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Changes in thalamic dopamine innervation in a progressive Parkinson's disease model in monkeys.

ABSTRACT: BACKGROUND:Dopamine loss beyond the mesostriatal system might be relevant in pathogenic mechanisms and some clinical manifestations in PD. The primate thalamus is densely and heterogeneously innervated with dopaminergic axons, most of which express the dopamine transporter, as does the nigrostriatal system. We hypothesized that dopamine depletion may be present in the thalamus of the parkinsonian brain and set out to ascertain possible regional differences. METHODS:The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was administered to adult macaque monkeys using a slow intoxication protocol. The treated macaques were classified into 2 groups according to their motor status: nonsymptomatic and parkinsonian. Dopamine innervation was studied with immunohistochemistry for the dopamine transporter. Topographic maps of the dopamine transporter-immunoreactive axon distribution were generated and the total length and length density of these axons stereologically estimated using a 3-dimensional fractionator. RESULTS:Parkinsonian macaques exhibited lower dopamine transporter-immunoreactive axon length density than controls in mediodorsal and centromedian-parafascicular nuclei. Dopamine denervation in the mediodorsal nucleus was already noticeable in nonsymptomatic macaques and was even greater in parkinsonian macaques. Reticular nucleus dopamine transporter-immunoreactive axon length density presented an inverse pattern, increasing progressively to the maximum density seen in parkinsonian macaques. No changes were observed in ventral thalamic nuclei. Dopamine transporter-immunoreactive axon maps supported the quantitative findings. CONCLUSIONS:Changes in the dopamine innervation of various thalamic nuclei are heterogeneous and start in the premotor parkinsonian stage. These changes may be involved in some poorly understood nonmotor manifestations of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Monje MHG

PROVIDER: S-EPMC7154739 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Changes in thalamic dopamine innervation in a progressive Parkinson's disease model in monkeys.

Monje Mariana H G MHG Blesa Javier J García-Cabezas Miguel Ángel MÁ Obeso José A JA Cavada Carmen C

Movement disorders : official journal of the Movement Disorder Society 20191204 3

<h4>Background</h4>Dopamine loss beyond the mesostriatal system might be relevant in pathogenic mechanisms and some clinical manifestations in PD. The primate thalamus is densely and heterogeneously innervated with dopaminergic axons, most of which express the dopamine transporter, as does the nigrostriatal system. We hypothesized that dopamine depletion may be present in the thalamus of the parkinsonian brain and set out to ascertain possible regional differences.<h4>Methods</h4>The toxin 1-met ...[more]

PMID: 31800134

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Project description:In both Parkinson's disease (PD) patients and MPTP-treated non-human primates, there is a profound neuronal degeneration of the intralaminar centromedian/parafascicular (CM/Pf) thalamic complex. Although this thalamic pathology has long been established in PD (and other neurodegenerative disorders), the impact of CM/Pf cell loss on the integrity of the thalamo-striatal glutamatergic system and its regulatory functions upon striatal neurons remain unknown. In the striatum, cholinergic interneurons (ChIs) are important constituents of the striatal microcircuitry and represent one of the main targets of CM/Pf-striatal projections. Using light and electron microscopy approaches, we have analyzed the potential impact of CM/Pf neuronal loss on the anatomy of the synaptic connections between thalamic terminals (vGluT2-positive) and ChIs neurons in the striatum of parkinsonian monkeys treated chronically with MPTP. The following conclusions can be drawn from our observations: (1) as reported in PD patients, and in our previous monkey study, CM/Pf neurons undergo profound degeneration in monkeys chronically treated with low doses of MPTP. (2) In the caudate (head and body) nucleus of parkinsonian monkeys, there is an increased density of ChIs. (3) Despite the robust loss of CM/Pf neurons, no significant change was found in the density of thalamostriatal (vGluT2-positive) terminals, and in the prevalence of vGluT2-positive terminals in contact with ChIs in parkinsonian monkeys. These findings provide new information about the state of thalamic innervation of the striatum in parkinsonian monkeys with CM/Pf degeneration, and bring up an additional level of intricacy to the consequences of thalamic pathology upon the functional microcircuitry of the thalamostriatal system in parkinsonism. Future studies are needed to assess the importance of CM/Pf neuronal loss, and its potential consequences on the neuroplastic changes induced in the synaptic organization of the thalamostriatal system, in the development of early cognitive impairments in PD.

Project description:In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Project description:The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring dopamine neurons in Parkinson's disease.

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Changes in thalamic dopamine innervation in a progressive Parkinson's disease model in monkeys.

Publications

Changes in thalamic dopamine innervation in a progressive Parkinson's disease model in monkeys.

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