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L’utilisation du cannabis peut précipiter la schizophrénie, en particulier chez les individus qui présentent une vulnérabilité génétique aux désordres mentaux. Des recherches humaines et animales indiquent que la neuréguline 1 (Nrg1) est un gène de susceptibilité à la schizophrénie. L’objectif de cette thèse est d’examiner si une modification du gène Nrg1 chez des souris mutante module les effets neuronaux et comportementaux des cannabinoïdes après traitement aiguë et chronique. De plus cette thèse examine les effets d'un pré-traitement au delta9-tétrahydrocannabinol, le principal composant psychotropique du cannabis, sur un modèle de flexibilité cognitive chez la souris. / Cannabis use may precipitate schizophrenia, especially in individuals who have a genetic vulnerability to the disorder. Human and animal researches indicate that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. This thesis aim at investigating if partial deletion of Nrg1 in mutant mice modulate the neuronal and behavioural effects cannabinoids after acute or chronic treatment. In addition, this thesis examine the effects of a pre-treatment with delta9-tetrahydrocannabinol, the main psychoactive constituent of cannabis, in a model of cognitive flexibility in the mice.

Les mécanismes neurologiques responsables du déclenchement et de l’homéostasie du sommeil, et du sommeil paradoxal (SP) en particulier, sont l’objet d’un nombre toujours plus important d’études du fait notamment de l’attention croissante portée aux pathologies associées. Les travaux rapportés dans cette thèse s’inscrivent parfaitement dans cette dynamique puisqu’ils ont pour objectif de mieux caractériser les populations neuronales mises en jeu dans la régulation du SP ainsi que leurs interactions. Dans cette optique, nous avons combiné différentes approches techniques complémentaires à savoir : neuroanatomie fonctionnelle, polysomnographie et pharmacologie sur animal libre de se mouvoir. Nous avons ainsi pu démontrer pour la première fois la nature glutamatergique des neurones du SLD, région pontique jouant un rôle central dans la mise en place du SP. De plus, s’il est généralement admis que ces neurones du SLD sont sous le contrôle de neurones GABAergiques situés au niveau de la partie ventrolatérale de la substance grise périaqueducale (VLPAG), le contrôle de ces derniers est encore soumis à controverse. Les résultats que nous avons obtenus suggèrent fortement que l’aire latérale de l’hypothalamus (LH) serait responsable de ce contrôle et donc de celui du SP. En effet, la LH est l’afférence majeure à la VLPAG activée lors d’une hypersomnie de SP. En outre, son inactivation par application locale de muscimol entraine la disparition totale du SP et l’activation des neurones GABAergiques de la VLPAG projetant sur le SLD. En parallèle, nous avons étudié le rôle du noyau réticulé paragigantocellulaire dorsal (DPGi) dans la genèse du SP. Bien que le DPGi fût déjà connu pour être responsable de l’inhibition du locus coeruleus (LC) durant les phases de SP, nous apportons ici un certain nombre d’arguments suggérant que le DPGi pourrait être responsable de l’inhibition, non seulement du LC, mais également de l’ensemble des neurones adrénergiques et noradrénergiques. Cela suggère donc que ce noyau joue également un rôle majeur dans la régulation du SP. Les données rapportées dans cette thèse permettent donc de mieux appréhender les mécanismes neuronaux contrôlant la survenue et la régulation du SP. En particulier, ils apportent de nouvelles données en faveur d’un rôle central de l’hypothalamus dans la régulation du SP puisqu’il constituerait le générateur principal de cet état. / A growing number of studies investigate the neurological mechanisms responsible for paradoxical sleep (PS) genesis and homeostasis. The work presented in this thesis aims to better characterize the neuronal populations implicated in PS regulation and their interrelations. To this purpose, we combined complementary techniques such as functional neuroanatomy, polysomnography and pharmacological approaches on freely moving animals. We thus demonstrated for the first time the glutamatergic nature of SLD neurons which are known to be responsible for muscle atonia and cortical activation characterizing PS. Moreover it is well established that SLD neurons are inhibited by GABAergic cells located inside the ventrolateral part of the periaqueductal gray (VLPAG). Consequently, the control of theses neurons, a crucial step for PS genesis is still a matter of debate. The results we obtained strongly suggest that the lateral hypothalamus (LH) would be responsible for this control and thus for PS. Indeed, LH is the main activated afferent to VLPAG during PS-hypersomnia and its inhibition by muscimol application totally suppresses PS and activates VLPAG GABAergic cells projecting to SLD. We also analyzed the implication of the dorsal part of the paragigantocellular reticular nucleus in PS regulation. Even if it was known that DPGi is responsible for locus coeruleus (LC) inactivation during PS, we brought new evidences showing that DPGi would actually inhibits all noradrenergic and adrenergic cells and not only LC suggesting that DPGi could be of importance for PS genesis. All our data allow us to better understand the PS neuronal network and suggest that, contrary to the classical view that PS is generated by the pons, LH would be the primary PS generator.

La première partie de ce travail concerne l'origine, la nature et la distribution des hydrocarbures présents dans les sédiments superficiels côtiers entre le delta du Rhône et le port de Cassis. Les teneurs en hydrocarbures totaux sont comprises entre 10 mg.kg-1 à 260 mg.kg-1 séd. sec. Seule la station 21 (émissaire de Cortiou) a un taux d'hydrocarbures très élevé (1067 mg.kg-1 séd. sec) comparativement aux autres stations.Nous avons montré que les hydrocarbures présents dans les sédiments avaient des origines multiples : biogène (apports terrestres et organismes marins) pétrolière (rejets pétroliers), hydrocarbures saturés et pyrolytique (résidus de combustion naturelle ou de combustion pétrolière).La deuxième partie traite d'une expérimentation de contamination artificielle en condition in situ par 20 m de profondeur dans le Golfe de Fos. Nous avons étudié l'évolution des hydrocarbures au bout de 1220 jours sur le site « HycarFos » à l'aide de carottiers fortement contaminés par du BAL 250 (20 g.kg-1 séd. humide).Les principaux résultats de cette étude montrent une disparition importante des hydrocarbures saturés au bout de 1220 jours avec une disparition préférentielle des n-alcanes par rapport aux alcanes ramifiés. Cette évolution est très nette dans les sédiments de surface (0-4 cm) mais également, à un degré moindre, dans les sédiments plus profonds (8-10 cm). Nos résultats sont en parfait accord avec ceux relatifs à l'évolution des hydrocarbures déversés massivement après un naufrage tel que celui de l'Amoco-Cadiz en 1978 sur les côtes bretonnes ou celui de l'Exxon Valdez en1989 sur les côtes d'Alaska. / The first part of this work concerns the origin, the nature and the distribution of hydrocarbons present in the coastal surface sediments located between the delta of the Rhone and Cassis harbor. Total hydrocarbons levels ranged from 10 mg.kg-1 to 260 mg.kg-1 sed dry weight. Only station 21 (Cortiou outfall sewer) has a very high hydrocarbon content (1067 dry mg.kg-1 sed. dry weight) compared to the other stations. Origins of hydrocarbons in surficial sediments are multiple : biogenic (terrestrial inputs, marine organisms), anthropogenic (petroleum contamination) and pyrolytic (residues of natural or anthropogenic combustions) The second part of the work deals with a study of the fate of oil in infralittoral coastal sediments. A field experimentation of artificial contamination has been conducted by 20 m of depth. We studied the evolution of hydrocarbons during a 1220 days period using PVC cores with or without a massive addition of crude Arabian Light oil (20 g.kg-1 sed wet.).The results of this study show clearly an important disappearance of saturated hydrocarbons after 1220 days with a preferential disappearance of n-alkanes compared to branched alkanes. This evolution is very well marked in the surface sediments (0-4 cm) but also, at a least degree, in the deeper sediments (8-10 cm). Our results are in good agreement with those related to the evolution of hydrocarbons in highly contaminated sediments by oil spills such as the Amoco-Cadiz in 1978 on the Brittany coasts or the Exxon Valdez in 1989 on the Alaska coasts.

Para compreensão da biologia dos tumores adrenocorticais são utilizados marcadores moleculares que em geral são genes reguladores do ciclo celular. AP-1 é um fator dimérico composto principalmente pelas proteínas JUN (JUN, JUNB e JUND) e FOS. Nesse projeto tivemos como hipótese que as proteínas da família JUN, se correlacionam com proteínas reguladoras do ciclo celular em tumores adrenocorticais, e poderiam ser utilizados no diagnóstico e prognóstico desse tipo de tumor. O objetivo foi analisar o padrão de expressão gênica e proteica (PCR e Immunobloting). A análise por PCR Array em culturas de células de tumores adrenais, mostrou que os genes da família JUN e o gene FOS estão pouco expressos nessas culturas, o que foi confirmado em ensaios de qPCR. Não foi possível determinar um padrão de expressão que diferenciasse os tipos de culturas celulares estudados, ou mesmo tumores adultos e pediátricos. Os tratamentos com ACTH aumentam a expressão da proteina JUN e JUNB, e podem ter certa importância em tumores responsivos à esse hormônio, que merecem análises futuras. / In order to have a better comprehension of adrenocortical tumor biology, molecular markers are utillized because they are in general cell cycle regulators. AP-1 is a dimeric factor, compound mainly by JUN (JUN, JUNB, JUND) and FOS proteins. In the present study, our hypothesis is that JUN proteins are correlated with others cell cycle regulatory proteins and could be utilized as a prognose and diagnostic predictor for adrenocortical tumors. To confirm our hypothesi the aim was genic and protein profile analyzes (PCR and Immunobloting). The PCR Array analysis showed that JUN and FOS gene expression were down regulated in these adrenocortical tumors cells which were confirmed through qPCR analysis. The genes expression analysis wasn´t able to stablish a standard of expression between the studied cell cultures or even between adults and pediatric tumors. The ACTH treatments increased JUN and JUNB proteins that may have some significance in responsive tumors to this hormone, and deserve further analysis.

O laser de baixa potência vem sendo utilizado em Odontologia com diversos objetivos, como diminuir o tempo de reparação de tecidos moles e duros e, atualmente, alguns profissionais tem utilizado esta ferramenta para o controle clínico da dor. O presente trabalho in vivo teve como objetivo avaliar quantitativamente os efeitos do laser de baixa potência (LBP) com diodo de GaAlAs (Gálio-alumínioarsenieto) no controle da dor após a expansão rápida da maxila (ERM), analisando a ativação de regiões cerebrais relacionadas à nocicepção, por meio da expressão de c-fos nos subnúcleos caudalis, interpolaris e oralis. Utilizou-se 75 ratos Wistar, machos, pesando em média 220g, que foram distribuídos em 4 grupos: Grupo Controle (n=5) animais não tratados (sem ERM e sem aplicação do LBP) e no período zero foram submetidos à eutanásia; Grupo Experimental I (n=20) animais submetidos apenas à aplicação do LBP no período zero e à eutanásia nos períodos 12, 24 48 e 72 horas após a aplicação do LBP; Grupo Experimental II (n=25) animais submetidos apenas à ERM e à eutanásia nos períodos 6, 12, 24 48 e 72 horas após a ERM; Grupo Experimental III (n=25) animais submetidos à ERM e logo em seguida o LBP no período zero; Os animais deste grupo foram submetidos à eutanásia nos mesmos períodos que o Grupo Experimental II. Após a eutanásia, os cérebros foram coletados e realizou-se secções coronais de 40 micrômetros. Os cortes foram processados para a imunohistoquímica para c-fos e analisados com o auxilio de um microscópio óptico. As células imunorreativas à proteína Fos foram contadas através do auxilio de um sistema de imagem (Image J). O teste de variância (ANOVA) foi usado seguido pelo pós-teste de Tukey, com nível de significância de 5%. O grupo que teve ERM apresentou um aumento significativo do número de neurônios Fos positivos nos subnúcleos interpolaris e caudalis 6 horas após a expansão maxilar, o que diminuiu expressivamente a partir de 12 horas, com um segundo pico no período de 24 horas (p<0,001). O grupo que teve aplicação do LBP teve redução expressiva do número de neurônios Fos positivos em todos os subnúcleos 12 horas após a aplicação da força (p<0,001). Os resultados sugerem que o LBP reduz a ativação neuronal de região nociceptiva e o mesmo seria uma possível alternativa para o alívio de dor em pacientes ortodônticos. / Low-level laser therapy (LLLT) has been used in Dentistry with many objectives, especially to decrease the time needed for bone and soft healing. Currently, some professionals have applied this tool for clinical management of pain. The aim of the present iin vivo study was to quantitatively evaluate the effects of Gallium-Aluminum- Arsenide (GaAlAs) low-level laser therapy (LLLT) on pain control after rapid maxillary expansion (RME) in young rats, by means of c-fos quantification in nociceptive related structures (caudalis, interpolaris and oralis subnuclei). A total of 75 male rats, weighting 220g, were assigned to 4 groups: Control Group (n=5) with no treatment (no RME and no LLLT); Experimental I (n=20) with LLLT without RME, evaluated at 12, 24, 48 and 72 hours; Experimental II (n=25) with RME without LLLT, evaluated at 6, 12, 24, 48 and 72 hours after RME; Experimental III (n=25) with RME and LLLT (54J/cm2), evaluated at 6, 12, 24, 48 and 72 hours after RME. The animals were euthanized, brain tissues were collected and coronal sections were cut at 40m, through the spinal trigeminal caudalis, spinal trigeminal interpolaris, and spinal trigeminal oralis subnuclei. The sections were processed for c-fos immunohistochemistry and were analyzed in light microscopy. The Image J software was used to quantify Fos immunoreactive neurons in sections of the rat brains. Statistical analysis was performed using ANOVA and Tukey tests with a significance level of 5%. In the experimental group I, Fos expression significantly increased in neurons in oralis and interpolaris subnuclei 6 hours after the maxillary expansion, then significantly decreased at 12 hours, and increased again at 24 hours (p<0.001). In experimental group III, Fos significantly decreased in neurons in all subnucleis 12 hours after force application (p<0.001). These results suggest that LLLT decrease cfos expression in neurons of nociceptive regions and it may be used as a therapeutic alternative to reduce pain in orthodontic patients.

A transição da adolescência (ADOLESC) para a idade adulta (ADULTO) é caracterizada por uma maturação de comportamentos, assim como de estruturas e sistemas do SNC. Este estudo investigou os efeitos da administração aguda e repetida de baixas doses de etanol (2,0 g/kg) em camundongos ADULTO (60 dias) e ADOLESC (28 dias), bem como a expressão de c-Fos e Egr-1 em distintas regiões cerebrais. Camundongos ADULTO e ADOLESC receberam agudamente salina (SAL) ou EtOH e sua atividade locomotora foi quantificada em campo aberto (CA). Uma hora após a injeção, a expressão de c-Fos e Egr-1 foi avaliada por imuno-histoquímica. Foram constatados: aumento na atividade locomotora e na expressão de c-Fos e Egr-1 nos animais tratados com EtOH. Outros animais ADULTO e ADOLESC foram tratados com EtOH ou SAL repetidamente (15 dias). Uma semana após o pré-tratamento, todos animais receberam etanol. A atividade locomotora foi quantificada e a expressão de c-Fos e Egr-1 foi avaliada. Os ADOLESC desenvolveram tolerância, enquanto que os ADULTO apresentaram sensibilização comportamental locomotora. A administração prolongada de etanol induziu alterações adaptativas diferenciadas, dependentes da idade, na expressão de c-Fos e Egr-1 em várias regiões encefálicas. / The transition from adolescence (ADOLESC) into adulthood (ADULT) is characterized by behavioral maturation, as well as of structures and systems of CNS. This study investigated the behavioral effects of acute and repeated administration of EtOH (2,0 g/kg) in ADULT and ADOLESC mice, as well as the c-Fos and Egr-1 expression induced by EtOH in distinctive brain structures. Locomotor activity from ADULT and ADOLESC mice acutely treated with either saline (SAL) or EtOH was measured in open field (OF). One hour after injections, c-Fos and Egr-1 expressions were evaluated by immunohistochemistry. The results demonstrated increased locomotor activity and increased c-Fos and Egr-1 expression in EtOH-treated mice. Other groups of ADULT and ADOLESC mice were treated repeatedly with SAL or EtOH during 15 days. One week after this pretreatment, all animals received an injection of EtOH. The locomotor activity was quantified and c-Fos and Egr-1 expressions were evaluated. While ADULT mice presented behavioral sensitization, ADOLESC mice developed tolerance. The repeated administration of EtOH induced an age-dependent differential expression of c-Fos and Egr-1 in several brain regions.