A formação de memórias de medo contextuais, como as estudadas no presente trabalho, requer a indução da plasticidade sináptica iniciada pela ativação de receptores transmembrana localizados nos neurônios de estruturas encefálicas como o hipocampo. O fluxo iônico mediado pelos receptores N-metil-D-aspartato (NMDARs) é essencial para ativar vias de sinalização intracelular que darão suporte à formação da memória. No entanto, esses receptores parecem não ser necessários em situações onde os animais passaram por uma experiência prévia similar a que está sendo aprendida. Dessa forma, um aprendizado anterior pode modificar os mecanismos de plasticidade que serão utilizados para codificar uma nova informação, caracterizando um fenômeno de metaplasticidade. Esse fenômeno ocorre quando os animais são pré-expostos ao local onde posteriormente serão submetidos a um aprendizado associativo ou quando são re-submetidos a mesma tarefa comportamental com dicas contextuais/espaciais diferentes. No presente trabalho, investigamos (i) os mecanismos de plasticidade sináptica (receptores) e de plasticidade não-sináptica (excitabilidade neuronal) recrutados para a formação do segundo aprendizado e (ii) se a independência dos NMDARs é mantida quando a memória anterior foi adquirida remotamente. Os animais utilizados nesse trabalho (camundongos ou ratos) foram expostos a dois aprendizados sequenciais realizados na tarefa de condicionamento aversivo ao contexto (CAC). O intervalo entre os condicionamentos foi de dois dias nos experimentos do Capítulo I e de três ou quarenta dias nos experimentos do Capítulo II. Cada aprendizado ocorreu em uma caixa de condicionamento com características próprias de formato, odor e iluminação (contexto A ou contexto B), sendo que o primeiro aprendizado ocorreu no contexto A e o segundo no contexto B. Nos experimentos do Capítulo I foram avaliadas no hipocampo dorsal as modificações na excitabilidade neuronal hipocampal induzidas pelo primeiro condicionamento, bem como os receptores envolvidos com a aquisição da memória subsequente e a sobreposição neuronal entre os dois aprendizados. Com a utilização do camundongo transgênico Teg-Tag foi possível identificar os neurônios recrutados para o primeiro aprendizado. Esse animal tem a expressão da proteína fluorescente verde (GFP, do inglês, green fluorescent protein) controlada pela ativação do gene c-fos, que é fisiologicamente transcrito após a atividade neuronal. Dessa forma, os neurônios ativados pelo aprendizado são marcados com GFP. Através da técnica de patch clamp foi observado que os neurônios GFP+ mantiveram a excitabilidade elevada por até dois dias após o treinamento no CAC. Além disso, a identificação dos neurônios recrutados 8 para o aprendizado subsequente foi realizada através da marcação imunofluorescente da proteína Fos, no seu pico de expressão endógena, noventa minutos após o re-treino. Foi observada uma maior sobreposição neuronal (GFP+, Fos+) quando os animais foram retreinados no mesmo contexto dois dias após o primeiro treino. Uma sobreposição intermediária (GFP+, Fos+) foi vista quando os animais tiveram o segundo condicionamento no contexto B, sendo ela significativamente maior do que a sobreposição nos animais não re-treinados. Adicionalmente, foi demonstrado que a aquisição do aprendizado subsequente é mediada por receptores metabotrópicos glutamatérgicos (mGluRs) ao invés de NMDARs. No Capítulo II foi investigado se uma memória remota, adquirida há quarenta dias, ainda seria capaz de influenciar nos mecanismos de plasticidade recrutados para aquisição do aprendizado subsequente. A dinâmica da consolidação sistêmica foi considerada nesses experimentos já que a evocação da memória remota passa a depender de estruturas encefálicas neocorticais, sem recrutar a atividade hipocampal. Apesar da evocação da memória remota não requerer a atividade hipocampal, foi observado que a aquisição do aprendizado subsequente a uma memória remota necessita a atividade de pelo menos uma sub-região do hipocampo (dorsal ou ventral). Complementarmente, os resultados indicaram que, quando o intervalo entre os aprendizados é aumentado (de três para quarenta dias), a formação do aprendizado subsequente, que era independente de NMDARs, volta a depender da plasticidade sináptica mediada por esses receptores no hipocampo (dorsal e ventral). Juntos, nossos resultados sugerem que o primeiro aprendizado causa um aumento da excitabilidade neuronal e modifica a plasticidade sináptica recrutada para o aprendizado subsequente, sendo este último mediado por mGluRs ao invés de NMDARs. Além disso, a metaplasticidade induzida pelo primeiro condicionamento é transiente; quando o intervalo entre as exposições é aumentado, o segundo aprendizado passa a depender novamente da ativação dos NMDARs. / Contextual fear memory formation, like the ones explored in the current work, requires the induction of the synaptic plasticity mediated by the activation of transmembrane receptors that are present in the brain structures as the hippocampus. The ionic flux through the N-methylaspartate- D-aspartate is crucial for activation of the intracellular signaling pathways that will support memory formation. However, these receptors are not necessary when animals had a prior similar learning. In this way, a previous learning can modify the plasticity mechanism that will be recruited to encode a new information, featuring a metaplasticity phenomenon. This phenomenon occurs when animals are pre-exposed to an environment where they will learn an associative learning later or when animals are re-exposed to the same behavioral task with distinct contextual/spatial cues. In the present study, we investigated (i) the synaptic plasticity mechanisms (receptors) and the non-synaptic plasticity mechanisms (neuronal excitability) required for the acquisition of the second learning and (ii) whether a subsequent learning that occurs in a remote time-point is still NMDAR-independent. The animals used in this study (mice or rats) were exposed to two sequential learnings that were performed in the contextual fear conditioning (CFC). The interval between conditionings were two days in the experiments of Chapter I and three or forty days in the experiments of the Chapter II. Each learning was performed in a box with differences on shape, odor and illumination (context A or context B). The first learning occurred in the context A followed by learning on context B. In the experiments of Chapter I it was evaluated the changes in the hippocampal neuronal excitability induced by the first conditioning, the receptors involved with the acquisition of the subsequent memory and the neuronal overlapping between the two sequential learnings. The Teg-Tag transgenic mouse allowed to identify the neurons activated for the first learning experience. This animal has the GFP expression under control of c-fos promoter that is activated by neuronal activity. It was shown by patch clamp that GFP+ neurons are still more excitable two days after learning. Also, the identification of neurons recruited for the subsequent learning was made through immunofluorescent staining of the Fos protein in its peak of endogenous expression, ninety minutes after learning. A greater overlapping (GFP+, Fos+) was observed when animals were retrained in the same context two days after first training. An intermediate overlapping was observed when animals were conditioned in the context B and this expression was significantly higher when compared to animals that were not 10 retrained in either context. Additionally, it was shown that acquisition of the subsequent learning is mediated by metabotropic glutamate receptors (mGluRs) instead of NMDARs In the Chapter II it was investigated whether a remote memory, acquired forty days earlier, is still able to influence in the synaptic plasticity mechanisms recruited for the acquisition of the subsequent learning. Systems consolidation dynamics was considered in these experiments because memory retrieval of a remote memory depends on neocortical brain regions, it not requires hippocampal activity. It was confirmed that hippocampus is not necessary for remote memory retrieval, however at least one longitudinal division of the hippocampus (dorsal or ventral) is essential for learning following a prior remote memory. Moreover, the results indicate that acquisition of the second learning is once again mediated by NMDARs in the hippocampus when the interval between learnings is extended from three to forty days. Altogether, our results suggest that the first learning lead to an increase in the neuronal excitability and modify the synaptic plasticity mechanism recruited for following learning, mGluR are required instead of NMDAR. Furthermore, the metaplasticity induced by first conditioning is transient; the second learning once again requires NMDARs activation when the interval between learnings is longer.

Le cortex cingulaire antérieur (CCA) est une région préfrontale située au centre d’un réseau permettant l’échange d’informations cognitives, motrices, limbiques et viscérales, la plaçant ainsi comme un sujet incontournable dans l’étude de pathologies complexes telles que les troubles anxio-dépressifs. Afin de pouvoir aborder ces pathologies chez la souris, nous avons établi par traçage neuronal le connectome complet des différentes aires composant le CCA. Nous avons ainsi montré qu’une grande majorité des structures de ce connectome communique de manière réciproque avec cette région et que, selon les aires cingulaires, des spécificités de densité d'innervation et de topographie peuvent exister. Ceci suggère des fonctions partagées mais également des rôles plus spécifiques à chaque aire. A partir de ce connectome, nous avons ensuite montré, par une approche optogénétique associée à des tests comportementaux, que l'activation répétée de la projection de l’amygdale au CCA est susceptible d'induire des comportements de type anxio-dépressif chez des souris naïves. Ce travail met donc en évidence le rôle d'une partie du connectome du CCA dans l'établissement des troubles de l'humeur. / The anterior cingulate cortex (ACC) is a prefrontal region located at the center of a network allowing the sharing of cognitive, motor, limbic and visceral information, placing it as an interesting target for the study of complex pathologies like mood disorders. To investigate these diseases in mice, we provided the complete connectome of each ACC areas by a tract-tracing approach. We demonstrated that the majority of structures constituting this connectome are reciprocally connected with the ACC and that some density and topographical connection specificities were observed among cingulate areas. These results potentially suggest some shared functions between cingulate areas, also completed by specific roles inherent to each area. Using this connectome, we demonstrated that the repeated activation of the amygdala projection to the ACC was able to induce anxiodepressive-like behaviors in naïve mice, by using optogenetics combined with behavioral tests. This study highlights for the first time the implication of a portion of the ACC connectome in the establishment of mood disorders.

Background: The aim of this thesis was to investigate the relationship of moral cognition and emotions to the pathophysiology of major depressive disorder (MDD). Patients with MDD may experience excessive guilt or self-blaming biases despite recovery from the depressed state. Since guilt is a moral emotion thought to motivate altruistic behaviours, it has been hypothesized that elevated self-blame in MDD may result in pathological increases to altruism in some patients. The relationship of self-blame to altruistic choices in individuals with remitted MDD (rMDD), however, has not been established. Guilt has been shown to activate the subgenual cingulate and adjacent septal region (SCSR) which is of known importance to the pathophysiology of MDD. Since MDD is thought to arise from network-level dysfunctions, and moral cognition and emotions are hypothesized to emerge from network-level binding, investigating resting-state SCSR functional connectivity in rMDD patients and healthy control (HC) participants could reveal networks of potential relevance both to MDD and to moral cognition and emotions. Chapter 2: We investigated whether melancholic rMDD patients could be distinguished from non-melancholic and HC groups on the basis of resting-state functional connectivity to an SCSR seed region. Lower SCSR-amygdala connectivity distinguished the melancholic rMDD group from non-melancholic and HC groups. Chapter 3: We investigated whether patients who remained resilient to recurring depressive episodes were distinguishable from recurring episode MDD and HC groups on the basis of resting-state connectivity to an SCSR seed region. Lower interhemispheric SCSR connectivity distinguished the resilient MDD patients from the recurring episode MDD and HC groups. Chapter 4: We measured explicit and implicit preferences for social options with and without altruistic motivations relative to selfish options in the rMDD and HC groups during emotion priming to modulate feelings of guilt. The rMDD patients explicitly preferred prosocial options (i.e., social options and altruism directed towards friends or colleagues) less than HC participants. Regardless of group, guilt priming increased explicit and implicit preferences for altruism towards strangers. Chapter 5: We investigated whether explicit and/or implicit preferences for prosocial options during guilt priming were correlated with resting-state connectivity to an SCSR seed region, and whether this relationship could distinguish the rMDD and HC groups. Across all participants, implicit prosocial choice preference negatively correlated with connectivity between the SCSR and right temporoparietal junction (TPJ). The relationship of SCSR-TPJ connectivity to implicit preferences for social options and for altruism towards friends and colleagues was weaker in the rMDD group compared to the HC group, particularly for implicit altruism. Conclusions: We identified resting-state SCSR networks associated with vulnerability to melancholia and with resilience to recurring depressive episodes. Patients with rMDD explicitly preferred options entailing social withdrawal, a symptom associated with MDD vulnerability. Irrespective of group, guilt motivated altruism towards strangers but not friends and colleagues. Implicit prosociality was negatively associated with connectivity in a social agency network, and the comparatively weak relationships between connectivity and implicit choice preferences in rMDD patients may reflect a vulnerability factor for MDD.

A formação de memórias de medo contextuais, como as estudadas no presente trabalho, requer a indução da plasticidade sináptica iniciada pela ativação de receptores transmembrana localizados nos neurônios de estruturas encefálicas como o hipocampo. O fluxo iônico mediado pelos receptores N-metil-D-aspartato (NMDARs) é essencial para ativar vias de sinalização intracelular que darão suporte à formação da memória. No entanto, esses receptores parecem não ser necessários em situações onde os animais passaram por uma experiência prévia similar a que está sendo aprendida. Dessa forma, um aprendizado anterior pode modificar os mecanismos de plasticidade que serão utilizados para codificar uma nova informação, caracterizando um fenômeno de metaplasticidade. Esse fenômeno ocorre quando os animais são pré-expostos ao local onde posteriormente serão submetidos a um aprendizado associativo ou quando são re-submetidos a mesma tarefa comportamental com dicas contextuais/espaciais diferentes. No presente trabalho, investigamos (i) os mecanismos de plasticidade sináptica (receptores) e de plasticidade não-sináptica (excitabilidade neuronal) recrutados para a formação do segundo aprendizado e (ii) se a independência dos NMDARs é mantida quando a memória anterior foi adquirida remotamente. Os animais utilizados nesse trabalho (camundongos ou ratos) foram expostos a dois aprendizados sequenciais realizados na tarefa de condicionamento aversivo ao contexto (CAC). O intervalo entre os condicionamentos foi de dois dias nos experimentos do Capítulo I e de três ou quarenta dias nos experimentos do Capítulo II. Cada aprendizado ocorreu em uma caixa de condicionamento com características próprias de formato, odor e iluminação (contexto A ou contexto B), sendo que o primeiro aprendizado ocorreu no contexto A e o segundo no contexto B. Nos experimentos do Capítulo I foram avaliadas no hipocampo dorsal as modificações na excitabilidade neuronal hipocampal induzidas pelo primeiro condicionamento, bem como os receptores envolvidos com a aquisição da memória subsequente e a sobreposição neuronal entre os dois aprendizados. Com a utilização do camundongo transgênico Teg-Tag foi possível identificar os neurônios recrutados para o primeiro aprendizado. Esse animal tem a expressão da proteína fluorescente verde (GFP, do inglês, green fluorescent protein) controlada pela ativação do gene c-fos, que é fisiologicamente transcrito após a atividade neuronal. Dessa forma, os neurônios ativados pelo aprendizado são marcados com GFP. Através da técnica de patch clamp foi observado que os neurônios GFP+ mantiveram a excitabilidade elevada por até dois dias após o treinamento no CAC. Além disso, a identificação dos neurônios recrutados 8 para o aprendizado subsequente foi realizada através da marcação imunofluorescente da proteína Fos, no seu pico de expressão endógena, noventa minutos após o re-treino. Foi observada uma maior sobreposição neuronal (GFP+, Fos+) quando os animais foram retreinados no mesmo contexto dois dias após o primeiro treino. Uma sobreposição intermediária (GFP+, Fos+) foi vista quando os animais tiveram o segundo condicionamento no contexto B, sendo ela significativamente maior do que a sobreposição nos animais não re-treinados. Adicionalmente, foi demonstrado que a aquisição do aprendizado subsequente é mediada por receptores metabotrópicos glutamatérgicos (mGluRs) ao invés de NMDARs. No Capítulo II foi investigado se uma memória remota, adquirida há quarenta dias, ainda seria capaz de influenciar nos mecanismos de plasticidade recrutados para aquisição do aprendizado subsequente. A dinâmica da consolidação sistêmica foi considerada nesses experimentos já que a evocação da memória remota passa a depender de estruturas encefálicas neocorticais, sem recrutar a atividade hipocampal. Apesar da evocação da memória remota não requerer a atividade hipocampal, foi observado que a aquisição do aprendizado subsequente a uma memória remota necessita a atividade de pelo menos uma sub-região do hipocampo (dorsal ou ventral). Complementarmente, os resultados indicaram que, quando o intervalo entre os aprendizados é aumentado (de três para quarenta dias), a formação do aprendizado subsequente, que era independente de NMDARs, volta a depender da plasticidade sináptica mediada por esses receptores no hipocampo (dorsal e ventral). Juntos, nossos resultados sugerem que o primeiro aprendizado causa um aumento da excitabilidade neuronal e modifica a plasticidade sináptica recrutada para o aprendizado subsequente, sendo este último mediado por mGluRs ao invés de NMDARs. Além disso, a metaplasticidade induzida pelo primeiro condicionamento é transiente; quando o intervalo entre as exposições é aumentado, o segundo aprendizado passa a depender novamente da ativação dos NMDARs. / Contextual fear memory formation, like the ones explored in the current work, requires the induction of the synaptic plasticity mediated by the activation of transmembrane receptors that are present in the brain structures as the hippocampus. The ionic flux through the N-methylaspartate- D-aspartate is crucial for activation of the intracellular signaling pathways that will support memory formation. However, these receptors are not necessary when animals had a prior similar learning. In this way, a previous learning can modify the plasticity mechanism that will be recruited to encode a new information, featuring a metaplasticity phenomenon. This phenomenon occurs when animals are pre-exposed to an environment where they will learn an associative learning later or when animals are re-exposed to the same behavioral task with distinct contextual/spatial cues. In the present study, we investigated (i) the synaptic plasticity mechanisms (receptors) and the non-synaptic plasticity mechanisms (neuronal excitability) required for the acquisition of the second learning and (ii) whether a subsequent learning that occurs in a remote time-point is still NMDAR-independent. The animals used in this study (mice or rats) were exposed to two sequential learnings that were performed in the contextual fear conditioning (CFC). The interval between conditionings were two days in the experiments of Chapter I and three or forty days in the experiments of the Chapter II. Each learning was performed in a box with differences on shape, odor and illumination (context A or context B). The first learning occurred in the context A followed by learning on context B. In the experiments of Chapter I it was evaluated the changes in the hippocampal neuronal excitability induced by the first conditioning, the receptors involved with the acquisition of the subsequent memory and the neuronal overlapping between the two sequential learnings. The Teg-Tag transgenic mouse allowed to identify the neurons activated for the first learning experience. This animal has the GFP expression under control of c-fos promoter that is activated by neuronal activity. It was shown by patch clamp that GFP+ neurons are still more excitable two days after learning. Also, the identification of neurons recruited for the subsequent learning was made through immunofluorescent staining of the Fos protein in its peak of endogenous expression, ninety minutes after learning. A greater overlapping (GFP+, Fos+) was observed when animals were retrained in the same context two days after first training. An intermediate overlapping was observed when animals were conditioned in the context B and this expression was significantly higher when compared to animals that were not 10 retrained in either context. Additionally, it was shown that acquisition of the subsequent learning is mediated by metabotropic glutamate receptors (mGluRs) instead of NMDARs In the Chapter II it was investigated whether a remote memory, acquired forty days earlier, is still able to influence in the synaptic plasticity mechanisms recruited for the acquisition of the subsequent learning. Systems consolidation dynamics was considered in these experiments because memory retrieval of a remote memory depends on neocortical brain regions, it not requires hippocampal activity. It was confirmed that hippocampus is not necessary for remote memory retrieval, however at least one longitudinal division of the hippocampus (dorsal or ventral) is essential for learning following a prior remote memory. Moreover, the results indicate that acquisition of the second learning is once again mediated by NMDARs in the hippocampus when the interval between learnings is extended from three to forty days. Altogether, our results suggest that the first learning lead to an increase in the neuronal excitability and modify the synaptic plasticity mechanism recruited for following learning, mGluR are required instead of NMDAR. Furthermore, the metaplasticity induced by first conditioning is transient; the second learning once again requires NMDARs activation when the interval between learnings is longer.

No description available.

In general, highly hypnotizable individuals ("highs") have exhibited greater abilities to focus attention and inhibit pain than low hypnotizable individuals ("lows"). Furthermore, highs appear to have faster neural processing than lows. The present study investigated differences between lows and highs in morphological volume of some brain structures associated with inhibitory and excitatory neural processing, particularly the corpus callosum (CC). Participants were 18 healthy university students, aged 18 to 29, with no history of concussion or medical disorders. They were in a functional Magnetic Resonance Image (fMRI) study examining the neurophysiology of pain and hypnotic analgesia (Crawford, Horton, Harrington, et al., 1998; Downs et al., 1998). As assessed by the group version (Crawford & Allen, 1982) of the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C; Weitzenhoffer & Hilgard, 1962), there were eight highs (four women and four men; SHSS:C M = 11.0) and 10 lows (five men and five women; SHSS:C M = 2.1). Highs were able to successfully eliminate perception of pain and distress to experimental noxious stimuli. Their anatomical MRIs were measured to assess relationships between brain structure volume (CC, medial cortex, anterior brain regions) and hypnotizability. In comparison to lows, highs had a significantly larger CC volume in the rostrum and isthmus, inferred to reflect larger transcallosal axon diameter or greater axon myelination. For highs, but not lows, there were significant relationships between forebrain volume and the total CC, rostrum, and splenium. Findings provide support for the neuropsychophysiological model of Crawford and her associates (e.g. Crawford, 1994a, 1994b; Crawford & Gruzelier, 1992) proposing a more effective attentional system of inhibitory processes in highs than lows. Furthermore, the data suggest that the more effective systems of attentional and inhibitory processes enhanced neural processing speed, and interhemispheric transfer times seen in highs than lows, may be associated with morphological differences in certain anterior and posterior CC regions. These regions are known to be involved in the allocation of inhibitory and excitatory transfer of information between hemispheres. / Ph. D.

No description available.

The body of work hereby presented aims at better defining the specific mechanisms underlying cognitive control and flexibility, and to investigate the neural substrates that might support these dynamics. More specifically, the anterior cingulate (ACC), dorsolateral prefrontal (dlPFC) and frontopolar (FPC) cortices have been proposed to play a fundamental role in monitoring and detecting the presence of environmental contingencies that require the recruitment of cognitive control (such as competition between responses in the presence of conflicting information), implementing cognitive control, and supporting higher-order cognitive processing, respectively. This thesis investigates the effects of damage to these regions, and of interference with their activity, on these processes. It also argues for the importance of dissociating possible separate cognitive control components that might differently contribute to behavioural adjustments (such as caution and attention/task-relevant processing), and provides one of the first attempts to quantify them within the parameters of a mathematical model of choice response-time, the Linear Ballistic Accumulator (LBA). The results confirm the crucial role of the dlPFC in modulating behavioural adjustments, as both damage and interference with this region’s activity significantly affect measures of conflict-induced behavioural adaptation. It is hypothesized that dlPFC might drive behavioural adjustments by encoding recent conflict history and/or supporting the automatization of a newly advantageous behavioural strategy during the early stages after a change in conflict levels. When a task does not involve competition between a habit and instructed behaviour, lesions or interference with ACC’s activity do not appear to affect behaviour in a manner that is consistent with the classic conflict-monitoring framework. It is suggested that its role might be better described as a more general monitoring and confirmatory mechanism that evaluates both actual and potential outcomes of an action, in order to proactively guide adjustments away from contextually disadvantageous responses. Finally, lesions to the FPC do not affect abstract-rule integration, but do impair the early stages of acquisition of a new abstract rule, when a previously rewarded rule stops being rewarded, and specifically when acquisition is dependent on self-initiated exploration. This suggests a role for FPC in the evaluation of multiple concurrent options in order to aid the development of new behavioural strategies.

Contexte : Jusqu’à 90% des fumeurs qui tentent d’arrêter de fumer vont rechuter dans l’année suivant la date d’arrêt. L’impulsivité, au même titre que le « craving », a démontré être un bon facteur de prédiction de la rechute tabagique. Ainsi, la présente étude visait à évaluer, à l’aide de la neuroimagerie fonctionnelle, l’influence de l’impulsivité sur les mécanismes neuronaux du « craving » de la cigarette. Parmi les régions cérébrales impliquées dans le « craving » de la nicotine, les cortex préfrontal dorsolatéral, orbitofrontal et cingulaire sont d’importantes structures dans les processus de contrôle de soi. Méthodes : 31 fumeurs chroniques ont passé une session de neuroimagerie durant laquelle ils devaient regarder des images appétitives de cigarettes et des images neutres. Ils ont ensuite dû inscrire le « craving » ressenti à la vue des images et répondre à un questionnaire portant sur les traits de personnalité de l’impulsivité (BIS-11). Résultats : Tel qu’attendu, le score d’impulsivité était positivement corrélé au « craving » rapporté par les participants à la vue d’images de cigarettes. Au niveau cérébral, plus les fumeurs présentaient de forts traits d’impulsivité, moins grande était l’activité du cortex cingulaire postérieur (CCP) durant le « craving ». Enfin, l’activité du CCP présentait une connectivité fonctionnelle négative avec l’insula, le cortex préfrontal dorsolatéral et le cortex cingulaire antérieur. Conclusions : Comme le CCP est le siège des processus de mentalisation et de référence à soi, nous suggérons que plus les fumeurs étaient impulsifs, moins ils prenaient conscience de leur état et moins ils en exerçaient un contrôle, donc plus ils ressentaient de forts « cravings ». En poussant plus loin, nos résultats mettent l’accent sur l’aspect identitaire (le soi, les mémoires autobiographiques) et l’aspect d’introspection en toxicomanie : deux avenues à explorer. / Background: 90% of cigarette smokers attempting to quit smoking relapse by one-year following their quit date. Impulsivity, as well as cue-induced cravings, have been shown to be good predictors of relapse for tobacco smoking; however, no study to date has examined their interaction and its neural substrates. The goal of this study was to determine the neural influence of trait impulsivity during functional imaging of cue-induced cigarette cravings. Among the brain regions involved in nicotine craving, the dorsolateral prefrontal cortex, the orbitofrontal as well as the cingulate cortex all play a significant role in self-control processes. Methods: Thirty-one chronic smokers passively viewed appetitive smoking-related and neutral images while being scanned. Participants also reported their level of craving and completed the BIS-11, a measure of trait impulsivity. Results: As hypothesized, we observed a significant positive relationship between impulsivity scores and reported craving. Impulsivity scores were negatively correlated with activity in the posterior cingulate cortex (PCC). The insula, dorsal anterior cingulate cortex and dorsolateral prefrontal cortex presented a negative connectivity with the PCC. Conclusions: Given that the PCC is involved in mentalization and self-relevant processing, it is possible that greater trait impulsivity in smokers is associated to a lower tendency to understand and use one’s mental and physical state to guide behavior. This may weaken their capacity for self-control and consequently, promotes more automatic and stronger cue-elicited smoking urges. Furthermore, our results highlight the important but undervalued role of identity (the self and autobiographic memories) and mindfulness in addiction.

Objectif : Cette thèse a pour objectif de mieux comprendre l’effet du stress sur la douleur aiguë et chronique. Devis expérimental : 16 patients souffrant de douleur chronique lombalgique et 18 sujets contrôles ont participé à une étude d’imagerie par résonance magnétique (IRM) et ont collecté des échantillons de salive afin de quantifier les niveaux d’hormone de stress (i.e. cortisol) la journée de l’étude (réponse réactive) et durant les sept jours consécutifs suivants (réponse basale). Étude 1 : Une première étude a examiné le lien entre les niveaux de cortisol basal, le volume de l’hippocampe et l’activité cérébrale évoquée par la douleur thermique chez des patients souffrant de douleur chronique et les sujets contrôles. Les résultats révèlent que les patients souffrant de douleur chronique avaient des niveaux de cortisol plus élevés que ceux des sujets contrôles. Chez ces patients, un niveau élevé de cortisol était associé à un plus petit volume de l'hippocampe et à davantage d’activation dans le gyrus parahippocampique antérieure (une région impliquée dans l'anxiété anticipatoire et l'apprentissage associatif). De plus, une analyse de médiation a montré que le niveau de cortisol basal et la force de la réponse parahippocampique explique statistiquement l’association négative entre le volume de l'hippocampe et l'intensité de la douleur chronique. Ces résultats suggèrent que l’activité endocrinienne plus élevée chez les patients ayant un plus petit hippocampe modifie le fonctionnement du complexe hippocampique et contribue à l’intensité de la douleur chronique. Étude 2 : La deuxième étude a évalué la contribution de la réponse de stress réactif aux différences interindividuelles dans la perception de la douleur aiguë chez des patients souffrant de douleur chronique et chez des sujets normaux. Les deux groupes ont montré des augmentations significatives du niveau de cortisol en réponse à des stimulations nocives administrées dans un contexte d’IRM suggérant ainsi que la réactivité de l’axe hypothalamo-hypophyso-surrénalien est préservée chez les patients lombalgiques. De plus, les individus présentant une réponse hormonale de stress plus forte ont rapporté moins de douleur et ont montré une réduction de l'activation cérébrale dans le noyau accumbens, dans le cortex cingulaire antérieur (CCA), le cortex somatosensoriel primaire, et l'insula postérieure. Des analyses de médiation ont indiqué que la douleur liée à l'activité du CCA explique statistiquement la relation entre la réponse de stress et le désagrément de la douleur rapportée par les participants. Enfin, des analyses complémentaires ont révélé que le stress réduit la connectivité fonctionnelle entre le CCA et le tronc cérébral pendant la douleur aiguë. Ces résultats indiquent que le stress réactif module la douleur et contribue à la variabilité interindividuelle de l'activité cérébrale et la réponse affective à la douleur. Discussion : Conjointement, ces études suggèrent dans un premier temps que la douleur chronique peut être exacerbée par une réponse physiologique inadéquate de l'organisme exposé à un stress récurrent, et en un second temps, que le CCA contribuerait à l'analgésie induite par le stress. Sur le plan conceptuel, ces études renforcent le point de vue prédominant suggérant que la douleur chronique induit des changements dans les systèmes cérébraux régissant les fonctions motivationnelles et affective de la douleur. / Goal : This thesis aimed at better understanding the impact of stress on acute and chronic pain. Experimental design: 16 patients with chronic low back pain pain and 18 control subjects participated in a functional magnetic resonance imaging (fMRI) study and collected saliva samples to quantify the levels of stress hormone (ie cortisol) the day of study (reactive response) and during the following 7 consecutive days (basal response). Study 1: The first study examined the associations between basal levels of cortisol, the hippocampal volumes, and brain activation to thermal stimulations in the low back pain patients and the healthy controls. Results showed that CBP patients have higher levels of cortisol than controls. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus (PHG), a region involved in anticipatory-anxiety and associative learning. Importantly, the results revealed that the cortisol levels and phasic pain responses in the PHG of the patients mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the higher levels of endocrine activity observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states. Study 2: The second study assessed the magnitude of the acute stress response to the noxious thermal stimulations administered in a MRI environment and tested its possible contribution to individual differences in pain perception. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared to their basal levels, suggesting normal hypothalamic–pituitary–adrenal axis reactivity to painful stressors in chronic back pain patients. Critically, individuals with stronger cortisol responses reported less pain unpleasantness and showed a reduction of BOLD activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula during heat pain. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness reported by the participants. Psychophysiological interaction further revealed that stress reduced functional connectivity between the aMCC and the brainstem during pain. These findings indicate that acute stress responses modulate pain in humans and contribute to individual variability in pain affect and pain-related brain activity. Discussion: Taken together, these studies firstly support recent theories suggesting that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor and secondly revealed the neural correlates of stress-induced analgesia. On a conceptual level, these findings are important because they strengthen the predominant view that chronic pain does not disrupt the acute response to stress and the sensory dimension of pain, but rather induces long-term changes in neural systems underlying affective-motivational functions.