Η νόσος Parkinson είναι μία νόσος νευροεκφυλιστικής φύσεως, η οποία αναπτύσσεται προοδευτικά και χαρακτηρίζεται κλινικά από κινητική δυσλειτουργία. Τα αίτια της νόσου μέχρι σήμερα είναι άγνωστα. Η εκφύλιση της ντοπαμινεργικής μελαινοραβδωτής οδού στη νόσο Parkinson οδηγεί σε επακόλουθη ελάττωση του νευροδιαβιβιστή ντοπαμίνη στο ραβδωτό σώμα και σε διαταραχή της ισορροπίας της λειτουργίας του κυκλώματος των βασικών γαγγλίων, γεγονός που έχει ως συνέπεια την εμφάνιση των κινητικών συμπτωμάτων της νόσου. Ο μυς weaver αποτελεί ένα εξαιρετικό πειραματικό μοντέλο για τη διαλεύκανση των μηχανισμών που ευθύνονται για την προοδευτική εκφύλιση των ντοπαμινεργικών νευρώνων, η οποία λαμβάνει χώρα ενδογενώς και προοδευτικά. Στην παρούσα διατριβή εξετάστηκε ο πιθανός ρόλος του οξειδωτικού στρες και της απόπτωσης στη νευροεκφύλιση των μυών weaver. Για το σκοπό αυτό μελετήθηκαν οι εγκεφαλικές περιοχές που εμπλέκονται άμεσα ή έμμεσα στη μελαινοραβδωτή νευροεκφύλιση καθώς και η παρεγκεφαλίδα. Επίσης, στις παραπάνω περιοχές, μελετήθηκε η έκφραση των αποπτωτικών/αντι-αποπτωτικών γονιδίων της οικογένειας bcl-2 καθώς και η έκφραση των προστατευτικών θερμοεπαγόμενων γονιδίων, Hsp27 και Hsp70. Οι παραπάνω μελέτες έγιναν σε φυσιολογικούς και weaver μύες 21 ημερών επειδή στο στάδιο αυτό η εκφύλιση των ντοπαμινεργικών νευρώνων έχει φτάσει στο 42% και οι ντοπαμινεργικοί δενδρίτες είναι ήδη μειωμένοι κατά 76%. Τα αποτελέσματα και τα συμπεράσματα της διατριβής συνοψίζονται στα παρακάτω: Οι weaver μύες παρουσίασαν σημαντική αύξηση του οξειδωτικό στρες στη παρεγκεφαλίδα και στο μεσεγκέφαλο που είναι οι εγκεφαλικές περιοχές στις οποίες συμβαίνει νευροεκφύλιση. Τα αποτελέσματα αυτά υποδηλώνουν ότι το οξειδωτικό στρες πιθανόν να συμμετέχει στη νευροεκφύλιση των περιοχών αυτών. Επίσης η παρεγκεφαλίδα και ο μεσεγκέφαλος εμφάνισαν υψηλά επίπεδα κατακερματισμένου DNA. Σημαντικά επίπεδα κατακερματισμένου DNA εμφάνισαν και άλλες περιοχές του εγκεφάλου που εξετάστηκαν. Τα αποτελέσματα αυτά υποδηλώνουν ότι η απόπτωση πιθανόν να συμμετέχει στη νευροεκφύλιση των περιοχών αυτών. Τόσο τα επίπεδα έκφρασης του αντιαποπτωτικού γονιδίου bcl2 όσο και τα επίπεδα έκφρασης των προστατευτικών και αντιαποπωτικών γονιδίων Hsp27 και Hsp70, βρέθηκαν αυξημένα στη παρεγκεφαλίδα των Weaver μυών υποδηλώνοντας ότι τα κύτταρα της παρεγκεφαλίδας επιστρατεύουν αμυντικούς μηχανισμούς έναντι του οξειδωτικού στρες και της απόπτωσης. / The Parkinson disease is a neurodegeneration disease that develops progressively and it is clinically characterized by motor disturbances. The degeneration of nigrostriatal dopaminergic innervations in Parkinson disease leads to subsequent decrease of dopamine neurotransmitter in corpus striatum and to disturbance of operational equilibrium of basal ganglia circuit. The result of this is the motor symptoms that the disease appears. The weaver mouse constitutes an excellent Parkinson model for understanding the mechanisms which are responsible for the progressive degeneration of the dopaminergic neurons. The roles of oxidative stress and apoptosis in the neurodegeneration of weaver mice were investigated. The brain regions that are involved directly or indirectly in nigrostriatal dopaminergic innervations as well as cerebellum were examined. In addition, the expression of the apoptotic/antiapoptotic genes of bcl-2 family as well as the expression of the protective heat shock protein genes, Hsp27 and Hsp70. were examined in the above brain regions. The results and conclusions of this work are summarized bellow: The weaver mice showed significant increase of the oxidative stress in cerebellum and midbrain which are the major regions where neurodigeneration takes place. These results suggest that oxidative stress is probably involved in the neurodigeneration of these regions. All brain regions of weaver mice examined showed significant increases in fragmented DNA with the higher fragmentation taking place in the cerebellum and in midbrain. These results suggest that apoptosis is may involved in the neurodegeneration of all these regions. The expression levels of the antiapoptotic gene bcl-2 as well as the expression of the protective heat shock protein genes, Hsp27 and Hsp70, were found to increase in the cerebellum of the weaver mice suggesting that the cerebellum cells recruit defense mechanisms against oxidative stress and apoptosis.

Στην παρούσα διατριβή μελετήθηκε το ντοπαμινεργικό και γλουταμινεργικό σύστημα των βασικών γαγγλίων, χρησιμοποιώντας δύο διαφορετικά μοντέλα ζώων. Ο πρώτος στόχος ήταν να εξεταστεί εάν η μεταφορά του γονιδίου TrkA σε νευρώνες της μέλαινας ουσίας (SN) ενήλικων επίμυων επιδρά στις νευροχημικές τους ιδιότητες, απουσία ή παρουσία εξωγενούς νευροαυξητικού παράγοντα (NGF) στο ραβδωτό σώμα. Η εκτοπική έκφραση του TrkA στην SN οδήγησε σε σημαντική μείωση του mRNA της υδροξυλάσης της τυροσίνης (TH), της TH ανοσοδραστικότητας και του mRNA του DAT στη δεξιά SN σε σύγκριση με την ετερόπλευρη, ενώ δεν βρέθηκε καμία διαφορά στο mRNA των υποδοχέων ντοπαμίνης D2 και της ειδικής δέσμευσης του [3Η]raclopride στην SN. Δεν παρατηρήθηκαν μεταβολές στις θέσεις δέσμευσης του [3Η]WIN35428 και της ανοσοδραστικότητας του DAT στο ομόπλευρο ραβδωτό σώμα, καθώς και στις θέσεις δέσμευσης των μετασυναπτικών υποδοχέων ντοπαμίνης D1 και D2, όπως καθορίζεται από τους ιχνηθέτες [3H]SCH23390 και [3Η] raclopride, αντίστοιχα. Επιπλέον, δεν βρέθηκαν σημαντικές μεταβολές στους υποδοχείς NMDA και AMPA. Τα αποτελέσματα αυτά δείχνουν ότι η εκτοπική έκφραση του TrkA στην SN ρυθμίζει αρνητικά την ΤΗ και οδηγεί σε ανεξάρτητες από τον NGF αποκρίσεις. O δεύτερος στόχος της διατριβής ήταν η μελέτη του ντοπαμινεργικού συστήματος σε ένα μοντέλο DYT1 δυστονίας μυός. Σε διαγονιδιακούς μυς με υπερκινητική και μη υπερκινητική συμπεριφορά παρατηρήθηκε μείωση των υποδοχέων ντοπαμίνης D2 στο ραβδωτό σώμα, όπως προσδιορίστηκε από τη δέσμευση του [3H]raclopride, και τoυ mRNA των D2 στην SNpc, σε σχέση με μη διαγονιδιακούς μυς. Δεν παρατηρήθηκε διαφορά στη δέσμευση του [3H]SCH23390 ή του [3H]WIN35428 στο ραβδωτό σώμα διαγονιδιακών μυών. Τα δεδομένα προτείνουν μία πιθανή εμπλοκή της ντοπαμινεργικής νευροδιαβίβασης στην παθοφυσιολογία της DY1 δυστονίας. / In the present thesis we examined the dopaminergic and glutamatergic neurotransmission systems of basal ganglia, using two different animal models. The first goal was to investigate whether TrkA gene transfer into substantia nigra (SN) neurons of adult rats influence some of their neurochemical properties, in the absence or presence of exogenous nerve growth factor (NGF) delivery in the striatum. Ectopic expression of TrkA in SN resulted in a significant decrease of tyrosine hydroxylase (TH) immunoreactivity, TH mRNA and DAT mRNA expression in the right SN compared to the contralateral side, while no difference was found in the mRNA expression of D2 DA receptors and [3H]raclopride binding in SN. No significant changes were seen in the density of DAT by measuring [3H]WIN35428 binding sites and DAT immunoreactivity in the ipsilateral striatum, as well as in the number of postsynaptic striatal D1 and D2 receptor binding sites, as determined by [3H]SCH23390 and [3H]raclopride, respectively. Furthermore, no significant changes were found in NMDA and AMPA receptors. These data suggest that ectopic TrkA expression in SN downregulates TH in nigral dopaminergic neurons and elicits NGF-independent responses. The second goal of the present thesis was to examine the dopaminergic system of basal ganglia in a mouse model of DYT1 dystonia. A decrease in striatal D2 binding sites, measured by [3H]raclopride binding, and D2 mRNA expression in substantia nigra pars compacta (SNpc) was revealed in affected and unaffected transgenic mice when compared with non-transgenic. No difference in D1 receptor binding and DAT binding, measured by [3H]SCH23390 and [3H]WIN35428 binding, respectively, was found in striatum of transgenic animals. These data suggest a possible involvement of dopamine neurotransmission in the pathophysiology of DYT1 dystonia.

Les crises d'épilepsie proviennent d'une synchronisation pathologique de réseaux neuronaux du cortex. Les crises motrices, générées à partir du cortex moteur primaire, sont souvent pharmaco-résistantes. La résection neurochirurgicale du foyer épileptique est rarement l'option thérapeutique de choix au regard des risques de deficits moteurs potentiellement induits par la résection. Les ganglions de la base ont un rôle important dans la propagation des crises. Des enregistrements par micro-électrode réalisés dans une précédente étude ont montré que les activités des structures d'entrée des ganglions de la base telles que le Putamen, le noyau caudé et le noyau sous-thalamique (NST) sont fortement modifiées pendant des crises motrices. Le taux de décharge moyen des neurones du NST et du Putamen augmente et le pourcentage de neurones oscillants synchronisés avec l'EEG durant la période ictale est plus élevé durant les crises que pendant la période inter-ictale. Des études pilotes chez l'humain ont montré un effet bénéfique potentiel de la stimulation cérébrale profonde (SCP) chronique du NST pour traiter les crises motrices pharmaco-résistantes. Le but de notre étude est d'évaluer les effets thérapeutiques de la SCP des structures d'entrée des ganglions de la base. Nous avons dans un premier temps développé un modèle primate de crise d'épilepsie motrice focale stable et reproductible par injection intra-corticale de pénicilline. Nous avons ensuite caractérisé la pharmaco-résistance du modèle. Nous avons implanté stéréotactiquement des électrodes de SCP dans le NST et le Putamen. Le stimulateur a été placé sous la peau dans le dos de l'animal. Un protocole de stimulation à 130 Hz à un voltage inférieur à l'apparition d'effets secondaires a été réalisé dans le NST. Le stimulateur était mis en marche au moment de l'injection de la pénicilline. Un protocole de stimulation à 0 volt a été réalisé comme condition contrôle. Chaque primate étant son propre contrôle. L'apparition des crises, leur nombre et leur durée ont été comparés par période de 1 heure entre la condition stimulée et non stimulée. Chaque session expérimentale a été menée sur une durée de plus de six heures. Nous avons évalué l'effet préventif de la SCP à haute fréquence (130 Hz) du NST sur les crises motrices. Nous avons également étudié l'effet préventif de la SCP à basse fréquence (5-20 Hz) du Putamen sur ce même modèle. Enfin, sur un autre primate, nous avons étudié l'effet combiné de la SCP du NST à haute fréquence et du Putamen à basse fréquence sur les crises motrices. Résultats : Les effets de la SCP chronique du NST à haute fréquence ont été analysés à partir de 1572 crises apparues au cours de 30 sessions expérimentales chez 3 primates. Les effets de la SCP préventive du NST ont été évalués sur 454 crises motrices durant 10 sessions expérimentales chez un primate. L'effet de la SCP du Putamen à basse fréquence a été analysé sur 289 crises durant 14 sessions chez 2 primates. Enfin l'effet combiné de la SCP du NST et du Putamen a été évalué sur 477 crises durant 10 sessions. Les meilleurs résultats ont été obtenus par SCP chronique du NST. L'apparition de la première crise était significativement retardée lorsque le primate était stimulé. Le temps total passé en situation de crise motrice était diminué en moyenne d'environ 69 % (p ≤0.05) par rapport à la condition non-stimulé au regard de la diminution significative du nombre de crises particulièrement durant les 3 heures après le début de la stimulation. La durée de chaque crise était modérément réduite. Les modes de stimulation mono-polaire ou bi-polaire avaient une efficacité similaire. La SCP préventive du NST n'a pas eu d'effet supérieur à la stimulation chronique du NST. La SCP chronique du Putamen à basse fréquence avait un effet positif mais principalement durant les deux premières heures de stimulation. L'effet combiné de la SCP du NST et du Putamen était inférieur à la SCP chronique du NST ou du Putamen. / Epileptic seizures arise from pathological synchronization of neuronal ensemble.Seizures originating from primary motor cortex are often pharmacoresistant, and many times unsuitable for respective surgery because of location of epileptic focus in eloquent area. Basal ganglia play important role in seizure propagation. Micro electrode recordings performed during previous studies indicated that input structures of basal ganglia such as GPe, Putamen and Subthalamic nucleus (STN) are strongly modified during seizures. For example the mean firing rate of neurons of the STN and Putamen increased and the percentage of oscillatory neurons synchronized with the ictal EEG was higher during seizures as compared to interictal periods. Pilot studies in humans have shown the possible beneficial effect of chronic DBS applied to STN in treatment of pharmacoresistant motor seizures. Our study was aimed at studying the therapeutic effect of electrical stimulation of input structures of basal ganglia . We first developed a stable, predictable primate model of focal motor epilepsy by intracortical injection of penicillin and we documented it's pharmacoresistence. We then stereotactically implanted DBS electrodes in the STN and Putamen. The stimulator was embedded at the back of the animals. Subthreshold electrical stimulations at 130 Hz were applied to STN. Stimulator was turned ON when penicillin was injected. Sham stimulation at 0 volt was used as a control situation, each monkey being its own control. The time course, number and duration of seizures occurring in each epochs of 1 h were compared during ON and sham stimulation periods. Each experimental session lasted uptoo 6 hours,We also studied preventive high frequency stimulation of STN and subthershold low frequency stimulation of Putamen with 5 Hz and 20 Hz in the same model .Finally we studied combined effects of high frequency STN and low frequency Putamen stimulation in one monkey Results: Data was analysed from 1572 seizures in 30 experiments in three monkeys for chronic STN stimulation , 454 seizures in 10 experiments in one moneky during preventive STN stimulation ,289 seizures from 14 experiments in two monkeys during LFS putamen stimulation and 477 seizures from 10 sessions during combined STN and Putamen stimulation in one monkey The best results were observed during chronic STN stimulation The occurrence of first seizure was significantly delayed as compared to sham situation. Total time spent in focal seizures was significantly reduced by ≥69% on an average (p ≤0.05) after STN stimulation, due to a significant decrease in the number of seizures especially so during the first 3 hours after stimulation. The duration of individual seizures reduced moderately. Bipolar and monopolar stimulation modes were equally effective Preventive HFS STN (in one specimen) was not found to be superior to acute stimulation. LFS Putamen alone was effective but mainly in first two hours of stimulation .In a combined HFS STN and LFS Putamen stimulation the effect of stimulation in terms of seizure control was modest and poor compared to HFS STN alone or LFS Putamen alone. This study provides original data in primates showing the potential therapeutic effect of chronic HFS-STN DBS to treat focal motor seizures . A discussion explaining these results and comparison with STN DBS in human motor seizures as well as future translational perspective in human therapeutics is provided.

INTRODUÇÃO: O processamento emocional pelo cérebro humano tem sido atualmente investigado através do uso de ressônancia magnética funcional (RMf). A RMf possibilita o estudo in vivo e não invasivo de mudanças na atividade cerebral regional em voluntários humanos saudáveis. O processamento emocional pode ser modulado através do uso de antidepressivos que influenciam sistemas neurais relacionados ao processamento emocional, através da modulação da ação de neurotransmissores como a serotonina e a noradrenalina. A clomipramina, um antidepressivo tricíclico, tem sido relacionada com efeitos de resposta clínica mesmo em voluntários saudáveis. Estudos utilizando a RMf permitem a investigação do efeito de antidepressivos nos sistemas neurais envolvidos no processamento emocional em indivíduos saudáveis que apresentam resposta ao uso destes medicamentos comparados a sujeitos que não apresentam resposta ao tratamento. MÉTODOS: Nesta tese, dezoito voluntários saudáveis foram investigados em relação a mudanças de atividade neural em resposta à indução emocional através da apresentação de fotografias do International Affective Pictures System (IAPS). Foram estudadas particularmente as emoções de raiva, felicidade e medo. Os voluntários foram submetidos ao tratamento prolongado com doses baixas de clomipramina por quatro semanas. A amostra foi subdividida em respondedores (n=6) e não respondedores (n=12) ao tratamento com clomipramina. A atividade neural foi estimada com o uso da RMf, através da mensuração do efeito blood oxygenation level dependent (BOLD). As imagens foram processadas e analisadas usando o programa Statistical Parametric Mapping (SPM). Indivíduos não respondedores foram comparados sob o efeito e na ausência de efeito da clomipramina, através de comparações planejadas utilizando t-teste pareado. Indivíduos respondedores foram comparados com os não respondedores sob o efeito da clomipramina através de t-teste não pareado. RESULTADOS: Nos voluntários não respondedores à clomipramina, a comparação entre os estados medicado versus não medicado evidenciou menor atividade neural na região da amídala quando sob efeito da clomipramina em resposta a estímulos de valência negativa. Demonstramos ainda, em paradigmas de valência positiva e negativa, diminuição da atividade neural no giro do cíngulo anterior, na ínsula e no putâmen na vigência da medicação. Quando foram comparados os indivíduos respondedores com os não respondedores sob efeito de clomipramina, um aumento consistente de atividade cerebral foi observado nos voluntários respondedores na região da ínsula. CONCLUSÕES: O uso prolongado de doses baixas de clomipramina apresentou ação em regiões cerebrais envolvidas com o processamento emocional. Quando indivíduos não respondedores foram comparados sob o efeito e sem o efeito da clomipramina, foi observada menor atividade amidalar durante o tratamento em resposta a estímulos de valência negativa, possivelmente devido à menor demanda neural na avaliação inicial do estímulo de valência negativa. Também foi observada menor ativação no giro do cingulo anterior, na ínsula e no putâmen na vigência do uso da clomipramina, possivelmente em associação a uma diminuição do mapeamento cortical de funções interoceptivas em resposta a estímulos emocionais positivos e negativos. Quando indivíduos respondedores foram comparados com os não respondedores ao tratamento prolongado com doses baixas de clomipramina, foi observada maior ativação insular nos indivíduos respondedores quando estavam sob efeito de clomipramina; estes resultados indicam que possivelmente os indivíduos que respondem ao tratamento antidepressivo são os que percebem mais as alterações de seu estado corporal durante o processamento emocional. / INTRODUCTION: The emotional processing by the human brain has now been investigated through the use of functional magnetic resonance imaging (fMRI). The fMRI technique allows the noninvasive study of in vivo changes in regional brain activity in healthy human volunteers. The emotional processing may be modulated through the use of antidepressants that influence neural systems linked to emotional processing, by modulating the action of neurotransmitters such as serotonin and norepinephrine. Clomipramine, a tricyclic antidepressant, has been reported to elicit clinical response even in healthy volunteers. Studies using fMRI allow the investigation of the effect of antidepressants on neural systems involved in emotional processing in healthy subjects showing response to the use of antidepressant drugs compared to subjects who do not respond to treatment. METHODS: In this thesis, eighteen healthy volunteers were investigated in relation to changes in neural activity in response to emotional induction through the presentation of photos of the International Affective Picture System (IAPS). We studied especially the emotions of anger, happiness and fear. The volunteers were subjected to prolonged treatment with low doses of clomipramine for four weeks. The sample was divided into responders (n = 6) and non-responders (n = 12) to treatment with clomipramine. The neural activity was estimated by using fMRI, by measuring the blood oxygenation level dependent effect (BOLD). Images were processed and analyzed using the Statistical Parametric Mapping (SPM) program. Non-responders were compared under two conditions: when using clomipramine, and after drug washout, using paired t-tests. Individuals who responded to clomipramine treatment were compared with non-responders under the effect of the drug by independent t-test. RESULTS: In volunteers not responding to clomipramine, a comparison between the non-medicated versus medicated states showed less neural activity in the region of the amygdala when under effect of clomipramine in response to stimuli of negative valence. We also demonstrated, both in the paradigms of positive and negative valence, decreased neural activity in the anterior cingulate gyrus, insula and putamen during the medicated state. When responders were compared with non-responders under the effect of clomipramine, a consistent increase in brain activity was observed in the former group in the insula. CONCLUSIONS: The prolonged use of low doses of clomipramine induced activity changes in brain regions involved in emotional processing. When non-responders were compared under the influence and without the effect of clomipramine, the amygdala displayed lower activity during treatment in response to stimuli of negative valence, possibly due to lower demand in the initial evaluation of stimuli of negative valence. There was less activation in the anterior cingulate gyrus, insula and putamen during the use of clomipramine, possibly in association with a decrease in the cortical mapping of interoceptive changes in response to positive and negative emotional stimuli. When responders were compared with non-responders after prolonged treatment with low doses of clomipramine, insular activation was greater in responders when individuals were under the effect of clomipramine. These results indicate that individuals who respond to antidepressant treatment are those who perceive more changes in their bodily state during emotional processing.

Les ganglions de la base forment un ensemble de structures sous-corticales connues pour leur implication dans les processus sensori-moteurs, cognitifs et motivationnels. L’objectif de ce travail était d’approfondir le rôle des neurones du noyau subthalamique (NST), des neurones de projections et interneurones cholinergiques du striatum et des neurones du globus pallidus externe (GPe) dans la mise en place et l’exécution d’un comportement dans différents contextes motivationnels. Nous nous sommes intéressés à l’influence de l’effort et de la récompense sur l’activité de ces neurones grâce à une approche comportementale associée à des enregistrements extracellulaires unitaires chez le singe éveillé. L’influence de ces facteurs a été appréhendée dans une tâche visuo-motrice dans laquelle différents niveaux d’effort et de récompense étaient imposés à l’animal. Nos résultats comportementaux ont montré une prise en compte de la valeur des stimuli par les animaux. Les résultats électrophysiologiques obtenus montrent une implication de chacune des populations étudiées dans le traitement des informations relatives à l’effort et à la récompense. Ils suggèrent un rôle des neurones du NST, du striatum et du GPe respectivement dans la mise en place, l’exécution et l’évaluation de l’action sur la base de la valeur subjective de la récompense. Nos résultats apportent des informations nouvelles sur les substrats neurophysiologiques qui sous-tendent les processus motivationnels dans la circuiterie des ganglions de la base. / The basal ganglia form a set of subcortical structures known to be involved in sensorimotor, cognitive and motivational processes. The aim of this work was to study the role of the subthalamic nucleus (STN) neurons, the cholinergic interneurons and the projection neurons of the striatum and the neurons of the external part of the globus pallidus (GPe) in the establishment and the execution of a behavior under different motivational contexts. We examined the influence of effort and reward on the activity of these neurons with a behavioral approach combined with extracellular recordings in awake monkeys. The influence of these factors has been investigated in a visuo-motor task in which different levels of effort and reward were imposed on the animal. Our behavioral results showed a consideration of the value of the visual stimuli by the animals. Electrophysiological results showed an implication of each of the neuronal populations studied in the encoding of force and reward related information. These data suggest a role of STN, striatum and GPe in the establishment, the execution and the update of the benefit of the action based on subjective reward value. Our results bring out new features on the neurophysiological substrates underlying motivational processes in basal ganglia circuitry.

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 experiment tested the hypothesis that 192 IgG-saporin lesions of the nucleus basalis magnocellularis (NBM) in rats would impair performance in a biconditional visual discrimination task, which requires configural association learning. Experiment used 22 male Long-Evan rats (Harlan Sprague-Dawley). Behavioral testing was conducted in two identical T-mazes. Rats were randomly assigned to either a bilateral 192 IgG-saporin lesion group (n = 10) or to a control group (n = 12). Results support the hypothesis that NBM is critically involved in configural but not simple association learning and suggest that NBM may be involved more generally in cognitive flexibility.

La stimulation à haute fréquence (SHF) du noyau subthalamique (NST) joue un rôle essentiel chez les patients Parkinsoniens dans l'amélioration des troubles moteurs pour lesquels la dopa-thérapie n'est plus satisfaisante. Tout comme l'administration à long terme de L-DOPA, la SHF du NST, peut aussi, selon l'intensité de stimulation, évoquer des mouvements dyskinétiques. Ces dyskinésies sont considérées comme un phénomène d'apprentissage moteur pathologique, secondaire à une altération de la transmission glutamatergique et sont sous-tendues par des modifications durables d'expression génique, notamment dans le striatum. L'objectif de ce travail de thèse est d'étudier et de comparer les mécanismes moléculaires des dyskinésies induites par la L-DOPA à celles induites par la SHF, en se focalisant plus particulièrement sur la sous unité NR2B des récepteurs NMDA. Dans un premier temps, nous avons montré par immunohistochimie que la sous unité NR2B est hyperphosphorylée dans le NST et l'EP suite à l'induction de dyskinésie par la SHF du NST chez l'animal sain. Ces résultats ont été confirmés par la suite dans un modèle animal de la maladie de Parkinson, le rat 6-OHDA. La comparaison de ces modifications avec celles observées chez le rat 6-OHDA rendus dyskinétique par un traitement chronique à la L-DOPA nous permet de suggérer que l'induction des dyskinésies est associée à une hyperphosphorylation de NR2B au sein d'une voie subthalamo-entopédonculaire alors qu'une activation de NR2B dans le striatum semble être impliquée dans l'expression des dyskinésies. Enfin, nos résultats mettent également en évidence une implication différentielle des deux structures de sorties des ganglions de la base dans les processus akinétiques et dyskinésiogènes. / High frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements Dyskinesia are thought to be a pathological learning process due to an overactive glutamate transmission within the basal ganglia. Moreover, several molecular changes seem to be involved in this process. The aim of the present study is to compare the molecular mechanisms of dyskinesia induced by L-DOPA and by STN-HFS, by focusing more particularly on the NR2B-containing NMDA receptor. We show by immunohistochemistry that NR2B subunit is hyperphosphorylated within the STN and the EP during a dyskinesiogenic STN-HFS in normal rats. Similar results are obtained from 6-OHDA rats, a model of Parkinson disease. Comparison of these results with those observed in 6-OHDA dyskinetic rats chronically treated with L-DOPA suggest that dyskinesia induction is associated with an hyperphosphorylation of NR2B within a subthalamo-entopeduncular network while activation of NR2B within the striatum seem to be involved in the expression of dyskinesia. A different implication of the two output of the basal ganglia in akinetic and dyskinesiogenic process is also demonstrated. STAR Date de soutenance : 8 juillet 2011 Thèse sur travaux: non

SAMMANFATTNING Bakgrund: Vid hjärnundersökningar finns även andra strukturer utanför hjärnan som är innerverade av nervsystemet. Det är möjligt att sjukdomen i hjärnan avspeglas där också. Det finns många sjukdomar och tillstånd med liknande symptom och att ställa rätt diagnos kan vara svårt. Många sjukdomar påverkar det autonoma nervsystemet och ett sätt att hitta rätt diagnos kan vara att undersöka hur det fungerar.  Syfte: Att se vilka variationer av radioaktivitetsupptag som fanns i parotiskörtlarna mellan patienterna som avbildades med 11C-PE2I PET/DT. Samt att kunna se om denna information kan utnyttjas till att identifiera dysfunktion av autonoma nervsystemet (MRT-bilder är även en tillhjälps verktyg). Metod: Studiedesignen var en retrospektiv kvantitativ studie. Hundra (konsekutiva) patienter indelades i grupper så som: normal, Parkinsons, Parkinsons sjukdom med kombination av vaskulära förändringar och atypisk Parkinson sjukdom. Isotopupptag i basala ganglier och parotiskörtlar har mätts. Några patienters MRT- bilder var tillgängligt till kvantifiering.   Resultat: kombinerade gruppen med Parkinsons sjukdom, atypisk Parkinsons sjukdom och vaskulära förändringar har en uppreglering av antalet fria dopaminreceptorer i parotis jämfört med friska (även i bara PSP samt bara vaskulära grupper) med (p &lt;0.05).   Slutsats: Det finns variation av upptaget mellan en del av grupper därmed kan sjukdomen i hjärnan avspeglas i körtlar också.   Nyckelord: Neurodegenerativa sjukdomar, Autonom dysfunktion, 11CPE2I-PET/DT, parotiskörtlar, basala ganglier / ABSTRACT Background: At brain examination, there are also other structures outside the brain that are innervated by the nervous system. It is possible that the disease of the brain is reflected there as well. There are many diseases and conditions with similar symptoms and making the right diagnosis can be difficult. Many diseases affect the autonomic nervous system and one way to find the right diagnosis may be to investigate how it works.     Purpose: to see what variations in radioactivity uptake were found in the parotic glands between the patients depicted with the 11C-PE2I PET/CT. As well as being able to see how valuable this information is in being used to identify dysfunction of the autonomic nervous system (MRT- images are also an aids tool).   Method: The study design was a retrospective quantitative study. One hundred (consecutive) patients were divided in groups such as normal, Parkinson's, Parkinson's disease with combination of vascular changes and atypical Parkinson's disease. Isotope uptake in basal ganglia and parotic glands has been measured. Some patients' MRT images were available for quantification.     Result: the results show that the combined group of Parkinson's disease, atypical Parkinson's disease and vascular changes has an upregulation of the number of free dopamine receptors in parotid compared to healthy ones (also in PSP only and only vascular groups) with (p &lt;0.05).    Conclusion: There is variation of uptake between some of the groups thus the disease in the brain can be reflected in glands as well.     Keywords: Neurodegenerative Diseases, Autonomic Dysfunction, 11CPE2I-PET/CT, Parotid Glands, Basal Ganglia

Les ganglions de la base (GB) forment un réseau de structures sous-corticales impliquées dans la motricité volontaire, mais aussi dans des aspects plus cognitifs et motivationnels du comportement moteur. La dopamine est un neuromodulateur essentiel au bon fonctionnement de ce réseau. La synapse cortico-sous-thalamique (cortico-NST) est une synapse glutamatergique (excitatrice) transmettant les informations corticales au noyau sous-thalamique (NST), ce qui forme la première partie d’une des trois voies des GB : la voie hyperdirecte. La voie cortico-NST est impliquée dans des tâches de type « go-no-go » (arrêt d’un acte moteur débuté) et dans les effets bénéfiques de la stimulation cérébrale profonde du NST sur les symptômes de la maladie de Parkinson. Cependant, les propriétés des synapses cortico-NST ne sont pas connues. Ce manque d’informations provient, en partie, de l’anatomie particulière de cette voie, qui rend l’étude in vitro de la synapse cortico-NST difficile. L’utilisation de l’optogénétique nous a permis de contourner ce problème. En associant cette technique à l’électrophysiologie sur tranches de cerveaux de rongeur, nous avons mis en évidence un effet inhibiteur des récepteurs dopaminergiques D5 sur la transmission cortico-NST. Nous montrons également que les propriétés de plasticité à court terme de cette synapse lui permettent de réduire l’influence des messages corticaux à haute fréquence sur le NST. Les résultats obtenus au cours de cette thèse montrent que l’optogénétique est un bon moyen d’étudier la synapse cortico-NST in vitro et contribuent à améliorer la compréhension des propriétés de la cette synapse. / Basal ganglia (BG) are a group of subcortical nuclei involved in action selection and in cognitive and motivational aspects of motor behavior. Dopamine is essential for proper functioning of BG. The cortico-subthalamic (cortico-STN) synapse is a glutamatergic (excitatory) synapse involved in signal transmission from cortex to subthalamic nucleus (STN). The cortico-STN synapse is the first synapse in the hyperdirect pathway, one of the three pathways of BG. Even if the cortico-STN pathway is involved in “go-no-go” tasks (stopping of an already started motor act) and in the beneficial effects of the high frequency stimulation of the STN on Parkinsonian symptoms, properties of the cortico-STN synapse are not well described. The lack of data is due, at least in part, to the specific anatomy of the cortico-STN pathway which does not allow the use of standard methods in vitro. The use of optogenetics allowed us to circumvent this issue. By coupling this approach with electrophysiology on brain slices in rodents, we show that dopaminergic D5 receptors stimulation reduces glutamatergic transmission at cortico-STN synapses. We also show that short-term plasticity properties of this synapse reduce the influence of high frequency cortical inputs on the STN. Our findings indicate that optogenetics enables studying the cortico-STN synapse in vitro and contributes to improving our knowledge of the properties of the synapse.