Ablation of the tail of the ventral tegmental area compensates symptoms in an experimental model of Parkinson's disease

Parkinson's disease is a neurodegenerative disorder partly caused by the loss of the dopamine neurons of the nigrostriatal pathway. It is accompanied by motor as well as non-motor symptoms, including pain and depression. The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) is a GABAergic mesopontine structure that acts as a major inhibitory brake for the substantia nigra pars compacta (SNc) dopamine cells, thus controlling their neuronal activity and related motor functions. The present study tested the influence of suppressing this tVTA brake on motor and non-motor symptoms in a rat model of Parkinson's disease. Using behavioral approaches, we showed that male Sprague-Dawley rats with bilateral and partial 6-hydroxydopamine SNc lesion displayed motor impairments in the rotarod test, impairments that were no more present following a co-lesion of the tVTA. Using a larger set of behavioral tests, we then showed that such SNc lesion also led to non-motor symptoms, including lower body weight, lower mechanical nociceptive thresholds in the forceps test and lower thermal nociceptive thresholds in the incremented hot-plate test, and a decreased sucrose preference in a 2-bottle choice paradigm. The excitotoxic co-lesion of the tVTA led to compensation of body weight, mechanical nociceptive thresholds and anhedonia-like behavior. These findings illustrate the major influence that the tVTA exerts on the dopamine system, modulating the motor and non-motor symptoms related to a partial loss of dopamine cells

Dopamine Transporter Binding Is Unaffected by L-DOPA Administration in Normal and MPTP-Treated Monkeys

BACKGROUND: Radiotracer imaging of the presynaptic nigrostriatal dopaminergic system is used to assess disease progression in Parkinson's disease (PD) and may provide a useful adjunct to clinical assessment during therapeutic trials of potential neuroprotective agents. Several clinical trials comparing dopamine agonists to L-DOPA or early vs. late L-DOPA have revealed differences between clinical assessment and imaging of the presynaptic dopaminergic system, hence questioning the comparability of these measures as neuroprotection outcome variables. Thus, results of these studies may have been affected by factors other than the primary biological process investigated. METHODOLOGY/PRINCIPAL FINDINGS: We tested the possibility that L-DOPA might interfere with DAT binding. Post-mortem DAT binding was conducted in normal and MPTP-treated macaque monkeys that were administered L-DOPA, acutely or chronically. In parallel, DAT SPECT was conducted in MPTP-treated animals that were administered chronic L-DOPA. [99mTc]TRODAT-1 SPECT binding was similarly reduced in all MPTP monkeys regardless of L-DOPA treatment. L-DOPA had no significant effect on post-mortem DAT binding either in saline or in MPTP-lesioned animals. CONCLUSIONS/SIGNIFICANCE: These data indicate that L-DOPA does not induce modifications of DAT expression detectable by SPECT of by DAT binding autoradiography, suggesting that differences between clinical assessment and radiotracer imaging in clinical trials may not be specifically related to L-DOPA treatment

Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia

Background: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP- protein kinase A and of the Rasextracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results: We here studied, in the gold-standard non-human primate model of Parkinson’s disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure

Unexpected toxicity of very low dose MPTP in mice: A clue to the etiology of Parkinson's disease?

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Lack of spontaneous age-related brain pathology in Octodon degus: a reappraisal of the model

International audienceNeurodegenerative diseases are characterized by the degeneration of specific brain areas associated with accumulation of disease-related protein in extra- or intra-cellular deposits. Their preclinical investigations are mostly based on genetically-engineered animals. Despite their interest, these models are often based on high level of disease-related protein expression, thus questioning their relevance to human pathology and calling for the alternate use of ecological models. In the past few years, Octodon degus has emerged as a promising animal model displaying age-dependent Alzheimer's disease-related pathology. As neurodegenerative-related proteins often co-deposit in the brain of patients, we assessed the occurrence of α-synuclein-related pathology in this model using state-of-the-art immunohistochemistry and biochemistry. Despite our efforts and in contrast with previously published results, our study argues against the use of Octodon degus as a suitable natural model of neurodegenerative disorder as we failed to identify either Parkinson's disease- or Alzheimer's disease-related brain pathologies

Early prenatal exposure to MPTP does not affect nigrostrial neurons in macaque monkey

International audienceThe discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that induces parkinsonism in both human and primate, has prompted the search for environmental toxins potentially responsible for idiopathic Parkinson's disease (PD). The present study reports the ultimate effects of MPTP intoxication of a female macaque monkey, which unraveled to be pregnant after parkinsonism had developed, upon its fetus. Detailed examination of the offpsring nigrostriatal pathway showed that tyrosine hydroxylase immunoreactivity in caudate-putamen nuclei and substantia nigra compacta (SNc) was not different from an age-matched control. Biochemical analysis of the tissue content of dopaminergic markers further suggested modification of metabolism in the MPTP-exposed monkey. These data suggest that early prenatal intoxication does not destroy nigrostriatal neurons, most likely because dopamine neurons had not developed yet when exposed to MPTP. Synapse 70:52-56, 2016. © 2015 Wiley Periodicals, Inc

Systemic scAAV9 variant mediates brain transduction in newborn rhesus macaques

International audienceTransgenic macaques would allow to study brain function and diseases. We report that an engineered adeno-associated virus serotype 9 variant (scAAV9) injected intravenously in newborn rhesus macaques results in efficient, exclusively-neuronal and widespread transduction of the brain. The present data pave the way to large-scale genetic modelling of brain diseases in the rhesus macaque

In vivo electrophysiological validation of DREADD‐based modulation of pallidal neurons in the non‐human primate

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Coordinated reset has sustained aftereffects in Parkinsonian monkeys.

Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients. ANN NEUROL 2012;72:816-820

Immediate-early gene expression in structures outside the basal ganglia is associated to l-DOPA-induced dyskinesia.

International audienceLong-term l-3,4-dihydroxyphenylalanine (l-DOPA) treatment in Parkinson's disease (PD) leads to l-DOPA-induced dyskinesia (LID), a condition thought to primarily involve the dopamine D1 receptor-expressing striatal medium spiny neurons. Activation of the D1 receptor results in increased expression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus. However, several dopaminoceptive structures in the brain that are likely to be affected by the exogenously produced DA have received little attention although they might play a key role in mediating those l-DOPA-induced abnormal behaviours. ΔFosB, ARC, FRA2 and Zif268 IEGs expression patterns were thus characterised, using unbiased stereological methods, in the whole brain of dyskinetic and non-dyskinetic rats to identify brain nuclei displaying a transcriptional response specifically related to LID. Within the basal ganglia, the striatum and the substantia nigra pars reticulata showed an increased expression of all four IEGs in dyskinetic compared to non-dyskinetic rats. Outside the basal ganglia, there was a striking increased expression of the four IEGs in the motor cortex, the bed nucleus of the stria terminalis, the dorsal hippocampus, the pontine nuclei, the cuneiform nucleus and the pedunculopontine nuclei. Moreover, the zona incerta and the lateral habenula displayed an overexpression of ΔFosB, ARC and Zif268. Among these structures, the IEG expression in the striatum, the bed nucleus of the stria terminalis, the lateral habenula, the pontine nuclei and the cuneiform nucleus correlate with LID severity. These results illustrate a global transcriptional response to a dyskinetic state in the whole brain suggesting the possible involvement of these structures in LID