Le traitement visuel répété d’un visage inconnu entraîne une suppression de l’activité neuronale dans les régions préférentielles aux visages du cortex occipito-temporal. Cette «suppression neuronale» (SN) est un mécanisme primitif hautement impliqué dans l’apprentissage de visages, pouvant être détecté par une réduction de l’amplitude de la composante N170, un potentiel relié à l’événement (PRE), au-dessus du cortex occipito-temporal. Le cortex préfrontal dorsolatéral (CPDL) influence le traitement et l’encodage visuel, mais sa contribution à la SN de la N170 demeure inconnue. Nous avons utilisé la stimulation électrique transcrânienne à courant direct (SETCD) pour moduler l’excitabilité corticale du CPDL de 14 adultes sains lors de l’apprentissage de visages inconnus. Trois conditions de stimulation étaient utilisées: inhibition à droite, excitation à droite et placebo. Pendant l’apprentissage, l’EEG était enregistré afin d’évaluer la SN de la P100, la N170 et la P300. Trois jours suivant l’apprentissage, une tâche de reconnaissance était administrée où les performances en pourcentage de bonnes réponses et temps de réaction (TR) étaient enregistrées. Les résultats indiquent que la condition d’excitation à droite a facilité la SN de la N170 et a augmentée l’amplitude de la P300, entraînant une reconnaissance des visages plus rapide à long-terme. À l’inverse, la condition d’inhibition à droite a causé une augmentation de l’amplitude de la N170 et des TR plus lents, sans affecter la P300. Ces résultats sont les premiers à démontrer que la modulation d’excitabilité du CPDL puisse influencer l’encodage visuel de visages inconnus, soulignant l’importance du CPDL dans les mécanismes d’apprentissage de base. / Repeated visual processing of an unfamiliar face suppresses neural activity in face-specific areas of the occipito-temporal cortex. This "repetition suppression" (RS) is a primitive mechanism involved in learning of unfamiliar faces, which can be detected through amplitude reduction of the N170 event-related potential (ERP). The dorsolateral prefrontal cortex (DLPFC) exerts top-down influence on early visual processing. However, its contribution to N170 RS and learning of unfamiliar faces remains unclear. Transcranial direct current stimulation (tDCS) transiently increases or decreases cortical excitability, as a function of polarity. We hypothesized that DLPFC excitability modulation by tDCS would cause polarity-dependent modulations of N170 RS during encoding of unfamiliar faces. tDCS-induced N170 RS enhancement would improve long-term recognition reaction time (RT) and/or accuracy rates, whereas N170 RS impairment would compromise recognition ability. Participants underwent three tDCS conditions in random order at ~72 hour intervals: right anodal/left cathodal, right cathodal/left anodal and sham. Immediately following tDCS conditions, an EEG was recorded during encoding of unfamiliar faces for assessment of P100 and N170 visual ERPs. P300 was analyzed to detect prefrontal function modulation. Recognition tasks were administered ~72 hours following encoding. Results indicate the right anodal/left cathodal condition facilitated N170 RS and induced larger P300 amplitudes, leading to faster recognition RT. Conversely, the right cathodal/left anodal condition caused increases in N170 amplitudes and RT, but did not affect P300. These data are the first to demonstrate that DLPFC excitability modulation can influence early visual encoding of unfamiliar faces, highlighting the importance of DLPFC in basic learning mechanisms.

Des études récentes ont montré que le noyau caudé interagissait avec le cortex préfrontal et qu’il pourrait être impliqué dans les fonctions exécutives. Le but de cette thèse était d’étudier la contribution du noyau caudé dans les fonctions exécutives, plus précisément dans des tâches de monitoring et de changement de règle, et d’observer comment ces régions fronto-striatales interagissent avec le réseau par défaut (RPD). Dans un premier temps, nous avons étudié le rôle du noyau caudé dans les deux types de monitoring : le monitoring d’origine interne, consistant à effectuer un suivi sur l’état de l’information en mémoire de travail afin de pouvoir faire un choix subséquent, et dans le monitoring d’origine externe où le suivi sur l’état des items est effectué par l’individu, mais la sélection est exécutée par une source externe. Il a été montré que le cortex préfrontal dorsolatéral (CPFDL) est impliqué dans les deux types de monitoring. À l’aide de l’imagerie par résonance magnétique fonctionnelle (IRMf), nos résultats ont montré une augmentation significative du signal BOLD au niveau du CPFDL dans les contrastes des conditions de monitoring d’origine interne et monitoring d’origine externe par rapport à la condition contrôle. De manière plus importante, une augmentation significative de l’activité a été observée dans le noyau caudé seulement dans les soustractions impliquant le monitoring d’origine interne par rapport à la condition contrôle, et par rapport à la condition de monitoring d’origine externe. En deuxième lieu, des études ont montré une contribution spécifique des régions fronto-striatales dans l’exécution d’un changement de règle. Toutefois, l’effet d’un changement de règle sur l’activité cérébrale n’a jamais été étudié sur les essais subséquents. À l’aide de l’IRMf, le cortex préfrontal ventrolatéral (CPFVL) et le noyau caudé ont montré une augmentation significative de leur activité lors des changements de règle continus et lors des changements de règles sporadiques par rapport à la condition contrôle, et aussi lors des essais où le maintien d’une même règle devait être effectué pour une courte durée par opposition au contrôle. Cependant, aucune activité fronto-striatale n’a été observée lorsqu’une même règle devait être appliquée pour une plus longue période. De plus, une diminution significative de l’activité du noyau caudé a été observée lors de la répétition de l’exécution d’une même règle suggérant une meilleure intégration de cette dernière. Finalement, plusieurs études ont montré une déactivation du RPD lors de l’exécution de tâches. À l’aide de l’IRMf, nous avons posé l’hypothèse que le RPD serait corrélé négativement avec les régions fronto-striatales lors de l’exécution d’une tâche de changement de règle. Nos résultats montrent une augmentation significative de l’activité des régions fronto-striatales lors d’une augmentation du nombre d’essais de changement de règle consécutif, pendant que le RPD montre une déactivation continue. De façon intéressante, pendant que les régions fronto-striatales montrent une diminution de leur activité lors de l’exécution d’une même règle pour une longue période, le RPD augmente son activité de façon significative. On conclut donc que le noyau caudé joue un rôle important dans la planification d’une nouvelle action lorsque plusieurs possibilités doivent être considérées en mémoire de travail, et ce en même temps. Finalement, le RPD montre une corrélation négative avec les régions fronto-striatales suggérant sa participation dans l’intégration d’une tâche devenant de plus en plus familière. / Recent studies have shown that the caudate nucleus interacts with the prefrontal cortex, and that it is involved in executive processes. The goal of the thesis was to investigate the role of the caudate nucleus in executive processes, and to observe how the frontostriatal regions are interacting with the default mode network (DMN). Firstly, we studied the role of the caudate nucleus in self-ordered monitoring, which consist of keeping track of which stimuli have been selected and which remains to be selected, and externally-triggered monitoring, which refers to keeping track of one’s selection when an external source is performing the selection. It has been shown that de dorsolateral prefrontal cortex (DLPFC) was particularly involved in both types of monitoring. Using functional magnetic resonance imaging (fMRI), a significant increase of activity has been observed in the DLPFC during both monitoring conditions vs control condition. Importantly, significant increased activity in the caudate nucleus was observed only in subtractions involving self-ordered monitoring (the self-ordered vs control and self-ordered vs externally-triggered conditions). Secondly, previous studies have shown a specific contribution of frontostriatal regions during set-shifting. However, the effect of set-shifting on subsequent trials had yet to be determined. Using fMRI, significant increase of activity was observed in the ventrolateral prefrontal cortex (VLPFC) and the caudate nucleus during shifting trials versus control and in trials where the same rule was applied for a few trials before a set-shift occurred. However, no frontostriatal activity was observed when the same rule was applied for a longer period. Decreased activity in the caudate nucleus correlated with increasing trial position in trials where no set-shift occurred, suggesting that the more a rule is executed, the better it is established. Finally, several studies have shown a deactivation of the DMN during the execution of a goal-directed task. Using fMRI, we hypothesized that the DMN was negatively correlated with the frontostriatal regions during the execution of a set-shifting task. Our results showed a significant increase of activity in the frontostriatal regions as more set-shifts are being performed while the DMN gets more deactivated. Interestingly, as decreased activity was observed in the frontostriatal regions during the execution of the same rule for a long period, the DMN showed increasing activity. We concluded that the caudate nucleus is specifically involved during the planning of a novel action when several possibilities are available at the same time. Finally, the DMN shows a negative correlation with the frontostriatal regions suggesting its contribution to the execution of a more familiar task.

Jusqu'à récemment, les patients souffrant d'épilepsie réfractaire aux traitements médicamenteux étaient destinés à un avenir incertain. Le recours à la chirurgie comme traitement alternatif offre l'espoir de mener un jour une vie normale. Pour déterminer si un patient peut bénéficier d’une intervention chirurgicale, une évaluation complète est cruciale. Les méthodes d’évaluation préchirurgicale ont connu des progrès importants au cours des dernières décennies avec le perfectionnement des techniques d’imagerie cérébrale. Parmi ces techniques, la spectroscopie proche infrarouge (SPIR), aussi connue sous le nom d’imagerie optique, présente de nombreux avantages (coût, mobilité du participant, résolution spatiale et temporelle, etc.). L’objectif principal de cette étude est de développer un protocole d'évaluation préchirurgicale de la mémoire. Une tâche de mémoire verbale incluant l’encodage, le rappel immédiat et le rappel différé de listes de mots a été administrée à dix adultes sains lors d’un enregistrement en imagerie optique. Les résultats obtenus suggèrent l’activation bilatérale des aires préfrontales antérieures et dorsolatérales ainsi que des aires temporales antérieures et moyennes. Les aires préfrontales et temporales antérieures semblent modulées par les différents processus mnésiques et la position du rappel dans le temps. La première fois qu’une liste est rappelée, l’activité hémodynamique est plus élevée que lors des rappels subséquents, et ce, davantage dans l’hémisphère gauche que dans l’hémisphère droit. Cette étude constitue la première étape dans le processus de validation du protocole à des fins cliniques auprès de patients épileptiques. / Until recently, patients with epilepsy refractory to drug treatments were intended to an uncertain future. Surgery as an alternative treatment offers hope to, one day, lead a normal life. In order to determine if a patient may benefit from a surgical intervention, a complete evaluation is essential. With the advancements in brain imagery techniques over the last few decades, preoperative evaluation methods have seen important progress. Among these techniques, near infrared spectroscopy (NIRS), also known as optical imaging, presents numerous advantages (cost, participant mobility, spatial and temporal resolution, etc.). The purpose of this study is to develop a preoperative evaluation protocol for memory assessment. During a NIRS recording, a verbal memory task including encoding, immediate and delayed free-recall of a list of words was administered to ten healthy adults. The results obtained revealed bilateral activation of anterior and dorsolateral prefrontal areas as well as anterior and median temporal areas. Prefrontal and anterior temporal areas seemed to be regulated by different memory processes and the recall location in time. The first time that a list is recalled, increased hemodynamic activity is observed in comparison to subsequent recalls, with a greater activity in the left hemisphere than in the right hemisphere. This study constitutes the first step in the validation process of the protocol for clinical needs among epileptic patients.

Bien que le passage du temps altère le cerveau, la cognition ne suit pas nécessairement le même destin. En effet, il existe des mécanismes compensatoires qui permettent de préserver la cognition (réserve cognitive) malgré le vieillissement. Les personnes âgées peuvent utiliser de nouveaux circuits neuronaux (compensation neuronale) ou des circuits existants moins susceptibles aux effets du vieillissement (réserve neuronale) pour maintenir un haut niveau de performance cognitive. Toutefois, la façon dont ces mécanismes affectent l’activité corticale et striatale lors de tâches impliquant des changements de règles (set-shifting) et durant le traitement sémantique et phonologique n’a pas été extensivement explorée. Le but de cette thèse est d’explorer comment le vieillissement affecte les patrons d’activité cérébrale dans les processus exécutifs d’une part et dans l’utilisation de règles lexicales d’autre part. Pour cela nous avons utilisé l’imagerie par résonance magnétique fonctionnelle (IRMf) lors de la performance d’une tâche lexicale analogue à celle du Wisconsin. Cette tâche a été fortement liée à de l’activité fronto-stritale lors des changements de règles, ainsi qu’à la mobilisation de régions associées au traitement sémantique et phonologique lors de décisions sémantiques et phonologiques, respectivement. Par conséquent, nous avons comparé l’activité cérébrale de jeunes individus (18 à 35 ans) à celle d’individus âgés (55 à 75 ans) lors de l’exécution de cette tâche. Les deux groupes ont montré l’implication de boucles fronto-striatales associées à la planification et à l’exécution de changements de règle. Toutefois, alors que les jeunes semblaient activer une « boucle cognitive » (cortex préfrontal ventrolatéral, noyau caudé et thalamus) lorsqu’ils se voyaient indiquer qu’un changement de règle était requis, et une « boucle motrice » (cortex postérieur préfrontal et putamen) lorsqu’ils devaient effectuer le changement, les participants âgés montraient une activation des deux boucles lors de l’exécution des changements de règle seulement. Les jeunes adultes tendaient à présenter une augmentation de l’activité du cortex préfrontal ventrolatéral, du gyrus fusiforme, du lobe ventral temporale et du noyau caudé lors des décisions sémantiques, ainsi que de l’activité au niveau de l’aire de Broca postérieur, de la junction temporopariétale et du cortex moteur lors de décisions phonologiques. Les participants âgés ont montré de l’activité au niveau du cortex préfrontal latéral et moteur durant les deux types de décisions lexicales. De plus, lorsque les décisions sémantiques et phonologiques ont été comparées entre elles, les jeunes ont montré des différences significatives au niveau de plusieurs régions cérébrales, mais pas les âgés. En conclusion, notre première étude a montré, lors du set-shifting, un délai de l’activité cérébrale chez les personnes âgées. Cela nous a permis de conceptualiser l’Hypothèse Temporelle de Compensation (troisième manuscrit) qui consiste en l’existence d’un mécanisme compensatoire caractérisé par un délai d’activité cérébrale lié au vieillissement permettant de préserver la cognition au détriment de la vitesse d’exécution. En ce qui concerne les processus langagiers (deuxième étude), les circuits sémantiques et phonologiques semblent se fusionner dans un seul circuit chez les individus âgés, cela représente vraisemblablement des mécanismes de réserve et de compensation neuronales qui permettent de préserver les habilités langagières. / As the one’s brain is structurally altered by the passage of time, cognition does not have to suffer the same faith, at least not to the same extent. Indeed, age-related compensatory mechanisms allow for some cognitive preservation. The elderly can therefore use new compensatory neuronal networks (neural compensation) or flexible pathways that are less susceptible to disruption (neural reserve) in order to maintain high levels of performance (cognitive reserve) during cognitive tasks. However, how these mechanisms affect cortical and striatal activity during set-shifting as well as during semantic and phonological processing has not been extensively explored. The purpose of this thesis was therefore to investigate how aging affects patterns of neural activity related to executive processes on the one hand and the use of lexical rules on the other. To this end we used functional Magnetic Resonance Imaging (fMRI) during the performance of a lexical analogue of the Wisconsin Card-Sorting Test. This task has been shown to strongly depend on fronto-striatal activity during set-shifting as well as on regions associated with semantic and phonological processing during semantic and phonological decisions, respectively. Two groups participated in our fMRI protocol: young individuals (18 to 35 years old) and older individuals (55 to 75 years old). Both younger and older individuals revealed significant fronto-striatal loop activity associated with planning and execution of set-shifts. However, while the younger group showed the involvement of a “cognitive loop” (including the ventrolateral prefrontal cortex, the caudate nucleus and the thalamus) when instructed that a set-shift would be required on following trial, and the involvement of a “motor loop” (including the posterior prefrontal cortex and the putamen) when the set-shift had to be performed, the older participants showed significant activation of both loops during the execution of the set-shift (matching periods) only. Young adults tended to present increased activity in the ventrolateral prefrontal cortex, the dorsolateral prefrontal cortex, the fusiform gyrus, the ventral temporal lobe and the caudate nucleus during semantic decisions and in the posterior Broca’s area, the temporoparietal junction and the motor cortical regions during phonological decisions, older individuals showed increased activity in the lateral prefrontal cortex and motor cortical regions during both semantic and phonological decisions. Furthermore, when semantic and phonological decisions were contrasted with each other, younger individuals showed significant brain activity differences in several regions while older individuals did not. In conclusion, our first study showed an age-related delayed cerebral activation phenomenon during set-shifting (previously observed only in few memory and language tasks). Based on those findings, we conceptualised the Temporal Hypothesis of Compensation (third manuscript) which is the existence of a compensatory mechanism characterised by age-related delayed cerebral activation allowing for cognitive performance to be preserved at the expense of speed processing. Regarding language processing (second study), semantic and phonological routes seem to merge into a single pathway in the elderly; these findings represent most probably neural reserve/compensation mechanisms on which the elderly rely to maintain an adequate level of performance.

Les comportements orientés vers un but sont complexes et font appel à un grand nombre de processus cérébraux. Le cortex préfrontal médian (mPFC) apparaît comme une structure clef dans la réalisation de ces comportements de par son rôle dans la planification. De plus, il existe au sein du mPFC des cellules signalant les lieux à forte valeur motivationnelle. L’activité de ces neurones pourrait être essentielle à la mise en place d’un comportement spatial dirigé vers un but. S’orienter vers un but nécessite aussi la construction d’une représentation stable de l’environnement, qui repose sur l’activité de l’hippocampe (HPC). Néanmoins, peu de travaux ont analysé le rôle respectif de ces deux structures, et leurs interactions, lors de l’acquisition et de la consolidation d’une stratégie comportementale orientée vers un but. L’objectif des recherches réalisées au cours de ma thèse est donc d’étudier l’implication de l’hippocampe et du cortex préfrontal médian du rat dans ce processus. Notre première étude a montré l’existence d’un codage prospectif au sein des neurones du mPFC durant la réalisation d’une tâche de mémoire de travail.L’activité des neurones signale à la fois, la séquence temporelle comportementale, et l’anticipation de la récompense, et jouerait ainsi un rôle dans les fonctions exécutives. Dans la deuxième étude, nous nous sommes intéressés aux structures cérébrales impliquées dans la mise à jour de la valence du but ainsi que dans sa rétention à long terme. Nos résultats ont montré que l’inactivation de l’hippocampe intermédiaire provoque des déficits dans le traitement à court terme d’un changement de valence. En revanche, l’inactivation du mPFC empêche le stockage à long terme de ce changement. L’activité de ces deux structures serait donc essentielle pour effectuer une mise à jour en temps réel de la valence d’un but et pour sa consolidation en mémoire à long terme. Leur interaction permettrait d’adapter rapidement et de façon durable la stratégie comportementale de l’animal face aux changements de l’environnement. / Goal-directed behaviors are complex and involve a variety of cognitive processes. Medial prefrontal cortex (mPFC) plays a key role in behavioral planning. More over, cells in the rat mPFC show specific firing modulations at location with a high motivational value. Such neuronal activity could be essential for the setting up installation of a goal-directed behavior. Further more, navigating to a spatial goal requires the building of a stable presentation of the environment which is hippocampus-dependent. So far however, only few studies have addressed the respective role of these two structures, and their interaction, during the acquisition and the consolidation of a goal directed-behavior. The work conducted during my PhD thesis aimed at studying the role of hippocampus and prefrontal cortex in this process. In a first study,we showed the existence of a prospective coding by mPFC neurons when the rat performs a working memory task. Neuronal activity signals both, the temporal sequence of the behavior, and the prediction of reward. These neurons would play a role inexecutive functions. In a second study, we focused on cerebral structures involved in the updating of the value of a goal as well as in its long-term retention. Our results showed that the inactivation of the intermediate hippocampus causes deficit in the short-term processing of a change in the goal value. On the other hand, the inactivation of the mPFC prevents long-term consolidation of this change. Integrity of this two structures would therefore be essential to perform an on-line updating of the goal value and for its long-term consolidation. Their interaction would be necessary to rapidly adapt, and in a lasting manner, the behavioral strategy of the animal when it faces an environmental change.

Na epilepsia do lobo temporal (ELT), alterações morfofuncionais em estruturas límbicas são classicamente acompanhadas de déficits cognitivos. Estudos anteriores revelaram que disfunções eletrofisiológicas em circuitos hipocampo-corticais são observadas durante o sono NREM (non rapid eye movement), onde eventos patológicos como fast ripples e IEDs (interictal epileptiform discharges) substituem gradativamente eventos fisiológicos, como as sharp-wave ripples (SWR). Tal substituição pode estar por trás dos prejuízos cognitivos observados tanto nos modelos animais como em pacientes, já que as SWRs são fundamentais para a transferência de informação do hipocampo ao córtex durante a consolidação de memórias. De maneira complementar, o sono REM também parece exercer um papel fundamental em processos mnemônicos, facilitando eventos de plasticidade sináptica e coordenando regiões encefálicas distantes por meio de acoplamento entre diferentes frequências oscilatórias, tais como teta e gama. Entretanto, as alterações no sono REM durante os processos de epileptogênese ainda foram pouco exploradas. Neste trabalho testamos a hipótese de que disfunções na coordenação rítmica durante o sono REM estariam associadas a prejuízos de memória que se manifestam na epileptogênese. Para isso, submetemos ratos Wistar adultos machos a protocolo de abrasamento rápido da amígdala basolateral, possibilitando a avaliação de alterações eletrofisiológicas gradativas durante o processo de epileptogênese. Foram realizados implantes crônicos de eletrodos para registro do potencial local de campo (LFP, Local Field Potential) nas regiões de CA1 e do córtex pré-frontal medial (mPFC, medial prefrontal cortex), além de eletrodos bipolares para estímulo na amígdala basolateral. Os protocolos de abrasamento foram realizados durante um período de 3 dias, aplicando-se diariamente 10 trens de estímulos a 50 Hz com duração de 10 segundos. Para avaliarmos os prejuízos cognitivos, os animais foram submetidos a testes de reconhecimento de objetos antes do início a após o término dos protocolos de abrasamento. O sonosubsequente às sessões de reconhecimento de objetos e aos protocolos de estimulações foram registrados diariamente. Além do prejuízo no reconhecimento de objetos e alterações eletrofisiológicas durante o sono NREM, como a substituição gradativa de ripples por IEDs, os animais submetidos ao abrasamento elétrico apresentaram um aumento na comodulação fase-amplitude entre oscilações teta e gama durante o sono REM após as estimulações, exibindo também uma correlação negativa entre a comodulação e a duração das pós-descargas induzidas pelos estímulos elétricos do abrasamento durante o sono subsequente a aplicação dos protocolos. Nossos achados ampliam a compreensão vigente sobre como alterações de oscilações cerebrais durante o sono, especialmente da fase REM, poderiam estar subjacentes a prejuízos de memória que ocorrem na ELT. / Morphofunctional changes in limbic structures are classically followed by cognitive deficits in Temporal Lobe Epilepsy (TLE) patients. Previous studies revealed that electrophysiological dysfunctions in hippocampal-cortical circuits are observed during NREM (non-rapid eye movement) sleep, where pathological events such as fast ripples and IEDs (interictal epileptiform discharges) gradually replace physiological events, such as Sharpwave Ripples (SWR). This replacement seems to describe the cognitive impairments observed in animal models and TLE patients since SWRs are fundamental for information transfer from the hippocampus to cortex during memory consolidation. Complementary, REM sleep also plays a significant role in mnemonic processes, facilitating synaptic plasticity events and coordinating distant brain regions by coupling different frequencies, such as theta and gamma. However, alterations in REM sleep during the epileptogenesis processes are poorly investigated. In this study, we tested the hypothesis that dysfunctions on rhythmic coordination during REM sleep would be associated with memory deficits showed during epileptogenesis. For this, we submitted adult Wistar rats to a rapid kindling protocol on basolateral amygdala (BLA), allowing the evaluation of progressive electrophysiological changes during the epileptogenic process. Chronic electrodes were implanted for the local field potentials (LFP) recording in the CA1 and medial prefrontal cortex (mPFC), as well as bipolar electrodes for BLA stimulation. The kindling protocols were performed during three days, applying ten trains of 50 Hz stimulations with ten seconds duration. Object recognition tasks were performed before and after the kindling protocol to evaluate cognitive impairment. Sleep recordings were performed daily after the object recognition or kindling application. Along with object recognition impairment and electrophysiological changes during NREM sleep, such as progressive SWR substitution by IEDs, kindled rats presented an increase in phase-amplitude comodulation between theta and gamma oscillations during REM sleep after stimulation sessions, which also correlates negatively with after-discharges (AD) duration induced by the kindling stimulation. Our findingsexpand the comprehension about how changes in brain oscillations during REM sleep underlies observed memory deficits in TLE.

A esquizofrenia é uma desordem altamente incapacitante que atinge cerca de 1% da população, envolvendo desequilíbrio da neurotransmissão dopaminérgica e uma hipofunção glutamatérgica. Portadores dessa doença apresentam deficiência do processamento de informações caracterizada por prejuízo no teste de inibição pré-pulso (prepulse inhibition - PPI). Essa condição pode ser reproduzida em modelos experimentais, pelo tratamento com psicoestimulantes, como a anfetamina (ANF) e atenuado/revertido pelo tratamento com antipsicóticos. O canabidiol (CBD) é o principal componente não psicotomimético da Cannabis sativa. Estudos clínicos e pré-clínicos sugerem que o CBD apresenta perfil antipsicótico, com baixa indução de efeitos adversos. Contudo, até o momento poucos estudos foram realizados com o objetivo de investigar os mecanismos farmacológicos e/ou moleculares envolvidos nesse perfil. Os prováveis mecanismos envolvidos com as propriedades antipsicóticas do CBD parecem envolver a ativação de receptores TRPV1 e o aumento da sinalização do endocanabinoide anandamida. No presente estudo, demonstramos que os receptores TRPV1 e o aumento da disponibilidade de anandamida parecem participar do perfil antipsicótico do CBD. Nessas investigações, não observamos participação dos receptores 5-HT1A. A microinjeção de CBD no córtex pré-frontal (CPF), estrutura envolvida com a fisiopatologia da esquizofrenia e um provável sítio para ação de antipsicóticos, não atenuou o prejuízo induzido por ANF no PPI. Recentemente, mecanismos epigenéticos, como a metilação do DNA, têm sido associados à fisiopatologia da esquizofrenia. Nesse sentido, avaliamos o envolvimento da metilação do DNA em estruturas envolvidas com a neurobiologia da esquizofrenia regulada por CBD, sobre as respostas comportamentais induzidas por drogas psicotomiméticas. Verificamos que a ANF causa um aumento da metilação global no estriado ventral, efeito bloqueado pelo pré-tratamento com CBD e de forma semelhante com o antipsicótico clozapina (CLZ). Não observamos alterações na metilação global no CPF. O tratamento com MK-801 não alterou a metilação global nas duas estruturas anteriormente citadas. Protocolo experimental semelhante foi utilizado em mais duas abordagens: (i) a expressão do fator neurotrófico do cérebro (BDNF), relacionado com a manutenção, crescimento e diferenciação dos neurônios está aumentada no hipocampo dos animais tratados com a associação CBD e ANF, padrão semelhante foi observado com a associação CLZ e ANF. (ii) a expressão de fosfo-histona acetilada, um marcador que indica alterações na cromatina, intimamente ligada com as alterações da expressão gênica está aumentada no núcleo acumbens e CPF dos animais tratados com a associação CBD e ANF. Os dados aqui apresentados sugerem que os receptores TRPV1 e o endocanabinoide anandamida parecem estar envolvidos com o perfil antipsicótico do CBD. Pela primeira vez foi demonstrado que tanto o pré-tratamento com CBD ou CLZ podem alterar o aumento da metilação global de DNA induzido por ANF. Além disso, a expressão de BDNF no hipocampo e a expressão de fosfo-histona acetilada podem ser outros mecanismos que merecem atenção em relação ao perfil antipsicótico do CBD. / Schizophrenia is a highly disabling disorder that affects about 1% of the population and involves impaired dopaminergic neurotransmission and glutamatergic hypofunction. Patients with this disorder have a deficiency in information processing characterized by disruption in the prepulse inhibition (PPI) test. This condition can be reproduced in experimental models by treatment with psychostimulants such as amphetamine and attenuated / reversed by treatment with antipsychotics. Cannabidiol (CBD) is the main non-psychotomimetic component of Cannabis sativa. Clinical and preclinical studies suggest that CBD has an antipsychotic profile, with low induction of adverse effects. However, to date, few studies have been carried out to investigate the pharmacological and / or molecular mechanisms involved in this outcome. The likely mechanisms involved with the antipsychotic properties of CBD appear to involve activation of TRPV1 receptors and increased endocannabinoid anandamide signaling. In the present study, we demonstrated that TRPV1 receptors and the increased availability of anandamide appear to participate in the CBD antipsychotic profile. In these investigations, we did not observe participation of 5-HT1A receptors. Microinjection of CBD in the prefrontal cortex, structure involved in the pathophysiology of schizophrenia and a probable site of antipsychotic action, did not attenuate the amphetamine-induced disruption in PPI. Recently, epigenetic mechanisms, such as DNA methylation, have been associated with the pathophysiology of schizophrenia. In this sense, we also evaluated the involvement of DNA methylation in structures involved with the neurobiology of CBD-regulated schizophrenia on behavioral responses induced by psychotomimetic drugs. We found that amphetamine causes increased global methylation in the ventral striatum, an effect blocked by pre-treatment with CBD and similarly with the antipsychotic clozapine. We did not observe changes in the global methylation in prefrontal cortex. Treatment with MK-801 did not alter the global methylation in the two aforementioned structures. Similar experimental protocol was used in two other approaches: (i) brain neurotrophic factor (BDNF) expression, related to the maintenance, growth and differentiation of neurons is increased in the hippocampus of animals treated with CBD and amphetamine; a similar pattern was observed with the association clozapine and amphetamine. (ii) the expression of acetylated phospho-histone, a marker indicating changes in chromatin, closely linked to changes in gene expression is increased in the nucleus acumbens and CPF in animals treated with the CBD and amphetamine combination. The data presented here suggest TRPV1 receptors and the endocannabinoid anandamide seem to be involved with the antipsychotic profile of CBD. For the first time it has been shown that both pre-treatment with CBD or clozapine may alter the increase in overall DNA methylation induced by amphetamine. In addition, the expression of BDNF in the hippocampus and the expression of acetylated phospho-histone may be different mechanisms that deserve attention in relation to the antipsychotic profile of CBD.

A depressão periparto (PPD) é subtipo altamente prevalente e subdiagnosticado do transtorno depressivo maior (MDD), e causa um importante sofrimento para a mulher, sua família e seu filho. Uma interação complexa entre hormônios, neurotransmissores e fatores genéticos e ambientais pode estar envolvida na etiologia da PPD. Contudo, estudos de neuroimagem na PPD ainda são escassos, particularmente os que identificam alterações neuroquímicas. Sabe-se que a região do córtex pré frontal dorsolateral (dlPFC) está relacionada à funções executivas no circuito pré frontal, e juntamente com o giro do cíngulo anterior (ACG) faz parte das vias neuronais envolvidas no processamento emocional, desde a geração, regulação e reavaliação do estado afetivo. Existem evidências de que ambas as áreas estejam disfuncionais na MDD. A avaliação neuroquímica obtida pela espectroscopia de próton por ressonância magnética (MRS) permite inferir o metabolismo, a neurotransmissão e a viabilidade do tecido neuronal de interesse destas áreas fronto-límbicas. Objetivo: comparar puérperas com depressão periparto (grupo PPD) com puérperas saudáveis (grupo HP) quanto à avaliação neuroquímica no dlPFC esquerdo e no ACG bilateral. Métodos: 36 puérperas do grupo PPD e 25 puérperas do grupo HP foram submetidas à duas entrevistas psiquiátricas estruturadas e à aplicação de questionários e escalas psicométricas, sendo a segunda avaliação realizada seccionalmente à MRS. A MRS foi adquirida pro MRI com campo de 3 Tesla, estando o volume de interesse (VOI) posicionado no dlPFC esquerdo e no ACG bilateral e processada pelo software LCModel. Os resultados neuroquímicos expressos em valores absolutos e normalizados pela creatina (razão metabólito/creatina) foram analisados por ANCOVA, incluindo a idade, o tempo de puerpério e o tipo de contraceptivo, enquanto covariáveis. Resultados: No dlPFC, o grupo PPD apresentou menores valores de Glu/Cr (-0,17; p=0,05), Glx (-0,95 mM; p=0,04), Glx/Cr (-0,22; p=0,03), NAA (-0,60 mM; p<0,01), e NAA/Cr (-0,13; p=0,02) em relação ao grupo HP. No ACG, o uso de hormônios contraceptivos somente com progestágenos resultou em um aumento dos valores de Glu (2,18 mM; p=0,03), Glx (1,84 mM; p=0,03), e redução de Cho/Cr (-0,08; p=0,03) quando comparados ao grupo que não utilizou somente progestágenos, independentemente dos grupos HP e PPD. Conclusão: Os níveis reduzidos de Glu e NAA no grupo PPD estão relacionados, respectivamente, à disfunção metabólica glutamatérgica e neuroglial no dlPFC, o que pode explicar sintomas cognitivos também relacionados à PPD, tal como já verificado no MDD. O uso de hormônios contraceptivos com progestágenos isoladamente interferiu com a neuroquímica do ACG, mas não se relacionou com a PPD. Embora o aumento do glutamato possa sugerir uma hiperfuncionalidade do ACG, e a redução da Cho/Cr representar diminuição de \"turnover\" da membrana lipídica ou da transdução sináptica, seu significado clínico e fisiopatológico ainda é incerto. Estes resultados contribuem com a compreensão dos substratos neuroquímicos de PPD / Peripartum depression (PPD) is a highly prevalent subtype of major depressive disorder (MDD) related to a significant loss for mother, family and baby. An Interaction between hormones, genetic, and environmental factors must be involved in its etiology. However, neuroimaging studies on PPD are still rare, particularly those that identify neurochemical changes. However, neuroimaging studies in PPD are still rare, particularly those that identify neurochemical changes. It is known that the region of the dorsolateral prefrontal cortex (dlPFC) is related to executive functions in the prefrontal circuit, and together with the anterior cingulate gyrus (ACG) is part of the neural pathways involved in emotional processing, including the generation, regulation, and reappraisal of affective state. And, there is evidence that both areas are dysfunctional in MDD. The neurochemical evaluation obtained by spectroscopy of proton magnetic resonance (MRS) allows to infer metabolism, neurotransmission and the viability of the neuronal tissue of interest these frontal-limbic areas. Objective: Compare postpartum women with peripartum depression (PPD group) with healthy postpartum women (HP group) regarding the neurochemical evaluation in the left dlPFC and bilateral ACG. Methods: 36 postpartum women of PPD group and 25 postpartum women of the HP group were subjected to two structured psychiatric interviews and questionnaires and psychometric scales, with the second evaluation performed sectionally at MRS. The MRS was obtained by 3-T MRI system with the volume of interest (VOI) positioned on the left dlPFC and bilateral ACG and processed by LC Model software. The neurochemical results expressed in absolute values and normalized by creatine (reason metabolite/creatine) were analyzed using ANCOVA, including age, postpartum time, the type of contraceptive as covariates. Results: In the dlPFC, PPD group presented significantly lower values of Glu/Cr (-0.17; p=0.05), Glx (-0.95mM; p=0.04), Glx/Cr (-0.22; p=0.03), NAA (-0.60mM; p<0.01), and NAA/Cr (-0.13; p=0.02) than HP. In ACG, progestogens isolated contraceptive hormones use resulted in significantly increased Glu (2.18mM; p=0.03), Glx (1.84mM; p=0.03), and reduced Cho/Cr (-0.08; p=0.03), compared to women without use them, regardless of diagnostic groups. Conclusions: The reduced levels of Glu and NAA in the PPD group are related respectively to the glutamatergic and neuroglial metabolic dysfunction in the dlPFC, which may explain cognitive symptoms also related to PPD as already verified in MDD. Progestogens isolated contraceptive hormones use interfered with neurochemistry of ACG, but not associated with PPD. Although the increase of glutamate may suggest an overactive ACG, and lower Cho/Cr represent decrease of the lipid membrane turnover or synaptic transduction its clinical and pathophysiological significance remains uncertain. These results contribute to the understanding of the neurochemical substrates of PPD

O estresse por isolamento social aplicado em ratos a partir do desmame e mantido durante o desenvolvimento encefálico tem sido utilizado como um modelo experimental de desordens psiquiátricas como a esquizofrenia. Tem sido demonstrado que o isolamento induz alterações morfológicas, comportamentais (como hiperatividade em um novo ambiente) e neuroquímicas semelhantes àquelas que ocorrem em humanos esquizofrênicos. Evidências sugerem que as sinapses glutamatérgicas sejam o sitio primário das anormalidades que ocorrem na esquizofrenia, sendo as alterações dopaminérgicas secundárias às glutamatérgicas. Nesse sentido, alterações nos mecanismos de regulação desta neurotransmissão pelos transportadores de glutamato podem contribuir para o desenvolvimento e/ou manutenção da esquizofrenia. Neste estudo analisamos o padrão de atividade locomotora e a expressão de transportadores de glutamato (EAAC1 e GLT1) no córtex pré-frontal e córtex entorrinal de ratos criados em isolamento a partir do desmame. Ratos Wistar machos (PND21) foram aleatoriamente alocados em 2 grupos (n=11-12): controle (agrupados, 3 animais/caixa) ou isolados (1 animal/caixa) por 10 semanas. Os animais foram testados no campo aberto (arena) durante 20 min. e registrados: números de cruzamentos (exploração horizontal), número de levantamentos (exploração vertical) e tempo despendido, tanto no centro como na periferia da arena. Os grupos foram comparados utilizando ANOVA ou teste t de Student (significante quando p 0.05). Os animais foram anestesiados (uretana-Sigma, 25%, 5ml/kg), perfundidos e os encéfalos retirados, congelados e posteriormente utilizados nos experimentos de imunoistoquímica. Secções (40m) do córtex pré-frontal (CPF) e córtex entorrinal (CE) foram utilizadas para o estudo da expressão de EAAC1 e GLT1. A criação em isolamento induziu hiperatividade, com um aumento no número total de cruzamentos em relação aos animais agrupados (F1,22=0,38; p<0,05), sendo mais consistente na periferia da arena e após 5 minutos de teste (73%, (F1,22=14,08; p<0,001). Em contraste, o isolamento induziu redução no número total de levantamentos (F1,22=0,27; p=0,05), principalmente no centro da arena (58%, F1,22=12,48; p<0,01), nos primeiros 15 minutos de teste e significante no 1° e 3° blocos de tempo (BT1 e BT3). Na periferia o isolamento induziu aumento significante no número de levantamentos em BT2 e BT3. O tempo despendido no centro e na periferia da arena pelos animais criados em isolamento foi, respectivamente, reduzido (54%; F1,22=11,11; p<0,001) e aumentado (65%; F1,22=11,20; p<0,01) quando comparados aos animais agrupados. A expressão de EAAC1 foi significantemente aumentada pelo isolamento no CPF (38%, t= 2,730, p=0,017). Em contraste, nenhuma diferença foi encontrada no CE (t= 1,892; p= 0,081). O isolamento não induziu alteração no número de células imunopositivas para GLT1 no CPF (t=-1,28; p=0,21). Entretanto, marcação fluorescente de GLT1 foi observada associada a células gliais e neuroniais do CPF e CE. Os resultados comportamentais sugerem: i) ratos Wistar criados em isolamento social apresentam hiperatividade em novo ambiente; ii) a hiperatividade locomotora somente é detectável após períodos maiores que cinco minutos de exposição a um novo ambiente; iii) o padrão de exploração apresentado pelos animais demonstra clara preferência pela periferia da arena. Os resultados moleculares fornecem evidências para a participação dos transportadores de glutamato na redução da neurotransmissão glutamatérgica no CPF de ratos criados em isolamento a partir do desmame. / Isolation rearing of rats from weaning has been used as an experimental model of psychiatric disorders like schizophrenia. It has been demonstrated that isolation induces morphological, behavioral (like hyperactivity in a novel environment) and neurochemical changes similar to those reported for humans with schizophrenia. Evidence suggest that glutamatergic synapses might be the site of primary abnormalities in this disorder with the dopaminergic changes being secundary to the glutamatergic ones. In this context, changes on the mechanisms of regulation of the glutamatergic neurotransmission through glutamate transporters may contribute to the development and/or maintenance of schizophrenia. In this study we analyzed the pattern of locomotor activity and the expression of glutamate transporters (EAAC1 and GLT1) in prefrontal cortex and entorhinal cortex of rats reared in social isolation from weaning. Male Wistar rats (PND 21) were randomly allocated in 2 groups (n=11-12): control (grouped, 3 animals/cage) or isolated (1 animal/cage) for 10 weeks. The animals were tested in the open field (arena) for 20min. and recorded: number of crossings (horizontal exploration), number of rearings (vertical exploration) and time spent either at the center or at the periphery of the arena. The groups were compared using ANOVA or Sudents \"t\" test (significance level was set at p 0.05). The animals were anesthetized (urethane-Sigma, 25%, 5ml/kg), perfused and the brains removed, frozen and further used on the experiments of immunohistochemistry. Sections (40m) of the prefrontal córtex (PFC) and entorhinal córtex (EC) were used for studying the expression of EAAC1 and GLT1. Isolation rearing induced hyperactivity, with an increase in the number of crossings related to grouped animals (F1,22=0,38; p<0,05), being more consistent at the periphery of the arena and after 5 minutes of test (F1,22=14,08; p<0,001). In contrast, isolation induced a decrease in the total number of rearings (F1,22=0,27; p=0,05), mainly in the center of the arena (58%, F1,22=12,48; p<0,01), in the first 15 minutes of test and significant on the 1st and 3rd blocks of time (BT1 e BT3). In the periphery isolation induced a significant increase in the number of rearings in BT2 and BT3. The time spent in both center and periphery of the arena by the rats reared in isolation was, respectively, decreased (54%; F1,22=11,11; p<0,01) and increased (65%; F1,22=11,20; p<0,01) when compared to grouped rats. The expression of EAAC1 was significantly increased by isolation in PFC (38%, t = 2,730, p = 0,017). In contrast, no change was found in EC (t = 1,892, p = 0,081). Isolation rearing did not induce alterations in the number of immunopositive cells for GLT1 in PFC (t= -1,28; p = 0,21). However, fluorescent labeling of GLT1 was seen associated to both glial cells and neuronal cells. The behavioral results suggest: i) Wistar rats reared in social isolation present hyperactivity in a novel environment; ii) the hyperactivity is only detectable after periods longer than 5 minutes; iii) the pattern of exploration showed by the animals demonstrate clear preference for the periphery of the arena. The molecular results provide evidence for the involvement of glutamate transporters on the reduction of glutamatergic neurotranmission in PFC of rats reared in isolation from weaning.

INTRODUÇÃO: A síndrome de Burnout é uma das consequências mais marcantes do estresse profissional, resultante da exposição prolongada a fatores interpessoais e emocionais, caracterizada por exaustão emocional, avaliação negativa de si mesmo, depressão e insensibilidade com relação a fatores ocupacionais e pessoais. Profissionais da área da saúde estão expostos a cenários clínicos com altos níveis de estresse e sujeitos ao desenvolvimento de Burnout durante suas carreiras. É uma entidade complexa e produz uma variedade de comportamentos que podem afetar diretamente o atendimento ao paciente. O estresse é uma resposta global do organismo que envolve as esferas física, emocional, mental e hormonal. OBJETIVO: Avaliar a prevalência de Síndrome de Burnout e sintomas de estresse nos médicos residentes de primeiro ano do Departamento de Pediatria da Faculdade de Medicina da Universidade de São Paulo e a correlação entre esta e a função cerebral de atenção por meio da execução de tarefa Stroop Color Word Test durante a realização de ressonância magnética funcional (RMf). MATERIAIS E MÉTODOS: Foram estudados 32 médicos residentes de pediatria, 25 do sexo feminino com média de idade de 24,8 ± 1,3 anos, todos com carga horária de trabalho semanal similar. Foram utilizados os questionários padronizados Maslach Burnout Inventory - MBI sendo considerado Burnout pontuação maior que 19 na subescala de exaustão emocional e maior que 6 na escala de despersonalização. Para a avaliação de estresse foi utilizado o inventário de sintomas de estresse de Lipp - ISSL, sendo considerado diagnóstico de estresse pontuações elevadas calculadas conforme o manual do ISSL. RESULTADOS: A síndrome de Burnout foi identificada em 50% da população estudada e estresse em 56,25%. Essa associação apresentou significância estatística (p=0,02). Ao analisar os mapas de RMf encontramos maior ativação do córtex pré-frontal dorso lateral a direita nos residentes que apresentaram Burnout, área envolvida nos mecanismos de atenção. CONCLUSÕES: A prevalência da Síndrome de Burnout e estresse em residentes de pediatria é elevada, correspondendo a 50% e 56% respectivamente, e está associada a maior ativação do córtex pré-frontal dorsolateral direito, área envolvida com mecanismos de atenção e cognição. Existe correlação entre as duas entidades clínicas com significância estatística e a prática de esportes está associada a menores taxas de Burnout / Burnout syndrome is one of the most important consequences of occupational stress. It is a result from prolonged exposure to emotional and interpersonal factors and characterized by emotional exhaustion, negative evaluation of oneself, depression and insensitivity. Health care professionals are exposed to clinical settings with high levels of stress and can develop burnout during their careers. It is a complex entity and produces a variety of behaviors that can affect directly patient care. Stress is a global response that involves physical, emotional, mental and hormonal aspects. In the present study we used Functional Magnetic Resonance Imaging (fMRI) to investigate a sample of pediatric residents from University of Sao Paulo with different levels of burnout syndrome in Burnout Maslach Inventory - MBI and stress during the execution of a low demand attention paradigm (Stroop color word test). Scores greater than 19 on the subscale of emotional exhaustion and greater than 6 on the scale of depersonalization in MBI was considered as Burnout. For the assessment of stress was used inventory of stress symptoms Lipp - ISSL, considered diagnostic of stress high scores calculated as the ISSL manual. We studied 32 residents, 25 females with a mean age of 24.8 ± 1.3 years, all with similar weekly workload. Burnout syndrome was identified in 50% of the study population and stress in 56.25%. This association was statistically significant (p = 0.02). By analyzing fMRI maps, an activation of the right dorsolateral prefrontal cortex was showed in residents with Burnout, an area involved in attention tasks