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.

Damage to the ventromedial prefrontal cortex (vmPFC) can lead to disturbances in personality, emotional dysregulation, impairments in social conduct, and difficulties in decision-making. Many researchers have likened the conduct of individuals with vmPFC lesions to that of criminal psychopaths, labeling the effects of vmPFC damage “pseudopsychopathy” or “acquired sociopathy.” However, although psychopathy—a condition marked by a distinct mosaic of antisocial personality traits and behaviors—has been studied and characterized as a psychological and behavioral disorder by many researchers, the overlap between acquired sociopathy and psychopathy remains ambiguous. This study assessed the severity of psychopathic personality traits in neurological patients with acquired damage to the vmPFC using both informant-report and self-report measures. On both informant-report and self-report measures, individuals with vmPFC damage showed no significant elevations across a wide range of psychopathic traits relative to demographically-matched neurologically healthy comparison participants and patients with damage outside of the vmPFC. The results showed only one trait, Fearlessness, that was significantly higher in patients with vmPFC lesions relative to the neurologically-healthy comparison group.

Nitric Oxide (NO) is a powerful endogenous free radical that has numerous biological functions including vasodilation and serves as a post synaptic second messenger in the central nervous system (CNS). Numerous studies implicate NO• involvement in CNS disorders such as schizophrenia and drug abuse. These studies address the direct in vivo determination of an FDA-approved NO• donor (nitroglycerin) on extracellular levels of NO• in the frontal cortex and core of the nucleus accumbens in a lightly anesthetized rat. State-of-the-art in vivo amperometric recording techniques coupled with a novel 4-channel low noise pre-amplifier system and new generation microelectrode arrays (MEAs) will be used to record extracellular levels of NO• at 100Hz before and during nasal administration of either placebo (1) or nitroglycerin. This studies will determine the feasibility of measuring NO• in the CNS while administering the NO• donor nasally and determine the amplitude and kinetic time course effects of a nasally delivered NO• donor in two rat brain areas, the frontal cortex and core of the nucleus accumbens.

Empathy plays a crucial role in our relationships with others and enhances personal well-being. The brain areas that are critical for the experience of on-line empathy and empathic behavior are not known. The current study investigated the neural substrates of empathy through the examination of whether the ventromedial prefrontal cortex (VMPC) is critical for empathy. For the first time, on-line empathic experience and behavior were measured in patients with brain damage to the VMPC. Six patients with bilateral damage to the VMPC were case-matched on specific demographic and neuropsychological criteria to two comparison groups: a brain damage group and a healthy adult group. On-line empathy was induced in an ecologically-valid manner in which the participant experienced live the sorrow of another person. The participant thought they would be playing an economic game against two opponents. However, during the study the participant overheard their game opponent experience deep sadness, revealing that it was the anniversary of their son's death (empathic induction.) A comparison neutral induction involved the participant overhearing their opponent converse with the research assistant about a neutral topic. On-line empathic experience was measured by a questionnaire completed before and after the inductions. Empathic behavior was measured implicitly through an economic game. It was defined as the degree of behavioral change on the game as a result of the empathic induction (after accounting for baseline behavior.) The economic game used to measure empathic behavior was the Repeated Fixed Opponent variant of the well-validated Ultimatum Game. This particular variant had not been studied in participants of a similar age range to the patient sample (younger and older adults). Furthermore, there is evidence for some aging-related differences in behavior on economic games, providing additional rationale to examine the behavior of healthy younger and older adults on the game. Consequently, game behavior of younger and older adults was measured and then used to implement a model of healthy game behavior in the experiment that investigated empathy in patients with damage to the VMPC. Patients with damage to the VMPC experienced poor on-line empathy and showed poor empathic behavior. Patients with brain damage to the VMPC reported significantly less on-line empathy than patients with brain damage to other regions. Empathic behavior was not shown by patients with damage to the VMPC as a result of the empathic induction and their behavior was significantly different from both the healthy and the brain damage comparison groups which showed increased empathic behavior due to the empathic induction. A specific role for the VMPC region in empathy was demonstrated by the finding that patients with damage to this region had less on-line empathy and empathic behavior than patients with brain damage to other regions. This study showed that the VMPC region of the brain is critical for empathy. Further research is needed to elucidate whether patients with brain damage to the VMPC show decreased empathic behavior in all domains or whether it is specific to monetary decision-making.

Orientadora: Luciana Pinato / Coorientadora: Leila M. G. Campos / Banca: Maria Angélica Spadella / Banca: Natália Freitas Rossi / Resumo: Introdução: Áreas encefálicas como hipocampo, hipotálamo, cerebelo e o córtex pré-frontal participam do controle de habilidades sociais fundamentais para a saúde e o bem-estar. Alterações bioquímicas nestas áreas podem alterar a expressão do comportamento social em quadros patológicos como depressão, esquizofrenia, distúrbios bipolares e em transtornos do neurodesenvolvimento. Esclarecer os mecanismos envolvidos nessas alterações é essencial para o desenvolvimento de ações terapêuticas nestes quadros. Estudos recentes mostraram que a melatonina e seu agonista agomelatina podem estar envolvidos na modulação do comportamento social principalmente por meio dos receptores MT1 e MT2. Porém, pouco se sabe sobre variações no conteúdo de melatonina e na expressão destes receptores em diferentes áreas encefálicas, em quadros que apresentam alterações no comportamento social. Objetivos: Avaliar a concentração plasmática de melatonina, a expressão gênica dos receptores de melatonina MT1 e MT2 em diferentes áreas encefálicas, e a localização e quantificação das células imunorreativas para MT1 e MT2 no córtex pré-frontal de modelo animal com aumento na interação social. Métodos: Amostras de sangue e de tecido encefálico foram obtidas de ratos com aumento na interação social (grupo mais social) e ratos com interação social considerada normal para a espécie (grupo controle). Com o intuito de confirmar as diferenças no comportamento de interação social entre os dois grupos, todos os animais ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Encephalic areas such as the hippocampus, hypothalamus, cerebellum, and prefrontal cortex participate in the control of social skills fundamental to health and well-being. Biochemical changes in these areas may alter the expression of social behavior in pathological conditions such as depression, schizophrenia, bipolar disorders and neurodevelopmental disorders. Clarifying the mechanisms involved in these changes is essential for the development of therapeutic actions in these frameworks. Recent studies have shown that melatonin and its agonist agonist may be involved in the modulation of social behavior mainly through the MT1 and MT2 receptors. However, little is known about variations in the content of melatonin and the expression of these receptors in different brain areas, in pictures that present changes in social behavior. Objectives: To evaluate the plasma concentration of melatonin, the gene expression of MT1 and MT2 melatonin receptors in different brain areas, and the localization and quantification of MT1 and MT2 immunoreactive cells in the animal model prefrontal cortex with increased social interaction. Methods: Blood and brain tissue samples were obtained from rats with increased social interaction (more social group) and rats with social interaction considered normal for the species (control group). In order to confirm the differences in behavior of social interaction between the two groups, all animals underwent behavioral evaluation. Plasma mela... (Complete abstract click electronic access below) / Mestre

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Définition du projet: "CYCLADES", un réseau d'ordinateurs ; le traitement par lots dans un réseau hétérogène ; définition d'un serveur de traitement par lot pour le réseau CYCLADES ; définition d'un poste d'accès banalisé. Différents éléments de la réalisation : étude de la mise en œuvre ; outils pour le développement et la mise au point ; évaluation de la solution adaptée.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.

Cette thèse traduit un premier aboutissement de 3 armées d'études et de réalisations dans le domaine de la télé-informatique en général et du réseau d'ordinateurs CYCLADES en particulier. Nous avons abordé les différentes étapes de ce projet en complète et étroite collaboration. En particulier la conception général du frontal réalisé a été le fruit d'échanges constants d'idées et de critiques entre nous. Par suite il aurait été irréaliste de séparer artificiellement le travail effectué en deux parties distinctes, même si la réalisation, par souci d'efficacité, a été ponctuellement partagée, selon les goûts momentanés de chacun. C'est pourquoi, il en a résulté un document unique qui reflète mieux l'homogénéité de la recherche. Ce document se veut non seulement une présentation du travail effectué, mais également une réflexion cri tique sur les domaines abordés. Sa rédaction a été partagée selon l'intérêt marqué par chacun pour présenter chacune des parties étudiées. Ainsi, tandis que Jean-François CHAMBON rédigeait les chapitres IV, VI, VII et les annexes, Bernard LE BIHAN se consacrait aux chapitres I, II, III, V et VIII.

Schizophrenia may result from altered gene expression leading to abnormal neurodevelopment. In a search for genes with altered expression in schizophrenia, cDNA library subtractive hybridization experiments using post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were performed. I found the mRNA of two neurodevelopmentally important genes, Nogo (RTN4) and calcium/calmodulin-dependent protein kinase II beta (CaMKIIβ), to be overexpressed in post-mortem frontal cortex tissues from patients who suffered with schizophrenia. I used the quantitative real-time polymerase chain reaction method to determined the mRNA levels of these genes in tissues from age- and sex-matched individuals. Nogo is a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The gene produces three splice variants, Nogo-A, B and C. I found Nogo-C mRNA to be overexpressed by 26% in schizophrenia. I also found a 17% reduction of Nogo-B mRNA in samples from individuals who had been diagnosed with severe depression. Furthermore, I showed that there is a direct correlation between the expression of both Nogo-A and -C and the presence of a CAA insert in the 3’UTR of the Nogo gene. CaMKII is a kinase localized at the postsynaptic density. The holoenzyme is primarily composed of the subunits α and β, encoded by two separate genes. It influences the expression of many neuroreceptors, in particular receptors of the glutamatergic pathway. CaMKII also mediates neural maturation during puberty, a time of onset of schizophrenia. The expression of CaMKIIα was elevated 29% in frontal cortex tissues of patients who suffered from depression. The expression of CaMKIIβ was elevated 27% in tissues of schizophrenia patients and 36% in tissues of patients diagnosed with depression. Upregulation of CaMKIIβ was associated with the presence of the CAA insert in at least one copy of the Nogo gene in a group containing both healthy subjects and patients with mental illness, possibly linking the CaMKII and Nogo pathways. The values for the expression of Nogo, CaMKIIα and CaMKIIβ were normalized to β-glucuronidase expression to minimize the effects of mRNA degradation. These results confirm that upregulation of Nogo-C and CaMKIIβ is likely associated with schizophrenia.