As metástases cerebrais são os tumores cerebrais mais freqüentes do sistema nervoso central. Entre as modalidades terapêuticas, a radiocirurgia (SRS) vem ganhando destaque nas duas últimas décadas como forma efetiva de tratamento associada com baixa morbidade e mortalidade. Porém, mesmo após ampla revisão da literatura, várias perguntas permanecem sem resposta sobre a radiocirurgia no tratamento das metástases cerebrais, perguntas estas principalmente relacionadas sobre as complicações tardias, dependência ao corticóide e relação das complicações com áreas cerebrais funcionais eloqüentes. O objetivo deste trabalho foi analisar a radiocirurgia como modalidade terapêutica das metástases cerebrais (MC) de uma grande série de casos, que estuda criteriosamente clínica e radiologicamente as lesões e identificando fatores preditivos para complicações, falha terapêutica e necrose pós-tratamento, a qual enfatiza principalmente localização da MC e suas relações com áreas eloqüentes cerebrais. Foi realizado estudo retrospectivo em 213 pacientes com 261 metástases cerebrais tratadas com radiocirurgia. Várias características demográficas deste grupo de pacientes foram analisadas, onde destacamos a boa distribuição de lesões de várias histologias tratadas e na grande maioria de pacientes em bom estado geral. Além disso, dividimos estes tumores de acordo com uma classificação estabelecida para relação com áreas eloqüentes em 3 grupos (graus I, II e III). No nosso estudo encontramos dependência ao corticóide em 24,3% dos casos, que se distribui em 15%, 25% e 29% nas lesões grau I, II e III respectivamente. O autor demonstra que o dobro das lesões localizadas nas áreas eloqüentes apresenta dependência ao corticóide, comparando-se com tumores em áreas não eloqüentes. Destacamos que a dependência ao esteróide ocorre em 54,5% dos tumores do tronco cerebral, 38,8% dos relacionados com centro motor/sensitivo, 35,5% daqueles relacionados com centros da fala e 20% dos casos relacionados com áreas visuais. Também nestes grupos específicos ocorreu queda destas taxas de dependência com o passar dos meses. Na nossa casuística, a SRS foi efetiva em 184 lesões tratadas (70,5%), diante de acompanhamento prolongado. As complicações em geral foram mais freqüentes em áreas eloqüentes, ocorrendo, especificamente, em 64,7% , 64,9% e 55,3% respectivamente, para lesões do tronco cerebral, centros da fala e áreas motoras/sensitivas. Dentre as muitas variáveis utilizadas encontramos diferenças significativas para complicações para casos com doença primária progressiva, lesões grau III (áreas eloqüentes), lesões do tronco cerebral e relacionadas com áreas motoras/sensitivas. Se estudarmos apenas os casos com falha terapêutica, notamos diferenças para predizer falha terapêutica em casos com doença sistêmica avançada, a não realização de radioterapia prévia e lesões relacionadas com áreas motoras/sensitivas e centros da fala. Foram considerados fatores preditivos de necrose pós-tratamento metástases de melanoma e carcinoma de células renais, presença de metástases outras além do encéfalo, realização prévia de radioterapia, doses acima de 20 Gy e tumores relacionados com áreas motoras/sensitivas. Em todas as análises, notamos diferenças significativas quanto maior o tamanho da lesão tratada. Não houve diferenças significativas quanto à efetividade ou complicações comparando as várias histologias, ocorrendo diferenças para o surgimento de necrose póstratamento em casos das lesões consideradas \"radioresistentes\" (melanoma e carcinoma de células renais). Considerando os resultados obtidos, concluise que a realização de radioterapia prévia a radiocirurgia esteve associada com maior efetividade e maior possibilidade de ocorrer necrose póstratamento. Doença primária em estágio avançado foi considerada como fator preditivo de complicação e de falha terapêutica. Lesões maiores apresentaram significativas diferenças para complicações, falhas terapêuticas e necrose pós-tratamento, do que lesões menores. Podemos concluir, ainda, que a localização da metástase cerebral deve ser considerada uma variável importante em predizer complicação do tratamento, visto que encontramos significativas diferenças para o surgimento de complicações em lesões localizadas em áreas eloqüentes (grau III) e ainda especificamente em lesões do tronco cerebral e em áreas motoras/sensitivas, comparando-se com demais regiões cerebrais. Tais áreas também apresentaram maior taxa de dependência ao corticóide / Brain metastases are the most common Central Nervous System tumors. Among the therapy options stereotactic radiosurgery has became in the last two decades an usefulness treatment technique attending with lower complication and mortality rate. However, even an extended literature review, many questions remain unclear about this therapy modality, mainly related with long-term complications, steroids dependency, and relations with brain eloquent areas. The goal of this project is analyze stereotactic radiosurgery as treatment modality for brain metastases in a large series, considering clinics and radiologic lesions aspects and identifying predictors factors for complications, treatment failure and treatment necrosis regarding the relation with brain eloquent areas. We retrospectively review 213 patients with 261 brain metastases treated with stereotactic radiosurgery. Several demographics aspects were analysed. We noticed a good distribution of histological groups and the performing patient status. We also lump these lesions in groups based on their location in relation with eloquent brain areas (grade I, II and III). This study found a general steroids dependency rate of 24,3% for all cases, occurring in 15%, 25% and 29% in lesions grade I, II and III respectively. That\'s twice the frequency for lesions located in eloquent brain areas compared with non eloquent located lesions. Specifically, the steroids dependency occurred in 54,5% of brain stem tumors, 38,8% tumors related with motor/sensory centers, 35,5% speech center tumors related and 20% of cases related with visual areas. Even in these subgroups the dependency rate decreases with time. The long-term tumor local control was achieved in 184 treated lesion (70,5%). Complications were more often found in eloquent areas, specifically in 64,7%, 64,9% and 55,3% respectively for brain stem, speech centers and motor/sensory related lesions. Among all variables we found significant differences for complications in cases of progressive primary disease, lesions grade III (located in eloquent areas), brain stem lesions, and related with motor/sensory areas. Regarding only treatment failure prediction, we noticed significances in cases of progressive primary disease, none previously radiated cases, and lesions related with motor/sensitive and speech areas. We considered predictors of treatment necrosis melanoma and renal cell carcinoma metastases, extra-cranial metastases, previously radiated patients, doses > 20Gy. In all analysis we found significant differences as bigger as the treated lesion. We did not find significant differences regarding efficacy and complication comparing all histological types. We identify statistically significant considering \"radioresistent\" tumors for treatment necrosis. Based on the results, we conclude that radiotherapy previously stereotactic radiosurgery were related higher effectiveness and treatment necrosis. Progressive primary disease predicts complications and treatment failure. Bigger lesions were statistically significant related with complications, treatment failure and necrosis compared with smaller ones. We can also conclude that brain location of metastases is an important variable to predict complications, with results that showed statistically significant differences found in grade III lesions, specifically brain stem tumors, lesions related in motor/sensitive areas, compared with non eloquent located lesions. These areas are also related with higher steroids dependency rates

Atenção consiste em conjunto de processos que leva à seleção ou priorização no processamento de certas categorias de informação, em detrimento de outras, possibilitando um processamento mais eficiente do que seria possível caso o sistema nervoso processasse os estímulos presentes no ambiente simultaneamente. A atenção participa da maioria das funções cognitivas humanas. Depende, portanto, de região cerebral com privilégios anátomo-fisiológicos, como o lobo parietal, cujo padrão de conectividade (áreas unimodais, córtex pré-motor, colículo superior, giro cingulado, giro parahipocampal, insula, córtex orbitofrontal) possibilita a integração sensório-motora e cognitiva necessária à atenção. Desde o início da década de 80 estudos sobre o lobo parietal tem sugerido uma reavaliação de suas funções, modificando a percepção comum de que esteja relacionado exclusivamente a desempenhar funções espaciais, incluindo uma suposta especialização do lobo parietal direito na distribuição da atenção no espaço. No entanto, a base fisiológica para a especialização do lobo parietal na orientação atencional é mal compreendida pelas seguintes razões: 1- lesão unilateral do lobo parietal direito determina deficiência de processamento atencional em relação ao hemiespaço contralateral, e raramente ocorre após lesão do lobo parietal esquerdo; 2- o processamento das informações pelo sistema visual humano varia sensivelmente em relação aos campos visuais, e a metodologia dos testes atencionais tradicionais não considera que o desempenho dos voluntários pode ser limitado pela visibilidade dos estímulos; a localização dos estímulos tem sido avaliada independentemente da disposição dos alvos no campo visual. Nossa proposta é padronizar as condições de estimulação no teste de Posner para orientação da atenção, considerando os limiares específicos de cada voluntário e avaliar as deficiências de orientação da atenção endógena e exógena nos planos horizontal, vertical e diagonal, em pacientes portadores de dano nos lobos parietais direito e esquerdo, secundário a neoplasia, e compará-las entre si e com voluntários saudáveis. Desse modo poderíamos contribuir para o conhecimento sobre as bases neurais da atenção e para o desenvolvimento de estratégias eficazes e individualizadas de reabilitação / Attention consists of processes that lead to selection or prioritization in processing certain categories of information over others, allowing more efficient processing than would be possible if the nervous system had to process the stimuli in the environment simultaneously. Attention integrates most of human cognitive functions. Therefore it depends on specific brain regions with anatomical and physiological privileges, such as the parietal lobe, which pattern of connectivity (unimodal areas, premotor cortex, superior colliculus, cingulate gyrus, parahippocampal gyrus, insula, orbitofrontal cortex) enables sensorimotor and cognitive integration required for attention. Since early of 1980´s the common perception that parietal lobe is related solely to performance of spatial tasks, including a supposed specialization of the right parietal lobe for the distribution of attention in space is changing. The physiological basis for the specialization of the parietal lobe in orienting of attention is poorly understood for the following reasons: 1 - unilateral lesion of the right parietal lobe attentional determines disability in attention processing of information which comes from the contralateral space, and rarely occurs after injury of the left parietal lobe 2 - the processing of information by the human visual system varies considerably in relation to visual fields, and traditional attentional testing methodology does not consider that performance of the volunteers may be limited by the visibility of the stimuli; the location of the stimuli has been evaluated independently on the targets position in the visual field. Our proposal is to standardize the conditions of stimulation in the Posner test for orienting of attention, considering the specific visual thresholds of each subject and evaluate exogenous and endogenous orientation of attention deficiencies in horizontal, vertical and diagonal plans, in patients with damage to the right and left parietal lobes, secondary to brain tumor, and compare them among themselves and with healthy volunteers. Thereby this approach could contribute for the knowledge about the neural bases of attention and therefore help to develop effective strategies for rehabilitation

INTRODUÇÃO: Alterações em circuito neural têm sido associadas com o transtorno depressivo maior. Entretanto, até o momento não se tem estudos investigando a associação entre a lesão do acidente vascular cerebral neste circuito e a incidência do episódio depressivo maior após o acidente vascular cerebral. Este estudo teve como objetivo principal investigar de modo prospectivo a associação entre o volume da lesão no circuito neural límbico-córtico-estriado-pálido-talâmico no hemisfério esquerdo e a incidência de episódio depressivo maior nos primeiros quatro meses posteriores ao acidente vascular cerebral isquêmico. Como objetivo secundário, visou investigar a associação entre o volume da lesão em regiões específicas do circuito e a incidência do episódio depressivo maior após o acidente vascular cerebral isquêmico. MÉTODOS: Neste estudo foram triados de modo consecutivo 326 pacientes admitidos na enfermaria de neurologia do Hospital das Clinicas de São Paulo. Destes, foram elegíveis 68 pacientes e foram acompanhados prospectivamente. A avaliação psiquiátrica consistiu na aplicação da entrevista clinica estruturada para diagnóstico pelo DSM-IV e no manual estruturado para entrevista da Escala de Hamilton para Depressão; o grau de comprometimento nas atividades de vida diária foi medido pelo Índice de Barthel; o grau de gravidade do acidente vascular cerebral foi mensurado pela escala para acidente vascular cerebral do National Institutes of Health e, a capacidade cognitiva foi avaliada pelo Miniexame do estado mental. As avaliações ocorreram em 3 momentos sendo a primeira em média 12,4 dias (+ 4,5) após o acidente vascular cerebral, a segunda em média 37 dias (+ 6) e, a terceira em média e 91,6 dias (+ 5,4) após o acidente vascular cerebral. As imagens por ressonância magnética foram realizadas dentro dos 15 dias posteriores ao acidente vascular cerebral em um aparelho de 1.5 Tesla (GE-Horizon LX) com protocolo específico. A localização do acidente vascular cerebral e o volume da lesão foram processados usando um método semi-automatizado baseado no Atlas Citoarquitetônico de Brodmann. Os grupos de pacientes com episódio depressivo maior e sem depressão foram comparados quanto aos dados clínicos e neurorradiológicos. RESULTADOS: Nos primeiros 4 meses posteriores ao acidente vascular cerebral 21 (31%) pacientes apresentaram episódio depressivo maior. Não houve diferenças entre os grupos com respeito à idade, distribuição por sexo, estado civil, condição empregatícia, lateralização hemisférica da lesão isquêmica, gravidade do infarto, comprometimento das atividades de vida diária e capacidade cognitiva. O volume da lesão no circuito límbico-córtico-estriado-pálido-talâmico no hemisfério esquerdo apresentou associação com a incidência do episódio depressivo maior (P=0,004) assim como, volume da lesão nas seguintes áreas específicas: córtex ventral anterior do cíngulo (AB24; P=0,032), córtex dorsal anterior do cíngulo (AB32; P=0,043), córtex subgenual (AB25; P=0,038), subículo (AB28/AB36; P=0,032) e amígdala (AB34; P=0,010). Este estudo tem algumas limitações como não avaliação de lesões isquêmicas subcorticais e outros possíveis fatores de risco para a depressão posterior ao acidente vascular cerebral. CONCLUSÕES: Os resultados fornecem evidências da existência de associação entre o volume da lesão do acidente vascular cerebral no hemisfério esquerdo no circuito límbico-córticoestriado- pálido-talâmico e a incidência do episódio depressivo maior posterior ao acidente vascular cerebral. / BACKGROUND: Dysfunction in the neural circuit has been etiologically related to major depressive disorder. However no study has investigated the role of lesion in these circuits and post-stroke major depression. The objective of this study was to prospectively investigate the association between stroke volume in left limbiccortical- striatal-pallidal-thalamic neural circuit and incidence of major depressive episode after stroke, and secondary to investigate the association between stroke volume in specific areas of the neural circuit and the incidence of major depressive episode after stroke. METHODS: From 326 consecutively screened patients admitted in the neuroclinical unit of Clinics Hospital, São Paulo, 68 were eligible and followed. The Structured Clinical Interview for DSM-IV and Hamilton Depression Scale were applied in the psychiatry evaluations. The stroke severity was evaluated using the National Institutes of Health Stroke Scale and the activities of daily living limitations were measured using Barthel Index. Cognitive capacity was measured using Mini Mental State Examination. The evaluations were done in three timepoints the first in mean of 12.4 (+ 4.5) days after stroke, the second in 37 (+ 6) days and, the third, 91.6 (+ 5.4) days after stroke. Magnetic resonance scans were performed within 2 weeks after stroke in a 1.5 Tesla (GE-Horizon LX) scanner. Stroke localization and volume quantification were performed using a semi-automated method based on the Brodmann Cytoarchitectonic Atlas. The depressed and non depressed patients were compared. RESULTS: Twenty-one patients (31%) experienced a new onset of major depressive episode within a four-month period after stroke. No differences were found between depressed and non depressed patients regarding age, gender distribution, marital status, employment status, ischemic lesion hemispheric lateralization, stroke severity, level of limitations in activities of daily living and cognitive capacity. Stroke lesion volume in the left limbic-cortical-striatal-pallidal-thalamic circuit was associated with incidence of major depressive episode (P=0.004). Complementary analyses revealed association the incidence of major depressive episode with larger stroke lesion volume in specific areas of this circuit, including the ventral anterior cingulate cortex (BA24; P=0.032), dorsal anterior cingulate cortex (BA32; P=0.043), subgenual cortex (BA25; P=0.038), hippocampal subiculum (BA28/BA36; P=0.032) and amygdala (BA34; P=0.010). There are some study limitations, as no subcortical ischemic stroke analyses and other possible risk factors for depression after stroke. CONCLUSIONS: The results of this study have shown evidence of an association between stroke lesion size in left hemisphere in the limbic-cortical-striatal-pallidalthalamic circuit and the incidence of major depressive episode after stroke.

Embora os glicocorticoides (GCs) sejam os anti-inflamatórios mais prescritos mundialmente, níveis elevados de GCs potencializam alguns aspectos da resposta inflamatória em regiões do encéfalo de ratos, dependentes da ativação dos receptores GR. Neste estudo visamos avaliar os efeitos dos glicocorticoides em alguns aspectos da resposta inflamatória induzida por LPS nas populações de células (neurônio, micróglia e astrócitos) primárias de córtex frontal derivadas de ratos Wistar neonatos. Através de ensaios EMSA e imunofluorescência, avaliamos indicativos da ativação do fator NFKB em culturas mistas e enriquecidas expostas ao pré-tratamento com CORT, seguido do estímulo inflamatório LPS. Verificamos que a CORT não exerceu sua clássica atividade anti-inflamatória, pois não foi capaz de diminuir a ativação do NFKB induzida pelo LPS nas culturas mistas, sugerindo ser parcialmente dependente da ativação de GR, concentração dos GCs e interações celulares, já que os astrócitos em culturas mistas exibem respostas diferentes quanto ao NFKB, mas a microglia e neurônios não. / Although glucocorticoids (GCs) are the most commonly prescribed anti-inflammatory worldwide, high levels of GCs enhance some aspects of the inflammatory response in brain regions of rats, dependent on activation of GR. In this study, we aim to evaluate the effects of glucocorticoids in some aspects of the inflammatory response LPS-induced in populations of cells (neurons, astrocytes, and microglia) in primary frontal cortex derived from newborn rats. Through EMSA and immunofluorescence assays, we evaluated the indicative factor NFKB activation in mixed and enriched cultures exposed to pretreatment with CORT, followed by the LPS inflammatory stimulus. We found that CORT did not exerted its classic anti-inflammatory activity, whereas it was not able to decrease the activation of NFKB LPS-induced in mixed cultures, suggesting be partially dependent on the GR activation, GCs concentration and cellular interactions, since astrocytes in mixed cultures exhibit different responses relative to NFKB, but neurons and microglia did not.

A estimulação epidural do córtex motor (ECM) é eficaz no tratamento da dor neuropática refratária, porém seus mecanismos de ação ainda são incertos. Sabendo que a ECM ativa a via analgésica descendente em ratos, fomos investigar o efeito da ECM sobre os núcleos serotonérgicos descendentes, dorsal da rafe (NDR) e magno da rafe (NMR) e sobre os neurônios da coluna posterior da medula espinhal (CPME). Ratos Wistar, submetidos à ECM, foram avaliados no teste de pressão da pata e seus tecidos foram avaliados frente à imunorreatividade (IR) para Egr-1 (marcador de ativação neuronal), serotonina (5HT) e substância P (SP). A ECM induziu antinocicepção em 62% nos animais, não alterou a ativação do NDR, entretanto ativou o NMR (67%), quando comparado com ratos não estimulados. A ECM aumentou a IR-5HT em 75% no NDR e em 92% no NMR. Na CPME, a ECM inibiu os neurônios nociceptivos (48%), porém não interferiu com a IR-SP. Estes resultados sugerem que a ECM induz analgesia, em parte, via ativação do sistema serotonérgico descendente. / Motor cortex stimulation (MCS) is effective in the treatment of refractory neuropathic pain; however, its mechanisms of action remain unclear. Since the MCS activates the descending pain pathway in rats, we investigated the MCS effect on the descending serotonergic nuclei, dorsal raphe nucleus (DRN) and the magnus raphe nucleus (MRN) and also on the neurons of the dorsal horn of the spinal cord (DHSC). Wistar rats, submitted to MCS, were evaluated by paw pressure test and its tissues were evaluated by immunoreactivity (IR) to Egr-1 (neuronal activation marker), serotonin (5HT) and substance P (SP). MCS induced antinociception by 62% in animals, although did not modify the NDR activation; however, activated the MRN (67%), when compared to control groups. MCS increased the IR-5HT by 75% in the NDR and 92% in the MRN. In the DHSC, MCS inhibited the nociceptive neurons (48%), however did not change the IR-SP. These results suggest that MCS induce antinociception, partly, by the descending serotonergic pathway activation.

The human cerebral cortex is a highly foliated structure that supports the complex cognitive abilities of humans. The cortex is divided by its cytoarchitectural characteristics that can be approximated by the folding pattern of the cortex. Psychiatric and neurological diseases, such as Huntington's disease or schizophrenias, are often related with structural changes in the cerebral cortex. Detecting structural changes in different regions of cerebral cortex can provide insight into disease biology, progression and response to treatment. The delineation of anatomical regions on the cerebral cortex is time intensive if performed manually, therefore automated methods are needed to perform this delineation. Magnetic Resonance Imaging (MRI) is commonly used to explore the structural change in patients with psychiatric and neurological diseases. This dissertation proposes a fast and reliable method to automatically parcellate the cortical surface generated from MR images. A fully automated pipeline has been built to process MR images and generate cortical surfaces associated with parcellation labels. First, genus zero cortical surfaces for each hemisphere of a subject are generated from MR images. The surface is generated at the parametric boundary between gray matter and white matter. Geometry features are calculated for each cortical surface to as scalar values to drive a multi-resolution spherical registration that can align two cortical surfaces together in the spherical domain. Then, the labels on a subject's cortical surface are evaluated by registering a subject's cortical surface with a population atlas and combining the information of prior probabilities on the atlas with the subject's geometry features. The automated parcellation has been tested on a group of subjects with various cerebral cortex structures. It shows that the proposed method is fast (takes about 3 hours to parcellate at one hemisphere) and accurate (with the weighted average Dice ~0.86). The framework of this dissertation will be as follows: the first chapter is about the introduction, including motivation, background, and significance of the study. The second chapter describes the whole pipeline of the automated surface parcellation and focuses on technical details of every method used in the pipeline. The third chapter presents results achieved in this study and the fourth chapter discusses the results and draws a conclusion.

This thesis presents an abstract model of the mammalian neocortex. The model was constructed by taking a top-down view on the cortex, where it is assumed that cortex to a first approximation works as a system with attractor dynamics. The model deals with the processing of static inputs from the perspectives of biological mapping, algorithmic, and physical implementation, but it does not consider the temporal aspects of these inputs. The purpose of the model is twofold: Firstly, it is an abstract model of the cortex and as such it can be used to evaluate hypotheses about cortical function and structure. Secondly, it forms the basis of a general information processing system that may be implemented in computers. The characteristics of this model are studied both analytically and by simulation experiments, and we also discuss its parallel implementation on cluster computers as well as in digital hardware. The basic design of the model is based on a thorough literature study of the mammalian cortex’s anatomy and physiology. We review both the layered and columnar structure of cortex and also the long- and short-range connectivity between neurons. Characteristics of cortex that defines its computational complexity such as the time-scales of cellular processes that transport ions in and out of neurons and give rise to electric signals are also investigated. In particular we study the size of cortex in terms of neuron and synapse numbers in five mammals; mouse, rat, cat, macaque, and human. The cortical model is implemented with a connectionist type of network where the functional units correspond to cortical minicolumns and these are in turn grouped into hypercolumn modules. The learning-rules used in the model are local in space and time, which make them biologically plausible and also allows for efficient parallel implementation. We study the implemented model both as a single- and multi-layered network. Instances of the model with sizes up to that of a rat-cortex equivalent are implemented and run on cluster computers in 23% of real time. We demonstrate on tasks involving image-data that the cortical model can be used for meaningful computations such as noise reduction, pattern completion, prototype extraction, hierarchical clustering, classification, and content addressable memory, and we show that also the largest cortex equivalent instances of the model can perform these types of computations. Important characteristics of the model are that it is insensitive to limited errors in the computational hardware and noise in the input data. Furthermore, it can learn from examples and is self-organizing to some extent. The proposed model contributes to the quest of understanding the cortex and it is also a first step towards a brain-inspired computing system that can be implemented in the molecular scale computers of tomorrow. The main contributions of this thesis are: (i) A review of the size, modularization, and computational structure of the mammalian neocortex. (ii) An abstract generic connectionist network model of the mammalian cortex. (iii) A framework for a brain-inspired self-organizing information processing system. (iv) Theoretical work on the properties of the model when used as an autoassociative memory. (v) Theoretical insights on the anatomy and physiology of the cortex. (vi) Efficient implementation techniques and simulations of cortical sized instances. (vii) A fixed-point arithmetic implementation of the model that can be used in digital hardware. / QC 20100903

En els últims anys, diversos treballs han demostrat que els astròcits participen activament en el desenvolupament i la plasticitat del sistema nerviós central, així com en la modulació de la neurotransmissió. Característicament, la majoria de les accions descrites dels astròcits sobre la fisiologia i la patologia neuronal són mitjançades per secreció vesicular. En el aquest treball s’han identificat les molècules implicades en l’exocitosi de cèl•lules astroglials. Malgrat que alguns components són comuns amb les neurones, altres com sintaxina 4, VAMP3 i SNAP23 s’expressen de forma específica en les cèl•lules astroglials. Tractaments activadors o de maduració diferencialment regulen l’expressió de diferents isoformes de proteïnes exocítiques en cèl•lules glials in vitro. Així, l’activació amb citocines proinflamatòries augmenta l’expressió d’algunes SNAREs i els seus reguladors en glia, com sintaxina4 i munc18b. La correlació entre els nivells d’expressió d’aquestes proteïnes exocítiques i l’augment de la secreció de mediadors d’activació i inflamació suggereix un important paper d’aquestes molècules en la secreció de cèl•lules activades. Amb l’objectiu d’estudiar la secreció regulada per calci en astròcits madurs s’ha obtingut un fenotip madur glial in vitro mitjançant l’activació de la via del AMPc. L’anàlisi global amb "gene set enrichment analysis" del transcriptoma astrocitari ha demostrat que l’increment en els nivells intracel•lulars d’AMPc reprimeix la immaduresa i activació dels astròcits i promou la seva maduració. Aquesta maduració dependent de la via del AMPc augmenta l’expressió de proteïnes exocítiques, com per exemple VAMP2, així com la via de secreció regulada per calci dels pèptids ANP i SgII. Finalment, mitjançant assajos de pèrdua de funció, es demostra un paper d’aquestes proteïnes en la secreció de pèptids glials. Aquests resultats suggereixen que diferents molècules d’exocitosi mitjancen diferents processos de secreció glials. Per altra banda, en aquesta tesi s’ha identificat un nou component de la via de secreció astroglial, tant in vitro com in vivo, la SgIII. En cèl•lules neuroendocrines SgIII actua com un receptor de direccionament a grànuls secretors. En cèl•lules astroglials SgIII presenta una forma molecular i una dinàmica de secreció diferencial a cèl•lules neuroendocrines. A més, hem demostrat una notable sobreexpressió d’aquesta proteïna en astròcits reactius en lesions traumàtiques, la qual cosa suggereix una participació de SgIII en els mecanismes de protecció o dany cerebral en lesions del sistema nerviós central. / In recent years, several studies have demonstrated that astrocytes influences neuronal development, function and plasticity through vesicular transmitter release. However, secretory pathways and the involved molecular mechanisms in astroglial cells are poorly known. In this study, we showed that a variety of SNARE and Munc18 isoforms were expressed by cultured astrocytes, with syntaxin-4, Munc18c, SNAP-23 and VAMP-3 being the most abundant variants. Exocytotic protein expression was differentially regulated by activating and differentiating agents. Specifically, proteins controlling Ca2+-dependent secretion in neuroendocrine cells were up-regulated after long-term 8Br-cAMP administration in astrocytes, but not by proinflammatory cytokines. We also analyzed the global transcriptome of cultured astroglial cells incubated with activators of cAMP pathways. cAMP analogs strongly upregulated genes involved in typical functions of mature astrocytes, whereas they downregulated a considerable number of proliferating and immaturity-related transcripts. Gene Set Enrichment Analysis and evaluation in situ of gene expression in astrocytes in different states showed that cAMP signaling conferred a mature and in vivo–like transcriptional profile to cultured astrocytes. Moreover, 8Br-cAMP treatment greatly increased the cellular content of exocytotic proteins such as VAMP-2 and stimulated Ca2+-dependent secretion of secretogranin-2 and ANP. Regulation of both exocytotic protein expression and Ca2+-dependent peptide secretion in astrocytes by differentiating and activating agents suggested that glial secretory pathways were adjusted in different physiological states. In this thesis, we showed the expression, transcriptional regulation, trafficking and release of the secretory pathway component SgIII in astroglial cells. In endocrine cells, SgIII is a key sorting receptor for peptide hormones while astrocytes produced and released a non-processed form. Moreover, SgIII expression was specifically upregulated in reactive astrocytes after perforating brain injury. These results showed that SgIII is a reliable component of the astrocyte secretory pathway and suggest important roles for glial SgIII in the glia–neuron communication.

The ability to correct balance disturbances is essential for maintaining upright stability. Recent literature highlights a potentially important role for the cerebral cortex in controlling compensatory balance reactions. The objective of this research was to provide a more detailed understanding of the specific neurophysiologic events occurring at the cortex following balance disturbances. More specifically, the focus was to determine whether the N1, a cortical potential evoked during balance control, and the error-related negativity (ERN), a cortical potential measured in response to errors during cognitive tasks, have similar cortical representation, revealing a similar link to an error detection mechanism. It was hypothesized that the N1 and ERN would have the same generator located in the anterior cingulate cortex (ACC). Fourteen healthy young adults participated in a balance task (evoked N1) and a flanker task (evoked ERN). Temporally unpredictable perturbations to standing balance were achieved using a lean and release cable system. Electromyography and centre of pressure were measured during the balance task. Reaction times and error rates were measured during the flanker task. Electroencephalography was recorded during both tasks. Source localization was performed in CURRY 6 using a single fixed coherent dipole model to determine the neural generator of the N1 and ERN. The results revealed that the locations of the N1 and ERN dipoles were different. The mean (n=9) distance between N1 and ERN dipoles was 25.46 ± 8.88 mm. The mean Talairach coordinates for the ERN dipole were (6.47 ± 3.08, -4.41 ± 13.15, 41.17 ± 11.63) mm, corresponding to the cingulate gyrus (Brodmann area 24). This represents the ACC, supporting results from previous literature. The mean Talairach coordinates for the N1 dipole were (5.74 ± 3.77, -11.81 ± 10.84, 53.73 ± 7.30) mm, corresponding to the medial frontal gyrus (Brodmann area 6). This is the first work to localize the source of the N1. It is speculated that the generator of the N1 is the supplementary motor area and that it represents the generation of a contingency motor plan to shape the later phases of the compensatory balance response based on sensory feedback from the perturbation.

Thesis (M.S.)--State University of New York at Binghamton, Department of Psychology, 2009. / Includes bibliographical references.