Substantia nigra

Résumé

La substantia nigra (substance noire, dite aussi locus niger) est un noyau du système nerveux situé au niveau du mésencéphale et du diencéphale sus-jacent, à la base des crus cerebri et ventralement par rapport au tegmentum. Son nom provient de la couleur des cellules qui composent ce noyau en raison de la présence de neuromélanine. La substantia nigra se subdivise en deux parties principales, la pars compacta d'une part et la pars reticulata d'autre part. Fonction La substantia nigra pars compacta est composée de neurones dopaminergiques. Ces neurones afférent d'autres structures du cerveau : le noyau caudé et le putamen, qui font partie d'un ensemble nommé le striatum. Ceci permet une libération de dopamine sur ces structures. La substantia nigra pars reticulata est composée de neurones GABAergiques. Ces neurones afférent notamment le globus pallidus, le thalamus, le colliculus supérieur, et le noyau pédonculo-pontin. La substantia nigra participe ainsi au contrôle de

Source officielle

https://fr.wikipedia.org/wiki/Substantia_nigra

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Publications associées (60)

Publications associées

Chargement

Personnes associées (9)

Personnes associées

Chargement

Unités associées (4)

Unités associées

Chargement

Concepts associés (58)

Concepts associés

Chargement

Cours associés (11)

Cours associés

Chargement

Séances de cours associées (22)

Séances de cours associées

Chargement

A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions

Vignayanandam Ravindernath Muddapu

In order to understand the link between substantia nigra pars compacta (SNc) cell loss and Parkinson's disease (PD) symptoms, we developed a multiscale computational model that can replicate the symptoms at the behavioural level by incorporating the key cellular and molecular mechanisms underlying PD pathology. There is a modelling tradition that links dopamine to reward and uses reinforcement learning (RL) concepts to model the basal ganglia. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it in the RL-based behavioural model, which simulates the arm reaching task. Our results successfully replicated the impact of SNc cell loss and levodopa (L-DOPA) medication on reaching performance. It also shows the side effects of medication, such as wearing off and peak dosage dyskinesias. The model demonstrates how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD. It was able to predict the optimum L-DOPA medication dosage for varying degrees of cell loss. The proposed model has a potential clinical application where drug dosage can be optimised as per patient characteristics.

FRONTIERS MEDIA SA2022

Chargement

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The resulting failure of the nigrostriatal pathway leads to profound dopamine deficiency, causing bradykinesia, tremor, rigidity and postural imbalance. The current therapeutic options for this disabling disorder remain symptomatic and are devoid of any impact on the neurodegeneration process per se. The development of neuroprotective and regenerative strategies constitute therefore an important challenge, in order to halt and possibly reverse the loss of the nigrostriatal pathway in PD. In the present study, we have investigated two different approaches to protect or restore the nigrostriatal dopaminergic system in rodent models of PD. In the first part, we examined the potential of a spontaneous dominant mutation in mice called slow Wallerian degeneration (Wlds) to confer protection of the dopaminergic pathway against the catecholaminergic toxin 6-hydroxydopamine (6-OHDA). Interestingly, the Wlds fusion protein proved capable to provide functional preservation of the nigrostriatal dopaminergic terminals. The observed Wlds-mediated protection of dopaminergic axons might help to further elucidate the mechanisms leading to the loss of dopamine axons in PD and conduct to the development of new therapeutic modalities for this disorder. In the second approach, we assessed the protective and regenerative potential of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) delivered via capsules in a rat model of PD. GDNF delivery by encapsulated cells resulted in regeneration of dopaminergic fibers and behavioral improvement in a bilateral 6-OHDA model in the rat. Importantly, GDNF withdrawal did not affect the morphological and behavioral effects in our model. The sustainability of the striatal dopaminergic reinnervation and behavioral performances following GDNF washout has important implications. It suggests that GDNF needs to be delivered only transiently to allow prolonged functional regenerative effect, rendering the retrievable capsules attractive to achieve this purpose in PD patients. The promising potential of GDNF to protect and regenerate the nigrostriatal pathway has been hampered by several recent studies showing that long-term GDNF overexpression in the intact nigrostriatal pathway induces a downregulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. In the last part of this work, we aimed therefore at investigating the effect of GDNF on other enzymes of dopamine biosynthesis, using a lentiviral vector-mediated gene transfer technique, in order to overexpress GDNF in rat striatum. We showed that in addition to TH downregulation, long-term GDNF overexpression results in tetrahydrobiopterin upregulation, and importantly in dopamine decrease in the intact striatum of rats. In a clinical perspective, dose and treatment duration of the trophic factor will thus have to be established and optimized with the aim of achieving beneficial neuroprotective effects while circumventing undesirable pharmacologic effects on dopamine biosynthesis. The discovery of new protective molecules such as the Wlds protein, as well as a better understanding of cellular effects of the promising neurotrophic factor GDNF might lead to the establishment of neuroprotective and neuroregenerative strategies for PD in the close future.

EPFL2005

Chargement

Although several genetic factors have been directly associated to Parkinsonâs disease (PD), no single pathway has emerged to explain the etiology of this neurodegenerative disease. To further understand the cause of Parkinsonâs disease (PD), it is therefore important to deter-mine if and which functional interactions exist between gene products linked to this complex brain disorder. Mutations in the gene encoding the E3 ubiquitin ligase Parkin are associated to autosomal recessive PD with early onset. Although the Parkin protein carries out various critical func-tions in the cell, its role in mitochondria quality control, by inducing the autophagic degrada-tion of damaged mitochondria, has attracted a lot of attention. Furthermore, Parkin has been found to control the transcription of PGC-1Î±, a master regulator of mitochondrial biogenesis. Based on the important role that mitochondria are considered to play in PD, and the evi-dence for the coordinated expression of Parkin and PGC-1Î±, we sought to explore in neurons how these two factors functionally interact to regulate mitochondria turnover and quality control. In cortical neuronal cultures, we found that Parkin and PGC-1Î± have synergistic effects on mitochondrial biogenesis, and that the co-expression of these two factors leads to a dramatic increase in the number of mitochondria per cell. We further explored the effects of these fac-tors on the mitochondrial function. Parkin was shown to enhance the maximal respiration rate of neurons exposed to a mitochondrial uncoupling agent only in the presence of PGC-1Î±. Consistent with this effect, the co-expression of Parkin and PGC-1Î± leads to rapid recovery of the mitochondrial membrane potential following mitochondrial uncoupling. Next, we explored the molecular changes, which may underlie the cooperation between Par-kin and PGC-1Î±. The expression of Tfam, an important mitochondrial transcription factor, was found to be controlled synergistically by these two factors. Furthermore, PGC-1Î± en-hances the turnover of Mfn2, a key ubiquitylation target of Parkin. This result suggests that part of the functional interaction between PGC-1Î± and Parkin may be mediated via the co-regulation of Mfn2, a critical factor in mitochondrial physiology which controls the dynamics of mitochondria as well as their association with the endoplasmic reticulum (ER). In the rat substantia nigra, Parkin activity has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1Î± is in-duced. Ultrastructural analysis shows that the conjunction of these two factors controls the density of mitochondria and their interaction with the ER. In PGC-1Î±-expressing dopamin-ergic neurons, the co-expression of mutated variants of Parkin associated with familial PD leads to accelerated degeneration. Overall, this study shows that Parkin, in conjunction with the transcription co-regulator PGC-1Î±, may play an important role in modulating the biogenesis of mitochondria as well as the quality control of this organelle. In nigral dopaminergic neurons which may critically depend on the mitochondria for their function and survival, the functional interaction be-tween these two factors should be further explored in the context of PD.

EPFL2016

Chargement

EPFL2016

EPFL2005