tau-GFP) is a powerful viable lineage tracer, allowing visualization of cell bodies, dendrites, and axons in exquisite detail. Here, we report the first rhesus monkey ESC line that ubiquitously and stably expresses tau-GFP. First, we derived a new line of rhesus monkey ESC (LYON-ES1) that show marker expression and cell cycle characteristics typical of primate ESCs. LYON-ES1 cells are pluripotent, giving rise to derivatives of the three germ layers in vitro and in vivo through teratoma formation. They retain all their undifferentiated characteristics and a normal karyotype after prolonged culture. Using lentiviral infection, we then generated a monkey ESC line stably expressing tau-GFP that retains all the characteristics of the parental wild-type line and is clonogenic. We show that neural precursors derived from the tau-GFP ESC line are multipotent and that their fate can be precisely mapped in vivo after grafting in the adult rat brain. Disclosure of potential conflicts of interest is found at the end of this article