La catégorisation est un ensemble d’opérations mentales qui permettent de classer les objets et les évènements. C’est un processus crucial pour de nombreuses situations, telles que la survie dans le monde animal, l’apprentissage chez l’enfant, ou encore le raisonnement abstrait et la résolution de problèmes. Les patients ayant des lésions du cortex préfrontal présentent des difficultés pour les tâches de catégorisation, et l’existence de ces difficultés est corrélée au handicap fonctionnel de ces patients. Dans une première partie, nous avons mis au point une tâche de catégorisation adaptée pour l’utilisation chez le patient, intitulée SimiCat. A l’aide de cette tâche, nous avons précisé les difficultés de catégorisation des patients et montré que les erreurs de type différenciations sont spécifiques des patients frontaux. La tâche SimiCat présente une très bonne valeur diagnostique pour distinguer les patients ayant une démence fronto-temporale de ceux ayant une maladie d’Alzheimer. Dans une deuxième partie, nous avons utilisé l’IRM fonctionnelle pour préciser les bases cérébrales de deux processus clés pour la catégorisation : l’abstraction et la détection de similitudes. Nous avons montré que l’abstraction repose sur le cortex préfrontal dorsolatéral gauche, alors que la détection de similitudes repose sur le cortex préfrontal ventrolatéral bilatéral. A l’aide de la morphométrie basée sur le voxel, nous avons montré que la variabilité des performances de catégorisation des sujets sains était corrélée au volume de la portion antérieure du gyrus temporal moyen et inférieur droit, avec un gradient postéro-antérieur selon le niveau d’abstraction de la catégorisation. Dans une troisième partie, nous avons mis au point une tâche de double amorçage sémantique que nous utiliserons pour étudier les processus de catégorisation automatique chez les patients ayant des lésions frontales et temporales. A partir de ces résultats, nous proposons un modèle d’organisation cérébrale pour la catégorisation, reposant sur les régions temporales antérieures, le cortex préfrontal ventrolatéral bilatéral et dorsolatéral gauche. Nos résultats permettent également de mieux comprendre les déficits de catégorisation des patients, ce qui permettra d’adapter leur prise en charge diagnostique et thérapeutique. / Categorization is a set of mental processes that allow classifying objects and events. It is crucial in various contexts such as survival in animals, concept learning in children, abstract reasoning and problem solving. Patients with brain lesions involving the prefrontal cortex are impaired in categorization tasks. Categorization impairment correlates with functional autonomy in dementia. In the first part, we have developed a task, named SimiCat that we designed in order to assess categorization abilities in patients. With the help of this task, we showed that differentiation errors are specific of frontal patients. The SimiCat task has a good diagnostic value to distinguish behavior variant Frontotemporal dementia from Alzheimer disease.In the second part, we assessed the brain correlates of categorization. With functional MRI, we showed that abstraction involves the left dorsolateral prefrontal cortex, while similarity detection involves bilateral ventrolateral prefrontal cortex. With voxel-based morphometry we showed that variability in categorization performances correlates with the volume of the right anterior temporal lobe, with a caudo-rostral gradient according to abstraction. In the third part, we developed a double priming task that we will use to assess automatic categorization processes in patients with temporal and frontal lesions. Based on these results, we propose a model of brain organization for categorization. This model involves both anterior temporal lobes, as well as bilateral ventrolateral and left dorsolateral prefrontal cortices. Our results also contribute to a better understanding and management of patients suffering from categorization deficits.

O córtex pré-frontal medial ventral (CPFMv) é uma estrutura límbica que está envolvida em respostas autonômicas associadas a reações aversivas. O CPFMv é dividido em córtex pré- límbico (PL), córtex infralímbico (IL) e córtex dorsopeduncular (DP). A estimulação elétrica ou química destas regiões causa respostas defensivas e alterações autonômicas tais como respostas cardiovasculares, dependendo da sub-região estimulada. O estresse de restrição (ER) causa alterações hormonais e respostas autonômicas, tais como aumento de pressão arterial (PA) e frequência cardíaca (FC). A ativação de neurônios presentes no CPFMv durante essa situação aversiva, assim como os resultados da inibição farmacológica das sinapses presentes no PL e IL sugerem o envolvimento destas estruturas na modulação das respostas cardiovasculares causadas pelo ER. Entretanto, os possíveis neurotransmissores presentes no vCPFM, envolvidos nesta modulação, ainda não foram elucidados. O sistema opioidérgico central modula o sistema cardiovascular inclusive durante situações aversivas, sendo que tanto receptores quanto peptídeos opióides estão presentes no CPFMv. Considerando o exposto acima, a hipótese a ser testada no presente trabalho foi que a neurotransmissão opioidérgica do PL e IL está envolvida na modulação das respostas cardiovasculares de aumento da PA e FC desencadeadas pelo ER. Assim, a administração de naloxona (antagonista não-seletivo de receptores opióides) no PL ou IL reduziu a resposta pressora e taquicardíaca induzida pelo ER, sendo o perfil da curva dose-inibição em forma de U-invertido. A administração de CTAP (antagonista dos receptores opióides µ) ou nor-BNI (antagonista dos receptores opióides ?) no PL também reduziu a resposta pressora e taquicardíaca induzida pelo ER, de forma semelhante à naloxona, sugerindo o envolvimento desses receptores na modulação das respostas cardiovasculares desencadeadas pelo ER, enquanto que no IL, apenas a administração de nor-BNI reduziu a resposta cardiovascular induzida pelo ER. O tratamento com naltrindole (antagonista ?-seletivo) em ambas as estruturas não alterou a resposta pressora e taquicardíaca gerada pelo ER. A administração de UPF-101 (antagonista ORL-1) no PL potencializou a resposta taquicardíaca, sem alterar a resposta pressora enquanto a administração no IL não gerou efeito. Em resumo, os resultados indicam que o sistema opioidérgico, presente no PL e IL, desempenha papel facilitatório sobre as respostas cardiovasculares induzidas pelo ER, enquanto o sistema nociceptina/orfanina FQ apresentaria papel inibitório. / The ventral medial prefrontal cortex (vMPFC) is a limbic structure involved in the mediation of autonomic responses associated to aversive situations. The vMPFC is divided into prelimbic cortex (PL), infralimbic cortex (IL) and dorsal peduncular cortex (DP). The electrical or chemical stimulation of these regions cause defensive responses and autonomic changes, such as cardiovascular responses, depending on the subregion stimulated. The restraint stress (RS) evokes hormonal and autonomic responses, as well as arterial pressure and heart rate increases. Neuronal activation in the vMPFM was reported during this aversive situation, and the pharmacological inhibition of synapses in the PL and IL has suggested the involvement of these structures in the modulation of cardiovascular responses caused by RS. However, the possible neurotransmitters present in vCPFM that are involved in this modulation have not yet been identified. Opioid peptides and their receptors are present in the CPFMv. Furthermore, the central opioid system is known to modulate the cardiovascular system, even during aversive situations. Therefore, the hypothesis of this study was that PL and IL opioid neurotransmission is involved in the modulation of cardiovascular responses caused by RS. Naloxone (opioid nonselective antagonist) administration in PL or IL reduced the pressure and tachycardiac response evoked by RS, with the dose-inhibition curve having an U-inverset shape. Similar to naloxone, the selective µ-opioid antagonist CTAP and the selective ?-opioid antagonist nor-BNI when administered into the PL also reduced the pressor and tachycardiac response induced by RS, thus suggesting an involvement of these receptors in the modulation of cardiovascular responses evoked by RS, while in the IL, only administration of nor- BNI reduced the cardiovascular response induced by RS. In both structures, the treatment with the selective ?-opioid antagonist naltrindole did not affect the pressor and tachycardic response caused by RS. The pretreatment of the PL with the selective ORL-1 antagonist UPF-101 increased the tachycardic response, without affecting the RSevoked pressor, while the administration of UPF-101 into the IL did not affect the RS-evoked cardiovascular response. In summary, the opioid system in PL and IL appear to play a facilitatory role on the cardiovascular responses induced by RS, while the system nociceptin / orphanin FQ would have an inhibitory role on these responses.

A administração sistêmica de canabidiol (CBD), o principal constituinte não psicomimético da Cannabis sativa, induz efeito antidepressivo em modelos préclínicos. O mecanismo de ação do canabidiol, no entanto, permanece pouco conhecido, podendo envolver a ativação de receptores serotoninérgicos do tipo 1A (5-HT1A). Ademais, as estruturas encefálicas envolvidas nesses efeitos permanecem desconhecidas. O córtex pré-frontal medial ventral (CPFmv), dividido em infra-límbico (IL) e pré-límbico (PL), recebe densa inervação serotoninérgica e desempenha importante papel na modulação da resposta emocional ao estresse e na neurobiologia da depressão. Dessa forma, o objetivo do presente trabalho foi avaliar a hipótese de que a administração de canabidiol no CPFmv, diferenciado em PL e IL, produz efeito tipo-antidepressivo por meio da ativação de receptores 5- HT1A. Para tanto, ratos Wistar canulados bilateralmente no CPFmv, receberam CBD (10, 30, 60 nmol/0,2?l) ou veículo intra-PL e CBD (30, 45 e 60nmol/0,2?l) ou veículo intra-IL e foram submetidos ao teste do nado forçado ou ao teste do campo aberto. Outro grupo de animais recebeu microinjeção (intra PL ou IL) do agonista de receptores 5-HT1A, 8-OH-DPAT (5, 10nmol/0,2?l) e foram submetidos aos mesmos testes. Um grupo adicional recebeu um antagonista 5-HT1A, WAY1006365 (10, 30nmol/0,2?l), seguido pela administração de 8-OH-DPAT (10nmol0,2?l) ou CBD (10 nmol0,2?l) intra-PL, ou 8-OH-DPAT (10nmol0,2?l) ou CBD (45 nmol0,2?l) intra-IL, e avaliados no teste do nado forçado. Os resultados demonstraram que a administração de CBD e de 8-OH-DPAT, intra-PL e intra-IL, reduziu significativamente o tempo de imobilidade no teste do nado forçado, um efeito tipoantidepressivo, sem alterar a atividade locomotora dos animais no teste do campo aberto. Além disso, a administração de WAY100635 intra-PL e intra-IL não alterou o tempo de imobilidade per se, mas foi capaz de bloquear os efeitos da administração do CBD e do 8-OH-DPAT. Esses resultados sugerem que a administração local do CBD no CPFmv induz efeito tipo-antidepressivo por meio da ativação de receptores 5-HT1A. Portanto, é possível que o CPFmv esteja envolvido no efeito tipoantidepressivo induzido pelo CBD. / Systemic administration of cannabidiol (CBD), the main non-psychotomimetic constituent of Cannabis sativa, induces antidepressant-like effects in pre-clinical models. The mechanism of action of Cannabidiol, which remains poorly understood, may involve serotonergic type 1A receptors activation (5-HT1A). Furthermore, the brain structures involved in these effects are still unknown. The ventral medial prefrontal cortex (vmPFC), divided in infra-limbic (IL) and pre-limbic (PL) subregions, receives dense serotonergic innervation and plays an important role in the modulation of emotional responses to stress and in the neurobiology of depression. Thus, the aim of this study was evaluate the hypothesis that the administration of cannabidiol into the vmPFC, differentiated into IL and PL, would induce antidepressant-like effect by activating 5-HT1A receptors. Therefore, male Wistar rats with cannulae bilaterally implanted into the Il and PL were given CBD (10, 30, 45, 60 nmol/0,2?l) or vehicle and were submitted to the forced swimming test or to the open field test. Another group of animals received microinjections (intra PL or IL) of the 5- HT1A agonist 8-OH-DPAT (5, 10nmol/0,2?l) and was submitted to the same tests. An additional group received an 5-HT1A antagonist, WAY100635 (10, 30 nmol/0,2?l.), followed by the administration of 8-OH-DPAT (10 nmol/0,2?l) or CBD (10 nmol0,2?l) intra-PL, or 8-OH-DPAT (10nmol0,2?l) or CBD (45 nmol0,2?l) intra- IL, and avaluated in the forced swimming test. The results showed that CBD and 8- OH-DPAT administration, intra-PL and intra-IL, significantly reduced the immobility time in the forced swimming test, an antidepressant-like effect, without changing the locomotor activity of the animals in the open field test. Moreover, the administration of WAY100635, intra-PL and intra-IL, did not change the immobility time per se, but blocked the CBD- and 8-OH-DPAT-induced effects. These results suggest that the local administration of CBD into the vmPFC induces antidepressant-like effects through the activation of 5-HT1A receptors. Therefore, it is possible that the vmPFC is involved in CBD-induced antidepressant-like effect.

A participação do córtex pré-frontal na memória episódica verbal e seu envolvimento na estratégia organizacional semântica têm sido demonstrados em vários estudos de neuroimagem funcional. Entretanto nenhum estudo anterior investigou os efeitos do treino cognitivo com uso de estratégia semântica sobre a cirtuitaria neural. No presente estudo Investigou-se a codificação da memória episódica verbal, por meio de ressonância magnética funcional (RMf). Quinze voluntários viram listas de palavras apresentadas em três condições de organização semântica: 1) RE relacionada estruturada, 2) RNE relacionada não estruturada e 3) NR não relacionada, antes e após trinta minutos de treino com uso de estratégia organizacional semântica. O principal objetivo foi verificar os efeitos do treino no padrão de ativação neural. Observou-se a participação de uma ampla rede de estruturas cerebrais. O giro frontal inferior e o córtex frontal ventrolateral foram mais ativados após o treino. O córtex pré-frontal dorsolateral e o órbito-frontal foram ativados nas condições RNE e RE antes do treino, as quais permitiram a manipulação e o uso organizacional da estratégia semântica. Os resultados sugerem que: 1) a ativação do giro frontal inferior BA 45 e do córtex pré-frontal ventrolateral BA 47 após o treino pode estar associada ao melhor desempenho da memória episódica verbal. 2) o córtex órbito-frontal BA 11 esteja possivelmente envolvido na mobilização de estratégias e o córtex pré-frontal dorsolateral BA 46 e 9 na manutenção e uso da estratégia mais eficiente / The participation of prefrontal cortex in episodic verbal memory and its involvement in organizational semantic strategy has been demonstrated in several studies of functional neuroimage. However any previous study investigated the effects of cognitive training with semantic organizational strategy use under neural circuitry. At the present study verbal episodic memory encoding were investigated, through functional magnetic resonance (fMRI). Words lists were visually presented to fifteen volunteers in three organizational semantic conditions: 1) RS related structured, 2) RNS related unstructured e 3) UR unrelated, before and after thirty minutes in organizational semantic strategy training. The main objective was to verify the effects of training on neural activation circuitry. The participation of an active broad structure cerebral network was observed. After training the inferior frontal gyrus and the ventrolateral prefrontal cortex were mainly activated. The dorsolateral prefrontal cortex and o orbitofrontal cortex were activated in RNS and RS conditions before training; witch enabled the application and manipulation of semantic organizational strategy. This result suggest: 1) better performance on retrieval and strategy uses after training might be associated to modification of neural activation pattern, and 2) orbitofrontal cortex BA 11 possibly is involved in strategies mobilization, and dorsolateral prefrontal cortex BA 46 e 9 in the uses and maintenance the most efficient strategy

La dopamine du cortex préfrontal (PFC) est impliquée dans l’apprentissage et dans la prise de décision liée à l’effort. Comme l’apprentissage ne peut se faire sans effort, il n’est pas clair aujourd’hui si la dopamine est nécessaire pour l’apprentissage, ou pour l’engagement de l’effort pour apprendre. Dans ce travail, les rats apprenaient à pousser un levier pour obtenir de la nourriture, soit avec (apprentissage par observation, LeO) ou sans (essai-et-erreur, TE) observation préalable d’un congénère exécutant la tâche. TE et la phase d’exécution de LeO nécessitent l’effort physique (overt learning), l’observation dans LeO ne requiert pas d’effort physique (covert learning). Avant chaque session, les rats recevaient des injections de SCH23390 ou de la saline dans le cingulaire antérieur (ACC) ou l’orbitofrontal (OFC). Si la dopamine est nécessaire à l’apprentissage, le blocage des récepteurs D1 affecterait aussi bien l’apprentissage overt que covert. Si la dopamine n’est pas requise pour l’apprentissage mais pour l’engagement de l’effort, le blocage affecterait l’apprentissage overt, et non covert. Les résultats montrent que le blocage de la dopamine dans ACC ou OFC supprime l’apprentissage overt, laissant intact l’apprentissage covert. Une fois les injections arrêtées, les rats récupèrent la capacité d’apprendre, mais dans le cas de ACC, pas la tolérance à l’effort. Ces résultats suggèrent que la dopamine dans ACC et OFC n’est pas nécessaire pour l’apprentissage, et que les déficits d’apprentissage pourraient reflèter une réduction de la tolérance effort à l’effort liée au blocage de la dopamine. / Because prefrontal cortex (PFC) dopamine plays a pivotal role in associative learning and in effort-related decision making, it is not clear as of today whether PFC dopamine activity is required for learning per se, or rather for engaging the effort necessary to learn. In this work, we used observational learning (LeO) and trial-and-error (TE) learning to dissociate learning from physical effort. Both TE and the execution phase of LeO require physical effort (overt learning). Observation does not require physical effort (covert learning). Rats learned to push a lever for food rewards either with or without prior observation of an expert conspecific performing the same task. Before daily testing sessions, the rats received bilateral ACC or OFC microinfusions of SCH23390, or saline-control infusions. If dopamine activity is required for task acquisition, its blockade should impair both overt and covert learning. If dopamine is not required for task acquisition, but solely for regulating effort tolerance, blockade should impair overt learning but spare covert learning. We found that dopamine blockade in ACC or OFC suppressed overt learning selectively, leaving covert learning intact. In subsequent testing sessions without dopamine blockade, rats recovered their overt-learning capacity but, in ACC experiments, the animals did not recover their normal level of effort tolerance. These results suggest that ACC and OFC dopamine is not required for the acquisition of conditioned behaviours and that apparent learning impairments could instead reflect a reduced level of effort tolerance due to cortical dopamine blockade.

Research on the neural correlates of lucid dreaming has recently gained more underlying data. By exploring seven studies that investigated the neural basis of lucid dreaming, this essay sought to examine which neural correlates are associated with lucid dreaming and how proposed neural correlates relate to phenomenological aspects. Dorsolateral prefrontal cortex (DLPFC) was judged as the region most associated with lucid dreaming, in support of a DLPFC hypothesis. Support for reactivation of DLPFC in lucid dreaming consisted of data from electroencephalography, functional magnetic resonance imaging, and transcranial direct current stimulation. Phenomenological aspects associated with this region involved meta-awareness, working-memory, decision-making, and conscious perception. Other regions of interest were parietal areas, frontal areas, and precuneus. Data was not always compatible, implying need for further research. The possibility of further research was judged as promising, based on a recent study inducing lucid dreaming in a significant percent of its test subjects.

Kahneman and Tversky (1979) first demonstrated that when individuals decide whether or not to accept a gamble, potential losses receive more weight than possible gains in the decision. This phenomenon is referred to as loss aversion. We investigated how loss aversion in risky financial decisions is influenced by sudden changes to wealth, employing both behavioral and neurobiological measures. We implemented an fMRI experimental paradigm, based on that employed by Tom et al. (2007). There are two treatments, called RANDOM and CONTINGENT. In RANDOM, the baseline setting, the changes to wealth, referred to as wealth shocks in economics, are independent of the actual choices participants make. Under CONTINGENT, we induce the belief that the changes in income are a consequence of subjects' own decisions. The magnitudes and sequence of the shocks to wealth are identical between the CONTINGENT and RANDOM treatments. We investigated whether more loss aversion existed in one treatment than another. The behavioral results showed significantly greater loss aversion in CONTINGENT compared to RANDOM after a negative wealth shock. No differences were observed in the response to positive shocks. The fMRI results revealed a neural loss aversion network, comprising the bilateral striatum, amygdala and dorsal anterior cingulate cortex that was common to the CONTINGENT and RANDOM tasks. However, the ventral prefrontal cortex, primary somatosensory cortex and superior occipital cortex, showed greater activation in response to a negative change in wealth due to individual's own decisions than when the change was exogenous. These results indicate that striatum activation correlates with loss aversion independently of the source of the shock, and that the ventral prefrontal cortex (vPFC) codes the experimental manipulation of agency in one's actions influencing loss aversion.

The maintenance of social/emotional information in working memory (SWM/EWM) has recently been the topic of multiple neuroimaging studies. However, some studies find that SWM/EWM involves a medial frontal-parietal network while others instead find lateral frontal-parietal activations similar to studies of verbal and visuospatial WM. In this study, we asked 26 healthy volunteers to complete an EWM task designed to examine whether different cognitive strategies- maintaining emotional images, words, or feelings- might account for these discrepant results. We also examined whether differences in EWM performance were related to general intelligence (IQ), emotional intelligence (EI), and emotional awareness (EA). We found that maintaining emotional feelings, even when accounting for neural activation attributable to maintaining emotional images/words, still activated a left lateral frontal-parietal network (including the anterior insula and posterior dorsomedial frontal cortex). We also found that individual differences in the ability to maintain feelings were positively associated with IQ and EA, but not with EI. These results suggest that maintaining the feelings of others (at least when perceived exteroceptively) involves similar frontal-parietal control networks to exteroceptive WM, and that it is similarly linked to IQ, but that it also may be an important component of EA.

Conversation is a highly interactive and coordinated effort between interactants. For example, interactants often mimic the behaviors and speech of one another and coordinate the timing of behaviors, or interactional synchrony. Despite being affected in certain neurological and psychiatric disorders, the neural mechanisms underlying these processes are not understood. The goal of this study is to understand the role of the ventromedial prefrontal cortex (vmPFC), an area of the brain involved in social and emotional behavior, for interpersonal coordination, including mimicry and interactional synchrony. To test the role of the vmPFC for mimicry, normal comparison (NC), brain damaged comparison (BDC), and participants with vmPFC damage interacted in two sessions with a research assistant (RA) who was performing a target behavior (1st session: nodding, 2nd session: face touching). The amount of time the participants spent nodding or touching their face in each session was recorded. NC and BDC participants tended to mimic the partner and nodded slightly more in the session in which the RA was nodding, and touched their face slightly more in the session in which the RA was touching their face. In contrast, vmPFC patients showed no difference in their behaviors in either session, suggesting that they were not influenced by the partner's behaviors and did not mimic them. In a second experiment, all of the above participant groups had a naturalistic conversation with an unfamiliar interactional partner. The conversational data were analyzed for numerous aspects of interpersonal coordination, including convergence of number of words, words per turn and backchannels, reciprocity of self-disclosures, the use of questions, interactional synchrony, and a time series analysis of response latency and speech rate. The vmPFC participants performed consistently worse than NC participants on convergence of words and words per turn, self-disclosures and asking questions. All brain-damaged participants were impaired on aspects of interactional synchrony, and no conclusive results were found for the time series analysis of response latency and speech rate. This study provides support for the hypothesis that the vmPFC is important for interpersonal coordination as the vmPFC group differed significantly from the NC group on the majority of the analyses. The final goal of this study was to understand the effects of traumatic brain injury (TBI) on interpersonal coordination. TBI patients participated in all of the experiments described above and preliminary results showed that they also seemed to be impaired on the mimicry task, and they performed slightly worse than NC participants on many of the interpersonal coordination analyses of the conversational data. This suggests that TBI also does seem to affect certain aspects of interpersonal coordination.

Schizophrenia is a devastating mental illness characterized by a broad range of clinical manifestations including hallucinations, social cognitive impairments, and disordered thinking and behavior, all of which impair daily functioning. The immune molecule complement component 4 (C4), located in the major histocompatibility locus (MHC) on chromosome 6 in humans, is highly associated with schizophrenia such that specific structural variants and regulatory regions increase the expression of C4 and confer greater risk for this brain disorder. Besides their established role in brain immune defense, complement proteins play a role in various stages of brain development including neurogenesis, migration and synaptic development. However, C4 has never been experimentally upregulated to determine the impact of increased expression of this immune gene on brain development. Here, I study the role of C4 in layer 2/3 pyramidal neurons in the medial prefrontal cortex of mice to study the hypothesis that C4 overexpression causes circuit dysfunction by leading to the pathological elimination of synapses. Specifically, neuronal connectivity was assayed by measuring dendritic spine density using confocal microscopy and functional connectivity through whole-cell electrophysiology recordings. Additionally, the role of microglia in altering the developmental wiring of the brain was examined by quantifying microglia engulfment in the medial prefrontal cortex. Lastly, complement-induced changes to the prefrontal cortex were accompanied by deficits in social behavior in both juvenile and adult mice. Overall, these studies show that C4 affects brain connectivity by reducing dendritic spine density and excitatory drive through enhanced microglia-engulfment of synaptic material which was sufficient to cause lasting deficits in mouse social behavior.