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Les représentations mentales, en particulier les représentations spatiales, sont étroitement associées à l'activation coordonnée de groupes de cellules dans l'hippocampe. Nous avons entrepris l'étude des propriétés et activités spontanées du réseau hippocampique (et plus particulièrement de la région CA3) afin de mieux en comprendre le fonctionnement, dans les situations normales et pathologiques. En effet, certaines pathologies neurodégénératives telle que la maladie de Parkinson serait potentiellement associées à des troubles cognitifs hippocampo-dépendants. Ainsi dans la première partie de ma thèse, nous avons caractérisé la dynamique temporelle des signaux excitateurs et inhibiteurs spontanés de l'hippocampe par une approche électrophysiologique in vitro sur tranches d'hippocampe mais aussi chez l'animal anesthésié grâce des enregistrements multi-unitaires multi-sites. Ces travaux nous a permis de mettre en évidence que les caractéristiques de la dynamique du réseau CA3 remplissent quelques critères essentiels au concept d'assemblées cellulaires. De plus, cette étude a mis en évidence les caractéristiques fonctionnelles de l'hippocampe chez l'animal normal. Ces résultats peuvent donc être utiles pour de futures études sur les pathologies hippocampo-dépendantes touchant le codage ou la mémoire spatiale telle que la maladie de Parkinson. Ainsi, dans la deuxième partie de ma thèse, nous avons étudié les altérations fonctionnelles du circuit hippocampique chez un modèle rat de la maladie de Parkinson. La maladie de Parkinson est une maladie neurologique qui affecte le système nerveux central et entraine des symptômes essentiellement moteurs. La cause est une dégénérescence des neurones dopaminergiques mais aussi noradrénergiques et sérotoninergiques. Cependant, en dehors des troubles moteurs, cette pathologie est aussi caractérisée par des troubles cognitifs notamment des déficits spatiaux. Notre projet a donc consisté à analyser les mécanismes par lesquels les déplétions monoaminergiques entraîneraient des troubles de l'apprentissage spatial. Ce travail a été réalisé chez le rongeur à l'aide d'une étude associant une approche comportementale et des enregistrements électrophysiologiques chez l'animal anesthésié mais aussi chez l'animal éveillé en comportement. Nous avons ainsi pu mettre en évidence des dysfonctionnements hippocampiques causés par des lésions contrôlées des différents systèmes mono-aminergiques (plus particulièrement dopaminergique et noradrenergique) impliqués dans la maladie de Parkinson. / Mental representations, especially spatial ones are closely related to correlated activity in cellular assembly in the hippocampus. In this work, we analyzed the properties and the spontaneous activity of the hippocampal network in order to unravel its functioning in normal and pathological conditions. Several neurodegenerative disorders such as Parkinson's disease seems to be also associated to cognitive disorder related to hippocampus dysfunction. We first characterized the temporal dynamic properties of spontaneous excitatory and inhibitory signal. We then studied the functional alteration of the hippocampal network in a rat model of Parkinson's disease using behavioral and electrophysiological investigations. Our work showed that controlled lesion of the various monoaminergic systems induced hippocampus dysfunction related to spatial disorientation.In the first part of my thesis, we characterized the temporal dynamic of excitatory and inhibitory signals with electrophysiological recordings in vivo on hippocampal slices but also in anesthetized animals with multi-units multi-sites recordings. These studies allowed us to highlight that dynamic of CA3 network meets the criteria of cells assembly concept. Moreover, we characterize the functional properties of hippocampus in physiological conditions. These results could be useful for further studies on hippocampo-dependant pathologies in the context of spatial coding and memory.Thus, in the second part of my work, we studied the functional alterations of hippocampal network in the context of Parkinson disease. This pathology is a neurodegenerative disease which affects the central nervous system and leads essentially to motor symptoms. The cause is the degeneration of dopamine neurons but also of noradrenalin and serotonin neurons. Nevertheless, this pathology is also associated to cognitive disorders notably a form of spatial disorientation. Our project consisted to analyze the mechanisms by which monoamines depletions led to spatial learning impairments. This work was realized on rats with a study combinating behavioral approach with electrophysiological recordings in anesthetized animals but also in awake animals. We showed that some monoamines depletions (and notably dopamine and noradrenalin depletions) led to spatial impairments in behavioral tasks correlated to a change in firing and coding of neurons of hippocampus.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Desidrodieugenol, conhecido como bis-eugenol, à um orto-dÃmero do eugenol que, similarmente ao eugenol, exibe atividades antiinflamatÃria e antioxidante. Eugenol, tambÃm, apresentou efeito antidepressivo, no entanto, as aÃÃes biolÃgicas do bis-eugenol em modelos experimentais para screening da atividade antidepressiva nÃo tem sido estudada. O presente estudo investigou a possÃvel atividade antidepressiva do bis-eugenol nos testes do nado forÃado e suspensÃo da cauda, em camundongos, e o envolvimento do sistema monoaminÃrgico neste efeito. A anÃlise neuroquÃmica das monoaminas no cÃrebro de camundongos submetidos ao tratamento agudo com bis-eugenol foi tambÃm realizado. AlÃm disso, os efeitos centrais do bis-eugenol foram avaliados em modelos animais de ansiedade tais como tempo de sono induzido por pentobarbital, teste da placa perfurada, labirinto em cruz elevado (plus maze), convulsÃes induzidas por pentilenotetrazol e teste do claro escuro. Bis-eugenol reduziu o tempo de imobilidade no teste do nado forÃado, o qual nÃo acompanhou as alteraÃÃes da ambulaÃÃo no teste do campo aberto na dose de 10 mg/kg, no entanto, a ambulaÃÃo foi induzida pelas doses de 25 e 50 mg/kg. O melhor efeito anti-imobilidade do bis-eugenol (50 mg/kg, i.p.) foi revertido pelo prÃ-tratamento dos camundongos com PCPA 100 mg/kg, i.p. (um inibidor da sÃntese de serotonina) por quatro dias consecutivos. Prazozin (1 mg/kg, i.p., antagonista α1-adrenoceptor), ioimbina (1 mg/kg, i.p., antagonista α2-adrenoceptor), SCH23390 (15 Âg/kg, s.c., antagonista do receptor D1) ou sulpirida (50 mg/kg, i.p., antagonista do receptor receptor D2). Bis-eugenol apresentou atividade ansiolÃtica no teste da placa perfurada, plus maze e claro/escuro que parece nÃo estar relacionado com o sistema gabaÃrgico, uma vez que o flumazenil, um antagonista dos benzodiazepÃnicos no sÃtio receptor gabaÃrgico, nÃo reverteu o efeito ansiolÃtico provocado pelo bis-eugenol no teste do plus maze. A anÃlise dos nÃveis de monoaminas e seus metabÃlitos, utilizando High Performace Liquid Chromatograph (HPLC), revelou um significativo aumento nos nÃveis de monoamÃnas (NA, DA e 5-HT) e seus metabÃlitos (DOPAC, HVA e 5-HIAA) no corpo estriado dos camundongos. O presente estudo sugere que o efeito anti-imobilidade observado com o tratamento agudo de biÂs-eugenol no teste do nado forÃado està relacionado ao sistema monoaminÃrgico, considerando o aumento dos nÃveis de monoaminas e seus metabÃlitos no cÃrebro. Foi observado um efeito ansiolÃtico do bis-eugenol que nÃo està relacionado com o sistema gabaÃrgico, uma vez que o flumazenil nÃo reverteu os efeitos do bis-eugenol no teste do plus maze. / Desidrodieugenol, known as bis-eugenol, is an ortho dimer that of similarly to eugenol was able to exhibits anti-inflammatory and antioxidant. Bis-eugenol has also showed antidepressant effect, however, the biological actions of bis-eugenol on experimental models for screening of antidepressant activity are still unknown. The present study investigated the possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and the tail suspension test (TST) in mice and the involvement of monoaminergic system in this effect. In addiction, the neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Besides, the central effects of bis-eugenol were evaluated, also, animal models of anxiety such as barbiturate-induced sleeping time, hole board, elevated plus maze, pentilenotetrazole induced-convulsions and white/black test. Bis-eugenol drecreased the immobility time in the FST which accompanying changes in ambulation in the open-field test at 10 mg/kg, i.p., nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The higher anti-immobility effect of bis-eugenol (50 mg/kg, i.p.,) was prevented by pre-treatment of mice with PCPA 100 mg/kg, i.p., ( inhibitor of serotonin synthesis, 4 consecutive days), prazozin (1 mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist), SCH23390 (15 Âg/kg, s.c., D1 receptor antagonist) or sulpiride (50 mg/kg, i.p., D2 receptor antagonist). Bis-eugenol showed anxiolytic activity in the hole board, elevated plus maze and white/black test and it seems there no performance of bis-eugenol on the gabaergic system, once flumazenil no reverted the anxiolytic effect of bis-eugenol in the plus maze test. Monoamines analysis using High Performace Liquid Chromatograph (HPLC) reveled a significant increase in 5-HT, NE, DA levels in brain striatum, as well as the metabolites DOPAC, HVA and 5-HIAA were also increased. The present study suggests that the anti-immobility or antidepressant-like effect of bis-eugenol in the FST is related to the monoaminergic system, likely due to increase of brain monoamines. An anxiolytic effects was observed which no related of the gabaergic system, once flumazenil no reversed the anxiety effects of the bis-eugenol in the plus maze test.

Over the recent years, venlafaxine has become the predominant antidepressant drug detected in municipal wastewater effluents (MWWE) and aquatic systems. However, very little is known about the effect of this drug in the aquatic environment on non-target organisms, including fish. Venlafaxine is a pharmaceutical compound designed to inhibit serotonin and norepinephrine reuptake, thereby increasing the synaptic availability of these neurotransmitters. In teleosts, the key aspect of stress adaptation involves the activation of the hypothalamus-pituitary-interrenal (HPI) axis, leading to the production of cortisol. Given that monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are involved in the regulation of a wide range of neuroendocrine responses, including stress axis function, my primary hypothesis was that venlafaxine acts as a neuroendocrine disruptor impacting the functioning of the corticosteroid stress axis in rainbow trout (Oncorhynchus mykiss). This hypothesis was tested through a series of in vivo exposure studies, as well as in vitro experiments, using environmentally relevant levels of venlafaxine, in order to tease out potential mode of action of this drug on target tissues involved in HPI axis functioning. The results suggest that venlafaxine alters monoamine neurotransmitter levels and their turnover rates in a region-specific manner in trout brain, and that the midbrain is the prime target. The monoamine changes may be responsible for the downstream effects on neuroendocrine responses coordinated in the hypothalamus, as this region receives monoaminergic inputs from the midbrain. The functional relevance of the above finding was confirmed by showing that venlafaxine exposure disrupted the neuroendocrine responses associated with social stress and appetite regulation. Functional downstream effects of HPI axis dysfunction were further confirmed by subjecting the fish to a handling disturbance, which revealed that the highly conserved cortisol and glucose responses to stressors were disrupted by venlafaxine. Also, there were tissue-specific effects of venlafaxine exposure on metabolic capacities, including enhanced gluconeogenesis and amino acid catabolism in the liver (a key glucose producing tissue), and alterations in the glycolytic capacity and sodium potassium ATPase activity in the gill (a key glucose utilizing tissue). The results suggest that the mode of action of venlafaxine may involve disruption of each target tissue involved in the HPI axis functioning. In vitro mechanistic studies indicated that hypothalamus functioning is disrupted by venlafaxine and this may involve effects mediated by serotonergic pathways. The reduced phosphorylation of cAMP response element binding protein (CREB) suggests that venlafaxine may impact downstream signalling cascades that are CREB-dependent. The transcript changes observed with venlafaxine in the hypothalamus include changes in mRNA levels of key genes involved in appetite regulation and stress response, including corticotropin releasing factor (CRF) and neuropeptide Y (NPY). At the pituitary level, venlafaxine impaired adrenocorticotropic hormone (ACTH) production, and this involved disruption of corticotropin releasing factor-receptor type 1 (CRF-R1), which is a key sensor for CRF stimulation. At the interrenal tissue level, the responsiveness of steroidogenic cells to ACTH stimulation was altered by venlafaxine and the mode of action appears to involve pathways upstream of the intracellular cAMP production. Also, cortisol biosynthetic capacity was disrupted by venlafaxine and this was accompanied by changes in transcript abundances of steroidogenic acute regulatory protein and cytochrome P450 side chain cleavage in the interrenal tissue. Taken together, the results demonstrate for the first time that the antidepressant venlafaxine, a human pharmaceutical contaminating aquatic systems, disrupts neuroendocrine responses and affects stress, feeding and metabolic responses in rainbow trout. The mode of action may include disruptions in brain monoamine levels and pathways involved in CREB signalling, while the exact mechanism of action remains to be elucidated. Exposure of fish to this pharmaceutical drug adversely affects the highly conserved adaptive responses that are essential to cope with subsequent stressors, and may translate into reduced fitness over the long-term. The findings underscore the necessity to understand the mechanisms of action of chemicals present in MWWE, and develop and utilize effective risk management strategies aimed at minimizing discharge of pharmaceuticals into the aquatic environment.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Hoodia gordonii passou a ser consumida hà sÃculos, com o intuito de promover uma reduÃÃo do apetite e da ingestÃo de Ãgua e comida, e atà os dias atuais à utilizada para este fim, em diversos paÃses. O presente estudo buscou investigar possÃveis alteraÃÃes comportamentais e metabÃlicas em roedores tratados com Hoodia gordonii, em diferentes perÃodos de tratamento. Para avaliar o peso corporal do animal, ratos foram pesados diariamente, no perÃodo do tratamento e mensurado o peso, a ingestÃo de Ãgua e comida. Para investigar as alteraÃÃes comportamentais (ansiedade e depressÃo) e neuroquÃmicas, os camundongos foram submetidos aos tratamentos de 1, 8 e 15 dias com Hoodia gordonii por via oral (25 e 50mg/kg), e em seguida realizados os testes comportamentais de Labirinto em Cruz Elevado (LCE), Campo Aberto (CA) e outros grupos de camundongos foram submetidos ao teste do Nado ForÃado (NF). Com intuito de investigar o envolvimento com o sistema monoaminÃrgico, no efeito de H. gordonii sobre a depressÃo, os camundongos foram prÃ-tratados com antagonistas especÃficos para receptores de dopamina D1 e D2, de noradrenalina α1 e α2, de serotonina 5HT1A, 5HT2A/2C, 5HT3A no teste do nado forÃado. AlÃm disso, outros grupos de camundongos foram prÃ-tratados com Hoodia gordonii por 1,8 e 15 dias e uma hora apÃs tiveram o corpo estriado removido para anÃlise da concentraÃÃo de monoaminas, atravÃs da tÃcnica de HPLC e o hipocampo para realizaÃÃo de experimentos de estresse oxidativo, por quantificaÃÃo dos nÃveis de glutationa reduzida, atividade da enzima catalase, nÃveis de nitrito/nitrato e malonildialdeÃdo. Foi realizado tambÃm teste de citotoxicidade pelo mÃtodo colorimÃtrico do MTT e estudo de genotoxicidade (DNA) em linfÃcitos humanos. Os resultados revelaram que o extrato reduziu o peso corporal dos animais, bem como a ingestÃo de Ãgua e comida. Nos testes comportamentais, observou-se um possÃvel efeito ansiogÃnico no LCE. No teste do campo aberto ocorreu uma reduÃÃo da atividade locomotora no 15 dia de tratamento e no teste do nado forÃado um efeito antidepressivo-sÃmile nos trÃs tempos de tratamento, observado pela reduÃÃo do tempo de imobilidade. Este efeito antidepressivo foi revertido com o prÃ-tratamento de antagonistas noradrenÃrgicos, serotonÃrgicos e dopaminÃrgicos utilizados no estudo. O extrato promoveu um aumento na concentraÃÃo de noradrenalina e serotonina em corpo estriado de camundongos apÃs 1 dia, e aumento de dopamina, noradrenalina e serotonina apÃs 15 dias. Na avaliaÃÃo do estresse oxidativo, nÃo se observou alteraÃÃes nos nÃveis de malonildialdeÃdo (MDA), na concentraÃÃo da enzima catalase, e da glutationa reduzida, e foi possÃvel verificar uma reduÃÃo na concentraÃÃo de nitrito em ambas as doses utilizadas, em hipocampo de camundongos nos trÃs tempos de tratamento. NÃo causou alteraÃÃes histopatolÃgicas hepÃticas e renais em camundongos, apÃs administraÃÃo aguda nas doses de 550 e 2000 mg/kg. Nas concentraÃÃes de 50 a 200Âg/mL nÃo desenvolveu citotoxicidade e no teste de genotoxicidade nÃo foi capaz de alterar o DNA celular de linfÃcitos humanos. Pode-se concluir que Hoodia gordonii mostrou resultados satisfatÃrios em roedores. Entretanto, à necessÃria a realizaÃÃo de outros estudos para garantir a seguranÃa no uso do extrato e futuramente possa trazer benefÃcios à populaÃÃo. / Hoodia gordonii has become consumed centuries, in order to promote a reduction in appetite, due to reduced food and water intake. Even today it is consumed in many countries. The present study investigated possible behavioral and metabolic alterations in rodents treated with Hoodia gordonii in different treatment periods. To evaluate body weight, the rats was weighted daily during the period of treatment and measured water and food intake. To investigate the behavioral (anxiety and depression) and neurochemical changes, the mice were tested for 1,8 and 15 days of treatment with Hoodia gordonii (25 and 50mg/kg, oral), the experimental models being performed in the Elevated Plus Maze (EPM), Open Field (OP) test and other group mice submitted the Forced Swimming (FN) test. In order, to investigate the involvement with the monoaminergic system, the mice were pretreated with specific dopamine D1 and D2; α1 and α2 of noradrenaline, serotonin 5HT1A, 5HT2A/2C, 5HT3A receptor antagonists in the forced swimming test. In addition, other groups of animals were pretreated with H. gordonii for 1,8 and 15 days and after one hour, the striatum were removed for HPLC analysis of monoamines and hippocampus for the experiments of oxidative stress, such as enzymatic activity quantification of low levels of glutathione, catalase enzime, nitrite/nitrate and malondialdehyde levels. The citotoxicity (MTT) and genotoxicity (DNA) test was conducted in human lymphocytes. The results showed that, the extract reduced the body weight of the animals, as well as, food and water intake. In the behavioral testing, Hoodia gordonii presented anxiogenic effect in the EPM, reduced locomotor activity on day 1, 8 and 15 of treatment and antidepressant-like effect after the first dose administration, with reduced immobility time. It was interacted with noradrenergic, dopaminergic and serotonergic receptors used in this study. The extract promoted an increase in levels of norepinephrine and serotonin in the striatum of mice after 1 day, and increased monoamines dopamine, noradrenaline and serotonin after 15 days. The oxidative stress was not able to alter the levels of malondialdehyde (MDA), catalase, reduced glutathione in the hippocampus of mice, reduced the concentration of nitrite in both doses used in the three treatment times. The cellular DNA of human lymphocytes was not changed. H. gordonii did not cause liver and kidney after administration of doses 550 and 2000 mg/kg histopathology changes. Concentrations of 50 at 200Âg/mL did not develop citotoxicity and genotoxicity test, was not able to change the cellular DNA of human lymphocytes. It can be concluded that, Hoodia gordonii showed great results in rodents. However, other studies itÂs necessary to ensure the safe use of the extract, and it can be approved or not in our country.

No description available.

Dans le système nerveux central, les monoamines modulent de nombreuses fonctions essentielles comme la locomotion, la motivation, la cognition, l’humeur et le sommeil. Le niveau extracellulaire de ces neurotransmetteurs est régulé par des transporteurs à haute affinité,cependant d’autres transporteurs, à faible affinité, peuvent contribuer à la recapture des monoamines, comme les transporteurs de cations organiques (OCT) et le transporteur plasmique des monoamines (PMAT). Récemment, l’implication des OCT dans différentes fonctions centrales, notamment le contrôle de l’humeur, la réponse au stress et aux antidépresseurs a été mise en évidence. Le rôle de PMAT dans le cerveau reste quant à lui encore peu caractérisé. Il transporte in vitro les monoamines, avec une préférence pour la dopamine et la sérotonine, avec des affinités submillimolaires. Ce transporteur est exprimé dans de nombreuses régions du cerveau humain et murin et dans différents types neuronaux. Par hybridation in situ fluorescente nous avons déterminé sa distribution cellulaire précise, dans des régions à fort niveau d’expression comme le complexe du cerveau antérieur basal (BFC) et des régions appartenant aux ganglions de la base comme le globus pallidus et la substance noire réticulée (SNr). Nous avons montré qu’il est fortement exprimé dans les neurones GABAergiques exprimant la parvalbumine, dans tous les interneurones cholinergiques dustriatum ainsi qu’une petite fraction des neurones cholinergiques du BFC. Il est également retrouvé dans certains noyaux monoaminergiques comme le locus coeruleus et les noyaux duraphé mais est absent des noyaux dopaminergiques, la substance noire compacte et l’aire tegmentale ventrale.Afin d’étudier sa fonction, nous avons exploité le système Cre-lox, approche couramment utilisée en biologie, en injectant un virus adéno-associé exprimant la recombinase Cre (AAVCre)dans la substance noire (SN) de souris comportant des allèles de PMAT floxés. Cette étude ne nous a pas permis de conclure quant à la fonction de PMAT dans la SN, mais nous a conduit à mettre en évidence une toxicité majeure de cet outil. Nous avons montré que l’injection d’AAV-Cre dans la SN entraine une perturbation anatomique et fonctionnelle des systèmes dopaminergiques et de la SNr, noyau de sortie des ganglions de la base, induisant des altérations comportementales importantes, avec une hyperlocomotion basale robuste et une insensibilité à la cocaïne, potentiellement par une action génotoxique.Nous avons également généré des souris invalidées constitutivement pour PMAT (PMAT-/-). Les tests comportementaux que nous avons commencés récemment nous ont révélé des altérations comportementales significatives chez ces souris de l’activité locomotrice dans un nouvel environnement ainsi que du niveau d’anxiété. Ces altérations pourraient résulter d'une perturbation des voies aminergiques en l’absence de PMAT. Nous poursuivrons cette étude par l'exploration d'autres aspects comportementaux ainsi que par l’évaluation des modifications neurochimiques engendrées par l'invalidation. Ces approches devraient fournir des pistes afin d’identifier les conséquences de l'absence de PMAT sur la signalisation aminergique, que l'on pourra explorer plus précisément par la suite sur le plan fonctionnel / High-affinity reuptake transporters exert a crucial role in the control of synaptic transmissionby ensuring the recycling of the released transmitters into the presynaptic terminals. Other typesof transporters such as Organic Cation Transporters (OCTs) and the Plasma MembranemonoAmine Transporter (PMAT), have been shown to transport, with low-affinity but highcapacity, aminergic neurotransmitters. While the role of OCTs in central nervous system hasbeen partially unraveled, the function of PMAT remains poorly characterized. In vitro, PMATtransports preferentially dopamine and serotonin and its expression is widespread in the brain,encompassing monoamine nuclei but also projection regions. In this study, we determined theprecise neuronal specificity of PMAT in several highly-expressing regions. We show that it isfound mostly in PV+ GABAergic neurons of basal forebrain and basal ganglia, in allcholinergic interneurons of the striatum and in some cholinergic neurons of basal forebraincomplex. These systems, highly regulated by monoamines, are important for locomotion,motivation, learning and wakefulness. Our result show that PMAT is located at a strategicposition to control the aminergic modulation of these integrated functions.To investigate the implication of PMAT in these regions, we used the Cre-lox technology, avalued and widely used approach for the study of gene function in vivo, injecting an adenoassociatedvirus expressing Cre recombinase in substantia nigra (SN) of mice in which PMATgene was floxed. In this study, we could not assess PMAT function in this SN but found thatAAV-CRE expression in this region produces major toxic effects. We showed that AAV-Creinjection in this region engenders a massive decrease of neuronal populations in both parscompacta and reticulata, leading to DA depletion in the nigrostriatal pathway. This wasassociated with a drastic behavioral phenotype with increased basal locomotor activity and lossof locomotor response to cocaine. Several hallmarks of Cre toxicity were found in SN of AAVCreinjected mice, including an increase of the DNA break markers. These observationsunderscore the need for careful control of Cre toxicity in the brain and reassessment of previous studies.To study the role of PMAT, we also generated PMAT knock out mice (PMAT-/-). Behavioralstudies that we just started have revealed significant impairments of locomotor activity in a newenvironment and anxiety level, supporting a possible disruption of monoaminergic systems inthese mice. On-going studies aim to explore other behaviors and search for eventualneurochemical changes provoked by PMAT invalidation. These experiments should providesome cues to understand which monoamines and circuits may be affected, that can beinvestigated functionnally and more specifically in a second step

La protéine STOP (MAP6) associée aux microtubules joue un rôle clé dans l'architecture neuronale et la plasticité synaptique, dont les dysfonctionnements sont considérés comme étant impliqués dans la physiopathologie des maladies psychiatriques. En accord avec cette hypothèse, la délétion de la protéine STOP chez la souris, conduit à des altérations neuroanatomiques, biochimiques et comportementales, en partie atténuées par des traitements antipsychotiques. Dans cette étude, nous avons tout d'abord examiné les possibles altérations des systèmes monoaminergiques chez les souris STOP KO. Chez les souris mutantes, les marqueurs sérotoninergiques et noradrénergiques sont accumulés dans le mésencéphale et, au contraire fortement diminués dans toutes les régions de projections du cerveau antérieur. De plus, ces déséquilibres monoaminergiques sont associés à une augmentation du statut dépressif, une diminution du statut anxieux et des déficits dans des tâches d'apprentissage et de mémorisation. Les effets d'un traitement chronique par la fluoxétine ou par l'épothilone D, un composé analogue du taxol stabilisant les microtubules, sur l'humeur et les performances cognitives des souris STOP KO ont aussi été évalués. Le traitement chronique par la fluoxétine induit des effets paradoxaux sur le statut dépressif et le statut anxieux des souris STOP KO suivant les tests effectués, probablement à cause d'une hypersensibilité au stress. En revanche, les traitements chroniques à la fluoxétine et à l'épothilone D ont amélioré la mémoire à court terme des souris STOP KO. Dans l'ensemble, ces résultats indiquent que la délétion de la protéine STOP chez la souris induit de fortes altérations de l'humeur et des performances cognitives et que la protéine STOP pourrait avoir un rôle crucial dans le développement des systèmes monoaminergiques. / The microtubule-associated STOP (MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. In line with this hypothesis, the deletion of STOP in mice leads to neuroanatomical, biochemical and severe behavioral alterations, partly alleviated by antipsychotics. In the present study, we first examined the likely monoaminergic alterations in STOP KO mice. In mutant mice, serotonin (5-HT) and norepinephrin (NE) markers are accumulated in the midbrain and, in contrast, deeply depleted in all forebrain projection areas. Moreover, these monoaminergic imbalance were associated with a depression-like behavior, a decreased anxiety status and impairments in learning and memory tasks. The effects of a chronic treatment by fluoxetine or by epothilone D, a taxol microtubule-stabilizing compound, on the mood status of STOP KO mice were also characterized. Chronic fluoxetine treatment induced paradoxical effets on depressive and anxious status of STOP KO mice, depending on the paradigm used, and probably due to hypersensitivity to stress. On the other hand, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Altogether, these data indicate that the deletion of STOP protein in mice caused deep alterations in mood and cognitive performances and that STOP protein might have a crucial role in the 5-HT and NE networks development.