Mon projet de thèse porte sur les altérations de la réponse dopaminergique dans la maladie de Parkinson (MP). Les troubles moteur de la MP sont améliorés par la L-Dopa (précurseur de la dopamine) et/ou les agonistes dopaminergiques. Cependant, ces traitements engendrent des effets secondaires moteurs (les dyskinésies) et non-moteurs. Ainsi, environ 15% des patients atteints de la MP sous agoniste dopaminergique vont présenter des addictions comportementales avec un syndrome de sevrage, et 3 à 4% des patients traités à la L-Dopa ou à l’apomorphine développent une prise compulsive de médicament. Ces complications motrices et non-motrices des thérapies dopaminergiques, font intervenir une dysfonction du réseau des ganglions de la base. Ce travail a exploré le lien entre l’accumulation de la protéine ΔFosB et les modifications des propriétés électriques des neurones impliqués dans l’expression des dyskinésies, en utilisant une technique d’inactivation sélective des neurones exprimant ΔFosB dans le striatum de rat et de singe. Mes travaux ont également évalué chez le singe, comment la L-Dopa modifiait les taux de monoamines pour engendrer les dyskinésies. Ceci m’a permis de montrer que les structures cognitives et limbiques sont elles aussi affectées et qu’elles pourraient être directement impliqués dans les dyskinésies. Sur cette base, j’ai étudié la physiopathologie des troubles du traitement de la récompense et démontré que la L-Dopa, le traitement de référence de la MP, peut acquérir des propriétés récompensantes proches de celles de la cocaïne dans un modèle rat de la MP par surexpression de gène codant pour l’α-synucléine mutée. J’ai également utilisé des procédures d’auto-administration intraveineuse chez le rat pour montrer que le Pramipexole, un agoniste dopaminergique couramment utilisé dans le traitement de la MP, possédait des propriétés renforçantes. Ceci m’a permis de souligner que des susceptibilités individuelles sous-tendraient le développement de ces addictions comportementales. Ces découvertes ont ensuite été complétées par des expériences montrant que les altérations liées à la MP modifiaient le trait d’impulsivité des rats et que les traitements dopaminergiques pouvaient empirer ces changements. / My PhD focused on the alterations of the dopaminergic response in Parkinson’s disease (PD). Motor impairments in PD are reduced by the dopamine precursor L-Dopa and/or dopamine agonists. However, these medications elicit motor (dyskinesia) and non-motor side-effects. Up to 15% of PD patients under dopamine agonists experience behavioral addictions and withdrawal syndrome, and 3-4% of patients treated with L-Dopa or apomorphine exhibit compulsive medication intake. Both motor and non-motor complications of dopaminergic therapies involve dysfunctions in the basal ganglia network. I explored the link between deltaFosB protein accumulation and the cellular electrical properties that trigger dyskinesia by using a cell-type specific inactivation of FosB expressing neurons of the striatum in rats and monkeys. I have also investigated in monkeys how L-Dopa modifies monoaminergic functions to mediate dyskinesia and demonstrated that limbic/cognitive structures are identically affected providing a basis for a non-motor component involved in motor side effects in PD. From this, I studied the pathophysiology of addiction-like disorders by revealing that L-Dopa, the most widely-used treatment for PD, can acquire rewarding properties similar to cocaine in a viral-mediated rat model of PD. I also used self-administration procedures in rats to demonstrate the rewarding properties of Pramipexole, a dopamine agonist commonly use in the treatment of PD, and identified individual susceptibilities in the development of addiction-like disorders. These findings were followed by additional work showing that PD alterations modify the impulsivity trait of rats and that medication might worsen these changes.

Le contrôle cognitif de l’action est un processus permettant de supprimer un comportement inapproprié au profit d’une action dirigée par l’intention. Il est particulièrement important en situation de conflit où l’expression de comportements alternatifs entre en compétition. Ce processus est largement soutenu par des réseaux cortico-sous-corticaux frontaux dont le bon fonctionnement est impacté par la maladie de Parkinson. Nous nous sommes intéressés au rôle de ces différentes structures cérébrales dans le contrôle cognitif de l’action en s’appuyant sur l’impact de la maladie de Parkinson et de ses traitements. Plus précisément, nous avons discuté des aspects dynamiques de sélection et de suppression des réponses impulsives tel que proposé par le modèle d’activation-suppression dans le cas de réponses oculaires. Nous avons donc adapté une tâche expérimentale de conflit classique, la Simon task, utilisant les mouvements oculaires, et validé son utilisation de notre dans le cadre de ce modèle. Les travaux suivant ont porté sur l’impact de divers facteurs sur ce processus. Nous avons montré que le vieillissement normal exacerbe la sélection impulsive des actions qui pourrait être compensée par la mise en place d’une inhibition sélective plus efficace. Ces résultats sont en accord avec de récentes théories proposant le recrutement plus important des structures préfrontales afin de pallier aux déficits cognitifs entrainés par le vieillissement. Nos résultats ont également indiqué que la maladie de Parkinson entraine une augmentation très importante de la sélection impulsive des actions ce que nous attribuons au dysfonctionnement des boucles cortico-sous-corticales causé par la maladie. Finalement, nous nous sommes intéressés à l’impact de la stimulation cérébrale profonde du noyau subthalamique. Nos résultats préliminaires n’ont pas montré d’effet de ce traitement sur les capacités de contrôle cognitif de l’action. Nous discutons l’ensemble de nos résultats à la lumière des travaux majeurs portant sur les structures cérébrales impliquées dans le contrôle cognitif de l’action et proposons plusieurs perspectives de recherches pouvant avoir un impact fondamental ou clinique. / Cognitive action control is a process that allows suppressing an inappropriate behavior to the benefit of an intentionally-guided action. It is particularly important in situations of conflict when alternative behaviors compete for their expression. This process relies mostly on cortical-subcortical networks which functioning is impaired by Parkinson’s disease. We were interested in the role of these different brain structures in cognitive action control by focusing on the impact of Parkinson’s diseases and its treatments. More precisely, we addressed the dynamic aspects of impulsive action selection and suppression as proposed by the recent activation-suppression model regarding oculomotor responses. We thus adapted a classical experimental conflict task, the Simon task, using eye movements, and validated its use within the context of the activation-suppression model. Our further work focused on the impact of several factors on cognitive action control. We showed that normal aging enhances impulsive action selection that could be compensated for by the set-up of a more efficient selective inhibition. These results are in accordance with recent theories proposing that age-related cognitive deficits are compensated for by an increased recruitment of prefrontal structures. Our results also revealed that Parkinson’s disease results in a strong increase in impulsive action selection which we attribute to the impairment of the cortical-basal ganglia loops. Finally, we were interested by the impact of deep brain stimulation of the subthalamic nucleus. Our preliminary results revealed no effect of this treatment on cognitive action control. We discuss all of our results according to previous researches on the brain structures involved in cognitive action control and we propose several perspective that can have a fundamental or clinical impact.

La maladie de Parkinson est une affection neurodégénérative principalement associée à la dégénérescence progressive des neurones dopaminergiques du mésencéphale provoquant un dysfonctionnement des noyaux gris centraux. En parallèle de symptômes moteurs bien connus, cette affection entraîne également l’émergence de déficits émotionnels impactant en outre l’expression et la reconnaissance des émotions. Ici, se pose la question d’un déficit de reconnaissance des émotions faciales chez les patients parkinsoniens lié au moins en partie aux troubles moteurs. En effet, selon les théories de simulation des émotions, copier les émotions de l’autre nous permettrait de mieux les reconnaître. Ce serait le rôle du mimétisme facial. Automatique et inconscient, ce phénomène est caractérisé par des réactions musculaires congruentes à l’émotion exprimée par autrui. Dans ce contexte, une perturbation des capacités motrices pourrait conduire à une altération des capacités de reconnaissance des émotions. Or, l’un des symptômes moteurs les plus fréquents dans la maladie de Parkinson, l’amimie faciale, consiste en une perte de la mobilité des muscles du visage. Ainsi, nous avons examiné l’efficience du mimétisme facial dans la maladie de Parkinson, son influence sur la qualité du processus de reconnaissance des émotions, ainsi que l’effet du traitement dopaminergique antiparkinsonien sur ces processus. Pour cela, nous avons développé un paradigme permettant l’évaluation simultanée des capacités de reconnaissance et de mimétisme (corrugator supercilii, zygomaticus major et orbicularis oculi) d’émotions exprimées sur des visages dynamiques (joie, colère, neutre). Cette expérience a été proposée à un groupe de patients parkinsoniens comparé à un groupe de sujets sains témoins. Nos résultats supportent l’hypothèse selon laquelle le déficit de reconnaissance des émotions chez le patient parkinsonien pourrait résulter d’un système « bruité » au sein duquel le mimétisme facial participerait. Cependant, l’altération du mimétisme facial dans la maladie de Parkinson et son influence sur la reconnaissance des émotions dépendraient des muscles impliqués dans l’expression à reconnaître. En effet, ce serait davantage le relâchement du corrugateur plutôt que les contractions du zygomatique ou de l’orbiculaire de l’œil qui nous aiderait à bien reconnaître les expressions de joie. D’un autre côté, rien ne nous permet ici de confirmer l’influence du mimétisme facial sur la reconnaissance des expressions de colère. Enfin, nous avons proposé cette expérience à des patients en condition de traitement habituel et après une interruption temporaire de traitement. Les résultats préliminaires de cette étude apportent des éléments en faveur d’un effet bénéfique du traitement dopaminergique tant sur la reconnaissance des émotions que sur les capacités de mimétisme. L’hypothèse d’un effet bénéfique dit « périphérique » sur la reconnaissance des émotions par restauration du mimétisme facial reste à tester à ce jour. Nous discutons l’ensemble de ces résultats selon les conceptions récentes sur le rôle des noyaux gris centraux et sous l’angle de l’hypothèse de feedback facial. / Parkinson’s disease is a neurodegenerative condition primarily resulting from a dysfunction of the basal ganglia following a progressive loss of midbrain dopamine neurons. Alongside the well-known motor symptoms, PD patients also suffer from emotional disorders including difficulties to recognize and to produce facial emotions. Here, there is a question whether the emotion recognition impairments in Parkinson’s disease could be in part related to motor symptoms. Indeed, according to embodied simulation theory, understanding other people’s emotions would be fostered by facial mimicry. Automatic and non-conscious, facial mimicry is characterized by congruent valence-related facial responses to the emotion expressed by others. In this context, disturbed motor processing could lead to impairments in emotion recognition. Yet, one of the most distinctive clinical features in Parkinson’s disease is facial amimia, a reduction in facial expressiveness. Thus, we studied the ability to mimic facial expression in Parkinson’s disease, its effective influence on emotion recognition as well as the effect of dopamine replacement therapy both on emotion recognition and facial mimicry. For these purposes, we investigated electromyographic responses (corrugator supercilii, zygomaticus major and orbicularis oculi) to facial emotion among patients suffering from Parkinson’s disease and healthy participants in a facial emotion recognition paradigm (joy, anger, neutral). Our results showed that the facial emotion processing in Parkinson’s disease could be swung from a normal to a pathological, noisy, functioning because of a weaker signal-to-noise ratio. Besides, facial mimicry could have a beneficial effect on the recognition of emotion. Nevertheless, the negative impact of Parkinson’s disease on facial mimicry and its influence on emotion recognition would depend on the muscles involved in the production of the emotional expression to decode. Indeed, the corrugator relaxation would be a stronger predictor of the recognition of joy expressions than the zygomatic or orbicularis contractions. On the other hand, we cannot conclude here that the corrugator reactions foster the recognition of anger. Furthermore, we proposed this experiment to a group of patients under dopamine replacement therapy but also during a temporary withdrawal from treatment. The preliminary results are in favour of a beneficial effect of dopaminergic medication on both emotion recognition and facial mimicry. The potential positive “peripheral” impact of dopamine replacement therapy on emotion recognition through restoration of facial mimicry has still to be tested. We discussed these findings in the light of recent considerations about the role of basal ganglia-based circuits and embodied simulation theory ending with the results’ clinical significances.

Le système visuel humain est complexe par son organisation anatomique et par son fonctionnement incomplètement élucidé. Il est fonctionnellement divisé en deux systèmes. Le premier système est destiné à la vision consciente communément appelée voie visuelle principale ou en anglais « image forming visual pathways ». Le second, appelé système secondaire ou accessoire, n’apporte pas d’information visuelle consciente, il est dit « non image forming visual pathway ». Ce dernier apporte à notre cerveau une information sur l’environnement telle que la sensation jour/nuit. Ses fonctions sont sous-tendues par l’afflux d’informations rétiniennes non visuelles sur des structures de l’hypothalamus comme le noyau supra-chiasmatique. Les deux systèmes visuels ont un substratum anatomique complexe faisant intervenir de nombreuses structures anatomiques au sein des différents étages du cerveau cortical et sous-cortical comme les noyaux gris centraux dits « Basal Ganglias » (BG). Le système visuel secondaire intervient aussi comme une structure de contrôle des mouvements oculomoteurs tels que la poursuite ou les saccades nécessaires pour explorer notre environnement. Ainsi les saccades oculomotrices sont sous le contrôle modulateur des BG. De ce fait l’étude des saccades apparait comme un très bon modèle pour explorer le fonctionnement du système extrapyramidal au cours des maladies neuro-dégénératives. Les connaissances actuelles sur ce système de contrôle des saccades proviennent essentiellement des études sur le primate non humain et sur des observations cliniques chez l’homme au cours de pathologies dégénératives ou toxiques des BG. L’observation des structures anatomiques, en particulier du réseau de la substance blanche cérébrale qui supporte les connections axonales, n’est pas accessible à l’imagerie clinique de routine. Pour décrire et étudier ces réseaux de connections, la notion de connectomique a été introduite il y a un dizaine d’années. Dans ce travail, nous nous sommes donné l’objectif de décrire le connectome des saccades oculomotrices sur un plan structurel. Nous avons exploré les structures sous-corticales intervenant dans le contrôle des saccades comme les BG, le colliculus supérieur et le pulvinar. Pour ce faire, nous avons utilisé l’imagerie IRM structurelle en diffuseur de tension (DTI) chez deux groupes de patients présentant une maladie neuro-dégénérative : un groupe souffrant de maladie de Parkinson chez qui une atteinte des BG et une dysfonction des saccades sont reconnues, et un groupe de trembleurs essentiels reconnu pour ne pas présenter de dysfonction des saccades et chez qui les BG sont épargnés. Le résultat de ce travail a permis pour la première fois une description in vivo du connectome des saccades chez l’Homme. Il a de plus montré des différences dans la structure du connectome dans les deux groupes de patients. Une meilleure connaissance de ce connectome pourrait permettre de mieux comprendre certains troubles oculomoteurs et aussi de suivre l’évolution de certaines maladies neurodegeneratives. / Visual system is complex by its anatomy and its function. Neuro-anatomists have been interested in understanding the link between the visual pathways and the brain for centuries. Classical brain fixation and dissection methods were used to describe the visual pathways identifiable macroscopically. Non–image visual pathway, particularly the part involves in saccadic eye movements network in human is still not mastered. Our current knowledge in SCM is based on animal studies, anatomic dissection and brain histopathology examination of specimens from patients with clinical basal ganglia (BG) disorders. Saccadic eye movements (SCM) are under the control of the basal ganglia (BG) and SCM circuitry within the BG represents a good model for studying pathology in the extra-pyramidal system. The diagnosis of Parkinson’s disease (PD), which affects SEM and its distinction from non-dopaminergic, essential tremor (ET) where SEM are not impaired can be challenging and still relies on clinical observations. Diffusion tensor imaging and fiber tractography (DTI-FT), a new MRI technology, can be used to evaluate the presence and integrity of white matter tracts using directional diffusion patterns of water. The purpose of this study is to use DTI-FT to analyse SEM networks within BG and compare the SEM neural pathways or connectome of patients clinically diagnosed with PD and ET. To date, there are no studies, using DTI-FT for the extensive exploration of non-image visual pathways and SCM circuits, notably the deep brain connections. For this goal, we introduced the concept of SCM connectomes, derived from the general concept of connectome. Our study used structural MRI to identify nuclei and fascicles of the SCM connectome in PD and ET patients; imageries were acquired in routine clinical conditions fitted for DBS surgery. We found a reduction of the fiber number in two fascicles of the connectome in PDcompared to ET group.

Ce travail porte sur l’étude fonctionnelle de deux gènes préférentiellement exprimés dans deux régions du cerveau touchées par des pathologies neurodégénératives : Capucine, un marqueur du striatum, structure qui dégénère au cours de la maladie de Huntington et Agpat4, un marqueur de l’aire tegmentaire ventrale et de la substance noire compacte, dont les neurones dopaminergiques sont sélectivement atteints lors de la maladie de Parkinson. Des lignées de souris invalidées pour ces gènes ont été générées au laboratoire et au cours de ma thèse j’ai procédé à leur caractérisation. L’expression striatale du gène de la Capucine étant significativement diminuée dans des modèles murins de la maladie de Huntington, nous avons souhaité évaluer son rôle éventuel dans la pathogenèse de cette maladie. Pour ce faire, nous avons examiné, dans le cadre d’une collaboration, l’effet du knock-out et de la surexpression du gène de la Capucine sur la vulnérabilité des neurones striataux à un fragment de la Huntingtine mutée dans un modèle murin de la maladie de Huntington. Les données montrent que la Capucine n’a pas d’effet significatif sur la toxicité du fragment de la Huntingtine mutée dans le modèle étudié.La protéine Agpat4 présente des homologies de séquence avec des acyltransférases impliquées dans le métabolisme des phosphoglycérides. J’ai réalisé des études d’expression par différentes techniques de biologie moléculaire qui montrent que le gène d’Agpat4 est exprimé dans la plupart des tissus catécholaminergiques. Pour déterminer l’activité endogène d’Agpat4 et son rôle physiologique dans les tissus où elle est exprimée, j’ai comparé le métabolome de tissus de souris invalidées pour le gène d’Agpat4 et sauvages par chromatographie en phase liquide couplée à la spectrométrie de masse. Mes résultats indiquent que l’invalidation du gène d’Agpat4 perturbe le métabolisme non seulement de différentes classes de lipides, notamment les lysophosphatidyléthanolamines, mais aussi celui des catécholamines. / This work concerns the functional study of two genes preferentially expressed in two brain regions affected by neurodegenerative diseases: Capucine, a marker of the striatum, a structure that degenerates in Huntington's disease and Agpat4, a marker of the ventral tegmental area and the substantia nigra pars compacta, whose dopaminergic neurons are selectively affected in Parkinson's disease. Mouse lines deficient for Capucine and Agpat4 have been generated in the laboratory and during my PhD thesis I carried out their characterization.As the striatal gene expression of Capucine is significantly reduced in mouse models of Huntington's disease, we wished to evaluate its possible role in the pathogenesis of this disease. In a collaborative work, we examined the effect of the knockout and overexpression of the Capucine gene on the vulnerability of striatal neurons to a mutant Huntingtin fragment in a mouse model of Huntington’s disease. The data show that Capucine has no significant effect on the toxicity of the mutant Huntingtin fragment in the considered model.The Agpat4 protein has sequence homologies with acyltransferases involved in the metabolism of phosphoglycerides. I conducted expression studies using different molecular biology techniques, which showed that the Agpat4 gene is expressed in most catecholaminergic tissues. To determine the endogenous activity of Agpat4 and its physiological role in the tissues where it is expressed, I compared the metabolomes of Agpat4-deficient and wild-type mice tissues by liquid chromatography coupled with mass spectrometry. My results indicate that Agpat4 deficiency alters not only the metabolism of different lipid classes, in particular lysophosphatidylethanolamines, but also the metabolism of catecholamines.

Pacientes com doença de Parkinson (DP) apresentam diversos sintomas não motores, dentre eles, alterações cognitivas. Déficits de função executiva podem ser observados desde os estágios iniciais da DP e impactam na independência funcional e na qualidade de vida. A função executiva é essencial para a realização de atividades de vida diária, que requerem integração cognitivo-motora. A realização de atividades cotidianas depende não só do sistema motor, mas também da interpretação e do processamento sensorial/ perceptual e da seleção e do planejamento da melhor estratégia motora. Sendo assim, um grande número de atividades de vida diária pode ser afetado por déficits na função executiva em pacientes com DP. Nessas tarefas, os componentes cognitivos e motores competem por recursos atencionais, o que pode prejudicar o desempenho em um ou em ambos os componentes. Entretanto, os estudos são muito direcionados para a análise de tarefas-duplas que envolvam equilíbrio em ortostatismo e marcha, mas contemplam pouco outras tarefas motoras. Os objetivos desse estudo foram (1) comparar o desempenho de pacientes com DP com o de um grupo controle nos testes de função executiva (Trail Making Test) e de fluência verbal (fluência semântica e fonêmica e diadococinesia oral /pataka/) e (2) investigar possíveis correlações entre função executiva e fluência verbal. O estudo foi realizado de maneira transversal, em uma única sessão, em uma avaliação de cerca de 50 minutos. Quarenta pacientes com DP (idade entre 50 e 79 anos, Hoehn & Yahr entre 2 e 3) e quarenta controles (com idade e escolaridade semelhantes) foram avaliados com o Trail Making Test, a fluência verbal semântica e fonêmica e o teste de diadococinesia oral. Na parte A do TMT, os participantes conectaram círculos numerados de 1 a 25, em sequência. Na parte B, os participantes conectaram círculos alternando números e letras (1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13). No teste de fluência verbal fonêmica, foi solicitado que os participantes dissessem palavras começando com a letra F. No teste de fluência verbal semântica, os participantes disseram o maior número de animais possível, em 60 segundos. No teste de diadococinesia oral, os participantes repetiram a sequência /pataka/ o mais rápido possível. Os grupos foram comparados por meio de análises de variância e as relações entre as variáveis foram investigadas pelo teste de correlação de Pearson. A análise de variância mostrou diferenças significativas entre grupos (F1,78=10,55; p=0,002) e entre partes do Trail Making Test (F1,78=154,02; p < 0,001). A parte B apresentou tempos maiores que a parte A (p < 0,001). Pacientes com DP disseram menos palavras nos testes de fluência verbal, em comparação aos controles (p < 0,001). Pacientes com DP repetiram a sequência /pataka/ menos vezes que os controles (p=0,019). Houve forte correlação entre o teste de fluência verbal fonêmica e a parte B do Trail Making Test (valor de r=-0,874 e p=0,001) e entre a diadococinesia oral e as partes A e B do Trail Making Test (valor de r=-0,824 e p=0,001). A correlação entre a parte B do Trail Making Test, que é uma medida de função executiva e reflete a habilidade de integração cognitivo-motora e as tarefas de fluência verbal, evidencia a importância do controle motor para as tarefas de fala. A tarefa da fala fornece não somente sobrecarga cognitiva, mas também motora para pacientes com DP. Esse conhecimento é importante para a prática clínica, uma vez que é necessário detectar a natureza do acometimento e da tarefa para usá-las de maneira adequada em programas de reabilitação / Patients with Parkinson´s disease (PD) can present several non-motor symptoms, including cognitive deficits. Executive function deficits can be observed since the early stages of PD and impact on functional independence and quality of life. The executive function is essential to the activities of daily living, which require cognitive-motor integration. The performance of activities of daily living depends not only on the motor system, but also on the sensory/ perceptual interpretation and processing and the selection and planning of the best motor strategy. Therefore, many activities of daily living can be affected by deficits in the executive function in patients with PD. In such tasks, cognitive and motor components compete for attentional resources, which may impair the performance of one or both tasks. However, most studies focus on to the analysis of dual-tasks involving orthostatic balance and gait, but they do not approach other motor tasks. The objectives of this study were (1) to compare the performance of patients with PD with a control group in executive function (Trail Making Test) and verbal fluency tests (semantic and phonemic and oral diadochokinesis /pataka/) and (2) to investigate possible correlations between executive function and verbal fluency. This was a cross-sectional study and the tests were performed individually in a 50-minute single session. Forty people with PD (aged 50 - 79 years, Hoehn & Yahr 2 - 3) and forty controls (with similar age and education) were evaluated with Trail Making Test (TMT, executive function), phonemic/semantic verbal fluency and oral diadochokinesis (/pataka/) tests. In part A of Trail Making Test, participants connected circles with the numbers 1-25, in sequence. In part B, participants connected circles in a sequence with alternated numbers and letters (1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13). In the phonemic verbal fluency test, participants were instructed to say words beginning with the letter F. In the semantic verbal fluency test, participants were instructed to say out loud as many animals as they could remember, in 60 seconds. In the oral diadochokinesis test, participants were asked to say the /pataka/ sequence as fast as they could. Groups were compared by analyses of variance and the relationships between the variables were investigated by Pearson correlation tests. Analysis of variance showed significant differences between groups (F1,78=10.55; p=0.002) and between Trail Making Test parts (F1,78=154.02; p < 0.001). Part B showed longer times than part A (p < 0.001). People with PD said fewer words in both fluency tests, compared to controls (p < 0.001). People with PD repeated the sequence /pataka/ less times than controls (p=0.019). There was a strong correlation between the phonemic verbal fluency test and the part B of Trail Making Test (r=-0.874 and p=0.001) and between the oral diadochokinesis test and both parts of the Trail Making Test (r=-0.824 e p=0.001). The correlation between the part B of Trail Making Test, which is an executive function measure and reflects the cognitive-motor integration ability, and the verbal fluency tests, evidences the importance of motor control for speech tasks. Speech tasks not only provide cognitive overload, but also motor overload in patients with PD. This knowledge is important in clinical practice, in which therapists must detect the nature of the disability and the task to use this information properly in rehabilitation programs

The model of basal ganglia function proposed by Albin, Young and Penney (1989) describes two anatomically independent motor pathways, the direct and indirect. However, under normal conditions striatal dopamine (DA) is required for the expression of motor behavior, and DAergic control of the two pathways (via D1 and D2 receptors, respectively) is dependent on co-activation. We tested for a possible breakdown of D1/D2 synergism using transgenic R6/1 mice bearing the human huntingtin allele (Htt). Motor stereotypy, observed prior to the onset of HD-related symptoms, was rated on a 5-point scale following activation of: A) D1 receptors alone, B) D2 receptors alone, and C) stimulation of both D1 and D2 receptors. Results revealed that mice with the HD allele, like their WT litter mates, depend on the co-activation of the indirect and direct motor pathways to facilitate deliberate behavior.

Introdução: Existem poucos dados a respeito do diagnóstico e prognóstico de crianças com acidente vascular encefálico isquêmico (AVE-i) devido a arteriopatia/vasculopatia pós-varicela e nenhuma revisão sistemática em crianças com arteriopatia/vasculopatia transitória. Objetivos: Relatar série de casos de sete crianças com AVE-i pós-varicela focando nos aspectos clínico/laboratoriais e no desempenho neuro-cognitivo 4 anos após e realizar revisão sistemática da literatura sobre a associação entre VZV e arteriopatia/vasculopatia transitória. Métodos: Revisão sistemática-Estudos relevantes foram buscados utilizando os seguintes bancos de dados: EMBASES; Pubmed; Bireme; LILACS e Web of Science. As buscas utilizaram as seguintes palavras-chave: arteriopatia transitória / vasculopatia ou pós-varicela ou arteriopatia focal e VZV. Os descritores usados para revisão sistemática foram: Arteriopatia transitória or vasculopatia transitória or arteriopatia pós-varicela or arteriopatia focal e VZV or varicela e aplicada a estratégia de PICO; População: crianças de 1 mês a 17 anos e 11 meses, com vasculopatia/arteriopatia em sistema nervoso central; Fenômeno de Interesse: VZV até 12 meses anterior; Comparação: Vasculopatia/Arteriopatia transitória sem associação com VZV; Outcome: VZV associado a vasculopatia. Os artigos selecionados foram analisados por 2 examinadores que validaram os artigos de acordo com a escala New Castle Otawa. Um terceiro examinador resolveu discrepâncias. Série de relato de casos: envolveu 7 crianças (5 meninos e 2 meninas) de 5 serviços de emergências pediátricas na cidade de São Paulo, Brasil, que apresentaram acidente vascular encefálico isquêmico pós-varicela confirmada com ressonância magnética de encéfalo e angioressonância magnética cerebral. Foi realizado coleta de líquido cefalorraquidiano para detecção do envolvimento do VZ: dosagem de anticorpos IgG e IgM anti-VZV; reação em cadeia de polimerase para DNA viral e detecção do envolvimento do vírus herpes simples tipo 1 e tipo 2 (anticorpos IgG e IgM anti-VHS 1 e 2). Foi aplicado o PSOM-Score na admissão e 4 anos após o AVE-i. Resultados: Na revisão sistemática foram selecionados 1003 artigos sendo que no final das avaliações apenas 11 artigos com moderado nível de evidência para associação entre arteriopatia transitória e VZV foram incluídos na nossa revisão. Em relação à série de casos, os 7 pacientes, com idades variando de 1,3 anos a 4 anos, apresentaram hemiparesia ao exame físico inicial e imagem de isquemia em região submetida à irrigação da artéria cerebral média ou interna após um tempo médio de 5,1 (± 3,5) meses do quadro clínico de varicela. Em 4 pacientes (57%) foram encontradas lesões vasculares e a detecção de IgG anti VZV no liquor ocorreu em 3 pacientes (42%). Nenhum paciente apresentou exantema, febre ou presença de anticorpos anti-herpes vírus tipo 1 e 2. Somente 1 paciente apresentou alteração nos exames de trombofilia (mutação em heterozigose da protombina). Todos apresentaram melhora nos índices de escore para sequelas. Nenhum apresentou novo episódio de AVE-i. Limitacão do nosso estudo: Limitado número de casos e pequeno número de estudos caso-controle ou estudos randomizados para realização de revisão sistemática. Conclusão: Encontramos moderado nível de evidência para associação entre arteriopatia transitória e VZV na revisão sistemática. Nessa série de casos foi observado o caráter não progressivo do AVE-i pós-varicela após 4 anos de seguimento através da avaliação de sequelas motoras, de linguagem e cognitivas. Observamos que a identificação do DNA viral e/ou presença intratecal de IgG anti-VZV não foram determinantes para o diagnóstico. Dessa forma existe necessidade de se buscar melhores marcadores diagnósticos de acidente vascular isquêmico pós-varicela em crianças / Introduction: Few data exist about the diagnosis and prognosis of children who were victims of an arterial ischemic stroke (AIS) caused by post-varicella vasculopathy/artheriopathy and there is no systematic review about children with transitory artheriopathy/vasculopathy. Objetives: To report seven cases of children who suffered post-varicella AIS, with special focus to the clinical/laboratory aspects, in addition to their neuro-cognitive performance after four years. We also perform a systematic review about the association between VZV and transitory artheriopathy/vasculopathy. Methods: Systematic review. Relevant studies were sought using the following data-bases: EMBASES; Pubmed; Bireme; LILACS and Web of Science. Searches used the following keywords: transitory artheriopathy/ vasculopathy or post varicella artheriopathy or focal artheriopathy and VZV. The PICO method was used for the selection of studies. Population: 1 month to 17 years-old, with vasculopathy/ artheriopaty in central nervous system; end-point: VZV up to 12 months before; Comparation: Transitory Vasculopathy/Artheriopaty without VZV; Outcome: VZV associated with vasculopaty/artheriopaty. One examiner performed study selection. The selected articles were analyzed by two examiners who validated the articles according to Newcastle Otawa scale. A third examiner resolved discrepancies. Series of cases: seven children were evaluated (5 boys and 2 girls) from five different pediatric emergency services within the city of Sao Paulo, Brazil, all presenting with arterial ischemic stroke (AIS) caused by post-varicella vasculopathy. Diagnosis was confirmed by Magnetic Resonance Imaging and Nuclear Magnetic Resonance Angiography. Virological diagnosis was determined using cerebrospinal fluid to detect: a) the presence of VZV DNA by polymerase chain reaction and VZV IgG and IgM antibodies and b) the involvement of the Herpes Simplex Virus type 1 and 2 (HSV 1 and 2 IgG and IgM Antibodies). The PSOM-score was applied at admission and four years after the AIS. Results: A total of 1003 publications was selected and at final evaluation only 11 articles were included with a moderate evidence level. Regarding the series of cases, seven patients, ages varying from 1.3 and 4 years, presented with hemiparesis at first physical examination and ischemic zones on imaging tests in areas irrigated by the middle cerebral artery or the internal carotid artery about 5.1 (± 3,5) months after varicella infection. Four patients (57%) had vascular lesions and three patients (42%) tested positive for VZV IgG antibodies in their CSF. No patient showed signs of exanthema, fever or IgG and IgM antibodies for Herpes Simplex Virus type 1 and 2. Thrombophilia testing came back altered for only one patient (heterozygous prothrombin gene mutation). All patients showed improvement on their sequelae scores. None recurred. Limits of this study: limited number of cases and small number of case- control studies or randomized studies for systematic review. Conclusions: We found moderate evidence level of association between transitory artheriopathy and VZV. In the series of cases, we observed the non-progressive aspect of the post-varicella AIS after four years, determined by the evaluation of motor, language and cognitive sequelae. We also observed that anti-viral DNA and/or the presence of intrathecal anti- VZV IgG antibodies were not determinants for the diagnosis. Therefore, we believe better diagnostic markers for post-varicella arterial ischemic stroke are necessary

D’après le postulat de Hebb, les circuits neuronaux ajustent et modifient durablement leurs poids synaptiques en fonction des patrons de décharges de part et d’autre de la synapse. La « spike-timing-dependent plasticity » (STDP) est une règle d’apprentissage synaptique hebbienne dépendante de la séquence temporelle précise (de l’ordre de la milliseconde) des activités appariées des neurones pré- et post-synaptiques. Le striatum, le principal noyau d’entrée des ganglions de la base, reçoit des afférences excitatrices provenant du cortex cérébral et du thalamus dont les activités peuvent être concomitantes ou décalées dans le temps. Ainsi, l’encodage temporal des informations corticales et thalamiques via la STDP pourrait être crucial pour l’implication du striatum dans l’apprentissage procédural. Nous avons exploré les plasticités synaptiques cortico- et thalamo-striatales puis leurs interactions à travers le paradigme de la STDP. Les principaux résultats sont :1. Les « spike-timing-dependent plasticity » opposées cortico-striatales et thalamo-striatales induisent des plasticités hétérosynaptiques. Si la très grande majorité des études sont consacrées à la plasticité synaptique cortico-striatale, peu ont exploré les règles de plasticité synaptique aux synapses thalamo-striatale et leurs interactions avec la plasticité cortico-striatale. Nous avons étudié la STDP thalamo-striatale et comment les plasticités synaptiques thalamo- et cortico-striatales interagissent… / According to Hebbian postulate, neural circuits tune their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebbian plasticity that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. The striatum, the primary entrance to basal ganglia, integrates excitatory inputs from both cerebral cortex and thalamus whose activities can be concomitant or delayed. Thus, temporal coding of cortical and thalamic information via STDP paradigm may be crucial for the role of the striatum in procedural learning. Here, we explored cortico-striatal and thalamo-striatal synaptic plasticity and their interplay through STDP paradigm. The main results described here are:1. Opposing spike-timing dependent plasticity at cortical and thalamic inputs drive heterosynaptic plasticity in striatumIf the vast majority of the studies focused on cortico-striatal synaptic plasticity, much less is known about thalamo-striatal plasticity rules and their interplay with cortico-striatal plasticity. Here, we explored thalamo-striatal STDP and how thalamo-striatal and cortico-striatal synaptic plasticity interplay. a) While bidirectional and anti-Hebbian STDP was observed at cortico-striatal synapses, thalamo-striatal exhibited bidirectional and hebbian STDP...

Η παρούσα διατριβή ασχολήθηκε με τη μελέτη της έκφρασης των υπομονάδων των υποδοχέων του γλουταμινικού οξέος και του γ-αμινοβουτυρικού οξέος (GABA) στα βασικά γάγγλια και τον φλοιό των εγκεφαλικών ημισφαιρίων του μυός weaver. Παράλληλα, μελετήθηκε η έκφραση των νευροπεπτιδίων εγκεφαλίνης και δυνορφίνης στα βασικά γάγγλια του μυός weaver. O μυς weaver χαρακτηρίζεται από προοδευτική, γενετικά επαγόμενη εκφύλιση των ντοπαμινεργικών κυττάρων του μεσεγκεφάλου, κυρίως αυτών οι οποίοι καταλήγουν στο ραβδωτό σώμα. Για αυτόν τον λόγο, θεωρείται ένα καλό μοντέλο της νόσου Parkinson και η μελέτη των νευροχημικών μεταβολών που συμβαίνουν στον εγκέφαλο του παραπάνω μυός, αποτελεί πολύτιμο εργαλείο για τη διερεύνηση των παθογενετικών μηχανισμών της νόσου. Mε την τεχνική του υβριδισμού in situ, προσδιορίστηκαν τα επίπεδα mRNA των υπομονάδων z1, ε1 και ε2 του υποδοχέα NMDA, των υπομονάδων KA2 και GluR6 του υποδοχέα καϊνικού οξέος, των υπομονάδων α1, α2, α4, β2 και β3 του υποδοχέα GABAA, καθώς και των πρόδρομων πολυπεπτιδίων προ-προεγκεφαλίνη και προδυνορφίνη. Η μελέτη πραγματοποιήθηκε σε φυσιολογικούς μύες (+/+) και μύες weaver (wv/wv), στις ηλικίες των 26 ημερών, 3 μηνών και 6 μηνών μετά τη γέννηση. Όσον αφορά στους υποδοχείς του γλουταμινικού οξέος, τα αποτελέσματά μας υπέδειξαν αύξηση στην έκφραση των υπομονάδων z1, ε2, ΚΑ2 και GluR6 στο ραβδωτό σώμα των μυών weaver, σε σχέση με τους φυσιολογικούς. Η αύξηση στο mRNA των υπομονάδων z1, ε2 και GluR6 παρατηρήθηκε μόνο στην ηλικία των 6 μηνών, ενώ το mRNA της υπομονάδας KA2, παρουσίασε αύξηση και στις τρεις ηλικίες που μελετήθηκαν. Οι αυξήσεις της έκφρασης των υπομονάδων z1, ε2, ΚΑ2 και GluR6 συμφωνούν και πιθανόν εξηγούν τις αυξήσεις στα επίπεδα των θέσεων δέσμευσης για τους υποδοχείς NMDA και μη-NMDA, οι οποίες έχουν βρεθεί από παλαιότερες μελέτες του εργαστηρίου μας στο ραβδωτό σώμα των μυών weaver ηλικίας 6 μηνών. Με βάση βιβλιογραφικά δεδομένα, υποστηρίζουμε ότι η καθυστερημένη αύξηση στην έκφραση των υπομονάδων z1, ε2 και GluR6 κατά πάσα πιθανότητα συντελείται μέσω επαγωγής του μεταγραφικού παράγοντα ΔfosB, σε απόκριση προς τη μείωση της ντοπαμίνης. Στον σωματοαισθητικό φλοιό των μυών weaver ηλικίας 26 ημερών, παρατηρήθηκε αύξηση στην έκφραση των υπομονάδων z1, ε1, ε2 και KA2, η οποία θα μπορούσε να οφείλεται στη μειωμένη θαλαμοφλοιϊκή γλουταμινεργική είσοδο. Όσον αφορά στους υποδοχείς GABAA, παρατηρήθηκε αύξηση στα επίπεδα mRNA των υπομονάδων α4 και β3, στο ραβδωτό σώμα των μυών weaver ηλικίας 6 μηνών, η οποία συμφωνεί και μπορεί να εξηγήσει την αύξηση στα επίπεδα των θέσεων δέσμευσης για τους υποδοχείς GABAA, η οποία έχει βρεθεί σε προηγούμενη μελέτη του εργαστηρίου μας, στο ραβδωτό σώμα των μυών weaver ηλικίας 6 μηνών. Σκοπεύουμε να ελέγξουμε την πιθανότητα, η αύξηση της έκφρασης της υπομονάδας α4, να υποδεικνύει μία αύξηση του αριθμού των εξωσυναπτικών υποδοχέων GABAA στους νευρώνες προβολής του ραβδωτού σώματος. Στην ωχρά σφαίρα των μυών weaver ηλικίας 6 μηνών, παρατηρήθηκε μείωση των επιπέδων mRNA των υπομονάδων α1 και β2, υποδεικνύοντας μία μείωση του αριθμού των υποδοχέων GABAA, η οποία ήταν αναμενόμενη, λόγω της αυξημένης GABAεργικής εισόδου στην εν λόγω εγκεφαλική περιοχή του μυός weaver. Στον σωματοαισθητικό φλοιό, παρατηρήθηκε μείωση στην έκφραση των υπομονάδων α2 και β2 και ταυτόχρονα αύξηση στην έκφραση των υπομονάδων α4 και β3. Με βάση βιβλιογραφικά δεδομένα, προτείνουμε ότι οι μεταβολές αυτές μπορεί να αντανακλούν μείωση στον αριθμό των συναπτικών και αύξηση στον αριθμό των εξωσυναπτικών υποδοχέων GABAA, σε απόκριση προς τη μειωμένη GABAεργική είσοδο προς τους νευρώνες του σωματοαισθητικού φλοιού του μυός weaver. Όσον αφορά στην έκφραση των πολυπεπτιδίων, το mRNA της προ-προεγκεφαλίνης, παρουσίασε αύξηση στο ραβδωτό σώμα των μυών weaver, μόνο στην ηλικία των 6 μηνών, ενώ το mRNA της προδυνορφίνης, παρουσίασε μείωση στην παραπάνω περιοχή, στην ηλικία των 26 ημερών και αύξηση στις μεγαλύτερες ηλικίες. Σύμφωνα με τα βιβλιογραφικά δεδομένα υποστηρίζουμε ότι: α) η καθυστερημένη αύξηση της έκφρασης της προ-προεγκεφαλίνης στο ραβδωτό σώμα του μυός weaver, οφείλεται στη μείωση της τονικής ανασταλτικής ρυθμιστικής δράσης της ντοπαμίνης στην έκφραση του εν λόγω γονιδίου και πιθανώς συντελείται μέσω του μεταγραφικού παράγοντα ΔfosB, β) ο παραπάνω μεταγραφικός παράγοντας είναι κατά πάσα πιθανότητα υπεύθυνος και για την καθυστερημένη επαγωγή της έκφρασης της προδυνορφίνης στο ραβδωτό σώμα των μυών weaver και γ) η μείωση του παραπάνω mRNA στην ηλικία των 26 ημερών οφείλεται στη μείωση της τονικής διεγερτικής δράσης της ντοπαμίνης στην έκφραση του εν λόγω γονιδίου. Τέλος, το γεγονός ότι οι μεταβολές των mRNA των διαφόρων υπομονάδων και νευροπεπτιδίων δεν ήταν οι ίδιες στις διάφορες ηλικίες που μελετήθηκαν υποδεικνύει ότι κατά την πρόοδο της ντοπαμινεργικής εκφύλισης των ντοπαμινεργικών νευρώνων του μεσεγκεφάλου διαφορετικοί μηχανισμοί ευθύνονται για την πρόκληση των αλλαγών στην έκφραση των υπό μελέτη γονιδίων. / In the present study we investigated the expression of the subunits of glutamate and γ-aminobutyric acid (GABA) receptors in basal ganglia and cerebral cortex of the weaver mouse. We also studied the expression of striatal neuropeptides, which are important neuromodulators of the synaptic transmission in the basal ganglia circuitry. The weaver mouse is characterized by a progressive, genetically induced degeneration of the mesencephalic dopaminergic neurons, especially those that project to the striatum. For this reason, the weaver mouse is a useful model for clarifying the pathogenetic mechanisms that underly Parkinson’s disease. Using the in situ hybridization method, the mRNA levels of the ΝΜDA subunits z1, ε1 and ε2, the kainate subunits KΑ2 and GluR6, the GABAA subunits α1, α2, α4, β2 and β3, as well as the mRNA levels of the precursor polypeptides pre-proenkephalin and prodynorphin, were estimated. The study was performed using wild-type (+/+) and weaver mice (wv/wv) of the following ages: 26 days, 3 months and 6 months. Concerning the glutamate receptors, an increase in the mRNA levels of z1, ε2, KA2 and GluR6 subunits was indicated in the weaver striatum, compared to the wild type. The z1, ε2 and GluR6 mRNA increases were observed only at the age of 6 months, whereas the KA2 mRNA increase was observed at all three ages studied. The increases in z1, ε2, ΚΑ2 and GluR6 mRNA expression are in agreement and probably explain the increased levels of ΝΜDA- and non-NMDA-sensitive binding sites that we had previously found in the 6 months old weaver striatum. Based on bibliographic data, we suggest that the delayed increases in z1, ε2 and GluR6 mRNA levels, are probably mediated by the delayed induction of the ΔfosB transcription factor, in response to the reduction of striatal dopamine levels. In the somatosensory cortex of 26 day old weaver mice, an increase in the levels of z1, ε1, ε2 and ΚΑ2 mRNAs was observed. The above increases can be attributed to the decreased thalamocortical glutamatergic imput. Concerning the GABAA receptors, the observed increases of the α4 and β3 mRNA levels in the 6 months old weaver striatum are in agreement and probably explain the increased levels of GABAA binding sites that we had previously found in the 6 months old weaver striatum. We are going to test the hypothesis, that the α4 mRNA increase might indicate an increase in the number of extrasynaptic GABAA receptors in striatal projection neurons. In the 6 months old weaver globus pallidus, the observed decrease in α1 and β2 mRNA levels was expected, since the GABAergic transmission is increased in the above region of the weaver brain. In the weaver somatosensory cortex, a decrease in the α2 and β2 mRNA levels and an increase in the α4 and β3 mRNA levels were observed. Based on bibliographic data, we suggest that the above alterations probably indicate a differential regulation of the synaptic versus extrasynaptic cortical GABAA receptors, in response to the decreased GABAergic presynaptic input to the weaver cortical neurons. Concerning the expression of the striatal neuropeptides, the pre-proenkephalin mRNA was increased in the weaver striatum, only at the age of 6 months. In contrast, prodynorphin mRNA was decreased in the 26 day old weaver striatum, whereas it was increased in the 3 and 6 months old weaver striatum. Based on bibliographic data, we suggest that: a) the delayed increase in the expression of pre-proenkephalin could be caused by the reduction of the tonic dopaminergic inhibitory control on the expression of the above gene in the dopamine-depleted weaver striatum and is probably mediated by the ΔfosB transcription factor; b) the above transcription factor could be responsible for the delayed induction of the prodynorphin expression in the weaver striatum as well, and c) the decrease of prodynorphin mRNA in the 26 day old weaver striatum could be attributed to the reduction of the dopaminergic stimulatory control on the expression of the above gene. Finally, the different pattern of expression alterations among the three ages studied indicates that distinct mechanisms are responsible for the observed changes, during the progress of the dopaminergic degeneration of the weaver brain.