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.

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.

Can the brain register the emotional valence of brief exposures of complex natural stimuli under conditions of forward and backward masking, and under conditions of attentional competition between foveal and peripheral stimuli? To address this question, three experiments were conducted. The first, a behavioural experiment, measured subjective valence of response (pleasant vs unpleasant) to test the perception of the valence of natural images in brief, masked exposures in a forward and backward masking paradigm. Images were chosen from the International Affective Picture System (IAPS) series. After correction for response bias, responses to the majority of target stimuli were concordant with the IAPS ratings at better than chance, even when the presence of the target was undetected. Using functional magnetic resonance imaging (fMRI), the effects of IAPS valence and stimulus category were objectively measured on nine regions of interest (ROIs) using the same strict temporal restrictions in a similar masking design. Evidence of affective processing close to or below conscious threshold was apparent in some of the ROIs. To further this line of enquiry, a second fMRI experiment mapping the same ROIs and using the same stimuli were presented in a foveal (‘attended’) peripheral (‘to-be-ignored’) paradigm (small image superimposed in the centre of a large image of the same category, but opposite valence) to investigate spatial parameters and limitations of attention. Results are interpreted as showing both valence and category specific effects of ‘to-be-ignored’ images in the periphery. These results are discussed in light of theories of the limitations of attentional capacity and the speed in which we process natural images, providing new evidence of the breadth of variety in the types of affective visual stimuli we are able to process close to the threshold of conscious perception.

L’ADHD (Attention-deficit/hyperactivity disorder) est une maladie du développement caractérisée par l’impulsivité, l’hyperactivité, et l’inattention. Les voies neuronales impliquées dans ces déficits indiquent des dysfonctionnements dans les réseaux catécholaminergiques frontal-sous-corticaux, impliquant l'innervation dopaminergique et noradrénergique. Des études récentes ont mis en évidence une hypersensibilité à la douleur chez les patients ADHD et soulignent une possible comorbidité entre l’ADHD et la douleur. Cependant, les mécanismes et les circuits neuraux impliqués dans ces interactions sont inconnus. Afin de décrypter cette relation, nous avons généré un modèle ADHD de souris à P5 par une lésion néonatale des voies dopaminergiques centrales avec la 6-Hydroxydopamine (6-OHDA) et nous avons démontré la validité du modèle pour mimer le syndrome ADHD. Ensuite, nous avons analysé les comportements douloureux dans le modèle de souris 6-OHDA. Ces derniers présentent un abaissement des seuils de la douleur, ce qui suggère que l’ADHD induit une sensibilisation à la douleur (comorbidité ADHD-Douleur). Nous avons confirmé à l’aide d’enregistrements extracellulaires unitaires, que les modifications de la sensibilité à la douleur des souris 6-OHDA sont dues à une augmentation de l’excitabilité des neurones nociceptifs de la moelle épinière. Cette sensibilisation passe donc par une altération de l’intégration sensorielle dans la moelle épinière via la mise en jeu de contrôles descendants. La connectivité "cortex cingulaire antérieur (ACC) – insula postérieur (PI)" est la clé dans cette comorbidité ADHD-douleur, impliquée dans les fonctions exécutives, les émotions et elle envoie aussi des projections vers la corne dorsale de la moelle épinière. En effet, en combinant les analyses électrophysiologiques, optogénétiques et comportementales, nous avons démontré que les effets de l’ADHD sur la sensibilisation douloureuse passent par la mise en jeu de l’ACC et de la voie ACC – PI. En conclusion, nous montrons que les conditions ADHD induisent une hyperactivation des neurones nociceptifs de la moelle épinière et une hypersensibilité à la douleur. Nous suggérons également que le circuit ACC – PI pourrait déclencher un dysfonctionnement des neurones de la moelle épinière sur la douleur dans les conditions ADHD. / Attention deficit hyperactivity disorder (ADHD) is characterized by the core symptoms of inattention, hyperactivity and impulsivity. Neural pathways underlying these deficits point to deficits within frontal-subcortical catecholaminergic networks, involving dopaminergic and noradrenergic innervation. Hence, impairment of the dopaminergic neurotransmission is a frequent target of ADHD medication. Low-dose psychostimulants, including methylphenidate (MpH) and amphetamines (AMP) are the most widely used treatments of ADHD. Recent evidence pointed to pain hypersensitivity in subjects with ADHD history, and suggests possible comorbidity of ADHD with pain. However, the mechanisms and neural circuits involved in these interactions are unknown. In order to understand this comorbidity, the first objective was to create a good animal model of ADHD. We generated a mouse model at P5 by neonatal disruption of central dopaminergic pathways with 6-Hydroxydopamine (6-OHDA) and we demonstrated the validity of the model to mimic ADHD syndrome. Next, we analyzed nociceptive responses in the 6-OHDA mouse model of ADHD. We found that 6-OHDA mice exhibited a marked decrease of withdrawal thresholds, suggesting that ADHD increase nociceptive sensitivity. Interestingly, by using in vivo electrophysiological recordings, we demonstrated that allodynia and hyperalgesia may be caused by neuronal hyperexcitability in the dorsal spinal cord. Moreover, we found that both lowered wihdrawal threshold and increased activity of nociceptive neurons in ADHD-like mice was not normalized by MpH. We tested the hypothesis that descending controls are responsible for pain alterations through the modulation of spinal circuits. The ‘anterior cingulate cortex (ACC) – posterior insular (PI)’ connectivity is at the cross-road of ADHD and pain, being involved in executive functions and emotions, as well as sending projections to the dorsal horn of the spinal cord. By combining electrophysiological, optogenetic and behavioral analyzes, we have shown that the effects of ADHD on painful sensitization involve the implication of ACC and the ACC - PI pathway. In conclusion, we showed that ADHD conditions induce spinal cord nociceptive neurons hyperactivation and pain hypersensitivity. We also suggest that the ACC - PI circuit may trigger dysfunction of spinal cord neurons in ADHD conditions.

O protocolo de teste/reteste no labirinto em cruz elevado (LCE) mostra que a experiência prévia no labirinto produz alterações duradouras nas respostas comportamentais de roedores. Nesse contexto, ratos submetidos ao LCE pela primeira vez apresentam um aumento característico na exploração dos braços abertos e uma redução dos comportamentos de avaliação de risco após a administração de drogas ansiolíticas. Na reexposição ao labirinto, porém, essas drogas tornam-se ineficazes em alterar as medidas tradicionais do LCE. Esse fenômeno foi inicialmente observado com o benzodiazepínico clordiazepóxido e referido como one-trial tolerance (tolerância de um ensaio OTT). A proposta do presente estudo é compreender a OTT por meio do exame dos fatores hormonais, cognitivos e neuroanatômicos envolvidos nesse fenômeno. A administração sistêmica do benzodiazepínico midazolam ou de metirapona, um bloqueador da síntese de glicocorticóides, reduziu a frequência dos comportamentos de avaliação de risco e dos níveis plasmáticos de corticosterona quando injetados antes das sessões teste ou reteste. Além disso, a reexposição de ratos ao LCE foi caracterizada por uma avaliação de risco mais proeminente, de acordo com a análise fatorial, e pela ativação de estruturas límbicas envolvidas com aspectos cognitivos do medo, como a região ventral do córtex pré-frontal medial (CPFm) e a amígdala, mostrada por meio da distribuição da proteína Fos. Midazolam administrado antes da primeira exposição ao LCE produziu uma redução significativa do número de neurônios Fos-positivos no córtex cingulado anterior, área 1 (Cg1) e nos núcleos anterior e pré-mamilar dorsal do hipotálamo. Por outro lado, midazolam causou uma redução no número de neurônios Fos-positivos no CPFm, amígdala, núcleo dorsomedial do hipotálamo e núcleos da rafe em ratos reexpostos ao LCE. Cg1 foi a única estrutura-alvo do benzodiazepínico em ambas as sessões. Resultados comportamentais similares aos produzidos pelo tratamento sistêmico foram obtidos com infusões de midazolam intra-Cg1. Esses resultados apontam para um papel crucial dos comportamentos de avaliação de risco no desenvolvimento da OTT e indicam o Cg1 como um importante sítio de ação ansiolítica dos benzodiazepínicos em roedores. / The elevated plus maze (EPM) test/retest protocol has shown that prior experience to the maze produces enduring changes in behavioral responses of rodents. In this context, rats submitted for the first time to the EPM display a characteristic increase in open arm exploration and reduced risk assessment behaviors after the administration of anxiolytic drugs. Upon re-exposure to the maze, however, these drugs become unable to change the traditional measures of the EPM. This phenomenon was initially observed with the benzodiazepine chlordiazepoxide and referred to as one-trial tolerance (OTT). The purpose of the present study is to understand the OTT through the exam of the hormonal, cognitive and neuroanatomical factors involved in this phenomenon. The systemic administration of the benzodiazepine midazolam or metyrapone, a glucocorticoids synthesis blocker, reduced the frequency of risk assessment behaviors and the corticosterone levels when injected before the test or retest sessions. Moreover, the re-exposure of rats to the EPM was characterized by more prominent risk assessment behaviors, according to the factor analysis, and by activation of limbic structures involved with cognitive aspects of fear, such as the ventral regions of the medial prefrontal cortex (mPFC) and amygdala, as shown through the distribution of the Fos protein. Midazolam injected before the first exposure to the EPM produced a significant decrease in the number of Fos-positive neurons in the anterior cingulate cortex, area 1 (Cg1), anterior and dorsal premammillary nuclei of hypothalamus. On the other hand, midazolam caused a decrease in the number of Fos-positive neurons in the mPFC, amygdala, dorsomedial nucleus of hypothalamus and raphe nuclei in rats re-exposed to the EPM. Cg1 was the only structure targeted by the benzodiazepine in both sessions. Behavioral results similar to those produced by systemic treatment were obtained with intra-Cg1 infusions of midazolam. These results point to a crucial role of the risk assessment behaviors in the development of the OTT and indicate the Cg1 as an important locus for the anxiolytic-like action of benzodiazepines in rodents.

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.

O protocolo de teste/reteste no labirinto em cruz elevado (LCE) mostra que a experiência prévia no labirinto produz alterações duradouras nas respostas comportamentais de roedores. Nesse contexto, ratos submetidos ao LCE pela primeira vez apresentam um aumento característico na exploração dos braços abertos e uma redução dos comportamentos de avaliação de risco após a administração de drogas ansiolíticas. Na reexposição ao labirinto, porém, essas drogas tornam-se ineficazes em alterar as medidas tradicionais do LCE. Esse fenômeno foi inicialmente observado com o benzodiazepínico clordiazepóxido e referido como one-trial tolerance (tolerância de um ensaio OTT). A proposta do presente estudo é compreender a OTT por meio do exame dos fatores hormonais, cognitivos e neuroanatômicos envolvidos nesse fenômeno. A administração sistêmica do benzodiazepínico midazolam ou de metirapona, um bloqueador da síntese de glicocorticóides, reduziu a frequência dos comportamentos de avaliação de risco e dos níveis plasmáticos de corticosterona quando injetados antes das sessões teste ou reteste. Além disso, a reexposição de ratos ao LCE foi caracterizada por uma avaliação de risco mais proeminente, de acordo com a análise fatorial, e pela ativação de estruturas límbicas envolvidas com aspectos cognitivos do medo, como a região ventral do córtex pré-frontal medial (CPFm) e a amígdala, mostrada por meio da distribuição da proteína Fos. Midazolam administrado antes da primeira exposição ao LCE produziu uma redução significativa do número de neurônios Fos-positivos no córtex cingulado anterior, área 1 (Cg1) e nos núcleos anterior e pré-mamilar dorsal do hipotálamo. Por outro lado, midazolam causou uma redução no número de neurônios Fos-positivos no CPFm, amígdala, núcleo dorsomedial do hipotálamo e núcleos da rafe em ratos reexpostos ao LCE. Cg1 foi a única estrutura-alvo do benzodiazepínico em ambas as sessões. Resultados comportamentais similares aos produzidos pelo tratamento sistêmico foram obtidos com infusões de midazolam intra-Cg1. Esses resultados apontam para um papel crucial dos comportamentos de avaliação de risco no desenvolvimento da OTT e indicam o Cg1 como um importante sítio de ação ansiolítica dos benzodiazepínicos em roedores. / The elevated plus maze (EPM) test/retest protocol has shown that prior experience to the maze produces enduring changes in behavioral responses of rodents. In this context, rats submitted for the first time to the EPM display a characteristic increase in open arm exploration and reduced risk assessment behaviors after the administration of anxiolytic drugs. Upon re-exposure to the maze, however, these drugs become unable to change the traditional measures of the EPM. This phenomenon was initially observed with the benzodiazepine chlordiazepoxide and referred to as one-trial tolerance (OTT). The purpose of the present study is to understand the OTT through the exam of the hormonal, cognitive and neuroanatomical factors involved in this phenomenon. The systemic administration of the benzodiazepine midazolam or metyrapone, a glucocorticoids synthesis blocker, reduced the frequency of risk assessment behaviors and the corticosterone levels when injected before the test or retest sessions. Moreover, the re-exposure of rats to the EPM was characterized by more prominent risk assessment behaviors, according to the factor analysis, and by activation of limbic structures involved with cognitive aspects of fear, such as the ventral regions of the medial prefrontal cortex (mPFC) and amygdala, as shown through the distribution of the Fos protein. Midazolam injected before the first exposure to the EPM produced a significant decrease in the number of Fos-positive neurons in the anterior cingulate cortex, area 1 (Cg1), anterior and dorsal premammillary nuclei of hypothalamus. On the other hand, midazolam caused a decrease in the number of Fos-positive neurons in the mPFC, amygdala, dorsomedial nucleus of hypothalamus and raphe nuclei in rats re-exposed to the EPM. Cg1 was the only structure targeted by the benzodiazepine in both sessions. Behavioral results similar to those produced by systemic treatment were obtained with intra-Cg1 infusions of midazolam. These results point to a crucial role of the risk assessment behaviors in the development of the OTT and indicate the Cg1 as an important locus for the anxiolytic-like action of benzodiazepines in rodents.

No description available.

Die neonatale Hypoxie, als Schwangerschafts- und Geburtskomplikation, ist der wichtigste prädisponierende Umweltfaktor in der Pathophysiologie der Schizophrenie. Sie führt zu einer Schädigung des Gehirns und einer Störung der Hirnentwicklung. Insgesamt sind die neurobiologischen Auswirkungen, insbesondere auf die Zellproliferation, unklar. Im Tiermodell konnten bereits Verhaltensauffälligkeiten ähnlich der Schizophrenie, infolge chronischer neonataler Hypoxie, festgestellt werden. Störungen in der Zellentwicklung könnten hierfür die Ursache sein. Die Hypothese, dass der Beginn der abnormalen Hirnentwicklung perinatal liegt, während erste klinische Symptome im frühen Erwachsenenalter manifest werden, unterstützt diese Ergebnisse. Die Hirnentwicklung der Ratte ist in der frühen postnatalen Periode vergleichbar mit der eines menschlichen Fötus im dritten Trimenon der Schwangerschaft und eignet sich daher pathologische Prozesse im zentralen Nervensystem des Menschen zu reflektieren. In der vorliegenden Arbeit wurde mit Hilfe postnataler Hypoxie die neuronale Zellproliferation in 20 männlichen Wistar-Ratten zu unterschiedlichen Zeitpunkten (postnataler Tag 13 und 39) untersucht. Die Hypoxietiere wurden vom postnatalen Tag vier bis acht einer Hypoxie, bestehend aus 11% O2 und 89% N2, ausgesetzt. Mit Hilfe der Bromodeoxyuridin-Peroxidasefärbung wurde die Zellproliferation in Hypoxie-vulnerablen Hirnregionen untersucht. Hierzu gehören der Gyrus cinguli, das Striatum, der Gyrus dentatus und die subventrikuläre Zone. Als Vergleich diente eine unbehandelte Kontrollgruppe. Durch ein Mikroskop mit Schrittmotorsystem und Stereo Investigator Software (MicroBrightField, UK) und der Optical Fractionator-Methode konnte erstmals festgestellt werden, dass Hypoxie-behandelte Tiere eine um 20% erhöhte Zellproliferation im Gyrus cinguli am postnatalen Tag 13 aufwiesen. Des Weiteren zeigte sich bei den Hypoxie-behandelten Tieren ein um 16% reduziertes Volumen im Striatum am postnatalen Tag 13. Am postnatalen Tag 39 zeigten sich keine signifikanten Unterschiede mehr. Diese Ergebnisse zeigen, dass ein vorübergehender Einfluss chronischer Hypoxie auf die Zellproliferation und das Volumen angenommen werden kann und das das Gehirn innerhalb gewisser Grenzen während der neuronalen Entwicklung tolerant gegenüber exogenen Noxen wie Hypoxie zu sein scheint. Die Ergebnisse bestätigen auch, dass nur ein kleiner Teil der Hypoxie-assoziierten Geburtskomplikationen zu einer Schizophrenie führt und der Erkrankung eine multifaktorielle Gen-Umwelt-Interaktion zugrunde liegt. Zukünftig könnte es, mit der besseren Kenntnis neurobiologischer Auswirkungen von Umweltfaktoren und genetischen Faktoren im Gehirn, möglich werden die Schizophrenie frühzeitiger zu erkennen und zu behandeln sowie behindernde Symptome zu reduzieren.