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A technique for designing and optimizing the next generation of smart process controllers has been developed in this dissertation. The literature review indicated that neural networks held the most promise for this application, yet fundamental limitations have prevented their introduction to commercial settings thus far. This fundamental limitation has been overcome through the enhancement of neural network theory. The approach taken in this research was to produce highly intelligent process control systems by accurately modeling the nervous structures of higher biological organisms. The mammalian cerebral cortex was selected as the primary model since it is the only computational element capable of interpreting and complex patterns that develop over time. However the choice of the mammalian cerebral cortex as the model introduced two new levels of network complexity. First, the cerebral cortex is a three dimensional structure with extremely complicated patterns of interconnectivity. Second, the structure of the cerebral cortex can only be realized when thousands or millions of neurons are integrated into a massive scale neural network. The neural networks developed in this research were designed around the Hebbian adaptation, the only training technique proven by the literature review to be applicable to massive scale networks. These design difficulties were resolved by not only modeling the cerebral cortex, but the process by which it develops and evolves in biological systems. To complete this model, an advanced genetic algorithm was produced, and a technique was developed to encode all functional and structural parameters that define the cerebral cortex into the artificial chromosome. The neural networks were designed by a cell growth simulation program that decoded the structural and functional information on the chromosome. The cell growth simulation program is capable of producing patterns of differentiation unique for any slight variations in the genetic parameters. These growth patterns are similar to patterns of cellular differentiation seen in biological systems. While the computational resources needed to implement a massive scale neural network are beyond that available in existing computer systems, the technique has produced output lists which fully define the interconnections and functional characteristic of the neurons, thereby laying the foundation for their future use in process control. / Ph. D.

This study compares the development of the human cerebral cortex of 224 girls and 284 boys in a series of cross-sectional analyses as measured by EEG coherence on normal children's brains (longisectional design). Correlations of these EEG readings taken from all brain regions between a mean age of 6 months and 16 years yield measures of synaptic communication. Time series of these measures reflect the changing growth patterns across the 16 years. Time series of mean EEG coherence are oscillating waves that travel across left-right and front-back spatial gradients in both hemispheres. Growth spurts in mean coherence correlate with the genetic process of synapse overproduction and pruning spurts correlate with synapse elimination. Growth processes in neural connections evident in each hemisphere were examined in detail. Principal components analysis with varimax rotation identified in-phase patterns of connectivity for 64 electrode-pair sites. Analyses of effect-size differences in mean and variance ratios assisted in determining the developmental patterns in each of the brain regions studied. The study finds gender differences in both neurological structures and the timing of their development, with the timing differences being most prominent. Each sex's postnatal development concentrates on networks that showed less cortical growth during early fetal development; i.e, females favor the right hemisphere and males favor the left. Gender differences are greatest in the left prefrontal medial and lateral regions and the right posterior region, supporting gender differences indicated by anatomical, neurological and psychometric assessments. These regions support cognitive tasks of language expression and articulation, spatial visualization, judgment and goal setting. Fine-grain analyses of 42 intrahemisphere electrode-pair sites indicate the timing difference at some sites is a phase shift less than a year; at other sites, the difference is substantial, not easily described by a phase-shift dimension. other gender differences related to rate of development are specified. / Ph. D.

Depression and other mood disorders, as well as cognitive and motor dysfunction have been linked with changes in monoamine levels in the brain. Environmental acetylcholinesterase (AChE) inhibitors, such as organophosphate insecticides (OPs), have also been shown to induce these problems. This study investigated whether insecticide-induced AChE inhibition, induced by chlorpyrifos (CPS), may contribute to the types of forebrain monoaminergic alterations associated with psychiatric, cognitive and motor dysfunction. Increased synaptic ACh, resulting from CPS-induced AChE inhibition, may alter the synthesis or release of monoamines through prolonged action of ACh on monoaminergic neurons that contain ACh receptors. Adult, male Sprague-Dawley rats were subjected to a single subcutaneous dose of CPS or corn oil vehicle. Brains were rapidly removed and the frontal cortex, hippocampus and striatum were bilaterally dissected on ice. These three regions from one side were assayed for AChE activity, while those from the opposite side were processed for high performance liquid chromatography with electrochemical detection (HPLC-ED) analysis of monoamine neurotransmitters and their metabolites. In the initial, exploratory experiment, inhibition of AChE activity was 66.8% in the frontal cortex, 43.8% in the hippocampus and 46.9% in the striatum, 7 days after a 60mg/kg dose of CPS. No significant differences in concentration of monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the hippocampus or striatum. However, in the frontal cortex of the CPS-treated rats there was a significant increase in median dihydroxyphenylacetic acid (DOPAC) concentration (P=0.019) and a very strong statistical trend toward increased dopamine (DA) concentration (P=0.0506). The second experiment examined the time course of AChE inhibition produced by a higher dose (200mg/kg) of CPS and how monoamine levels changed in conjunction with this pattern of AChE inhibition. Percent inhibition of AChE activity in CPS-treated animals, at 4, 14 and 21 days post-exposure was 77.0%, 86.6% and 81.9% in the frontal cortex, 86.1%, 85.9% and 83.2% in the hippocampus and 90.1%, 89.8% and 85.5% in the striatum. No significant differences in monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the hippocampus or striatum. A statistical trend toward a decrease in serotonin (5-HT) was seen in the frontal cortex at 14 days (P=0.0753) following CPS exposure. A very consistent, yet non-significant pattern of an increase in monoamines at 4 days post-CPS was observed in all instances, except for 5-hydroxyindoleacetic acid (5-HIAA) in the striatum. Therefore, the final experiment employed a more powerful design to focus on monoamine levels during, or shortly after, the change in AChE activity that rapidly follows exposure to 200mg/kg CPS. This experiment also employed a behavioral analysis on the day of sacrifice to assess the presence or absence of clinical signs of toxicity associated with this dose. Of the 30 CPS-treated rats, only 1 animal displayed a single behavioral sign of cholinergic poisoning. Percent inhibition of AChE activity at 2 and 4 days after treatment was 81.4% and 79.4% in the frontal cortex, 53.4% and 83.5% in the hippocampus, and 80.5% and 87.8% in the striatum. No significant changes in monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the frontal cortex or hippocampus. However, a significant increase in DOPAC (P=0.0285) in the striatum, 2 days after CPS treatment, was observed. In addition, a strong statistical trend toward decreased striatal 5-HT (P=0.0645) was reported 4 days after CPS treatment. The only significant correlation between AChE activity and monoamine concentration was observed for 5-HIAA in the striatum of CPS-treated, 2 day survivors (P=0.0445). However, it was of low magnitude (r=0.525, r2=0.276). CPS has a limited capacity to produce changes in monoamine neurotransmitters and/or their metabolites in the frontal cortex and striatum of the mammalian brain. These changes are primarily seen in the dopaminergic system. Alterations of monoamines do not appear to be strongly associated with incident levels of AChE inhibition. The biological implication of the limited OP induced changes in central monoamines remains significant, as changes in monoamines in the CNS nervous system have been linked to psychiatric, cognitive and motor dysfunction. / Master of Science

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 3 uppsatser. Även tryckt utgåva.

The cerebral cortex is one of the most complex and divergent of all biological structures and is composed of hundreds of different types of highly interconnected neurons. This complexity underlies its ability to perform exceedingly complex neural processes. One of the most important questions in developmental neurobiology is how such a vast degree of diversity and specificity is achieved during embryogenesis. Furthermore, understanding the cellular and genetic basis of cortical development may yield insights into the mechanisms underlying human disorders such as mental retardation, autism, epilepsies and brain tumors. <p>During this Phd-project, we set out to identify novel transcription factors involved in cortical neurogenesis. Therefore, we initially took advantage of a model of in vitro embryonic stem cell (ESC)-derived corticogenesis that was previously established in the lab (Gaspard et al. 2008) and from several previously generated ESC lines that allow overexpression of specific transcription factors potentially involved in corticogenesis (van den Ameele et al. 2012). <p>Among the genes tested, Bcl6, a B-cell lymphoma oncogene known to be expressed during cortical development but without well-characterized function in this context, displayed a strong proneurogenic activity and thus became the main focus of this thesis. <p><p>During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is well known to be important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signalling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition.<p>We showed that Bcl6 starts to be expressed specifically during the transition from progenitors to postmitotic neurons and is required for proper neurogenesis of the mouse cerebral cortex. Bcl6 promotes this neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. Bcl6 triggers exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD+-dependent deacetylase Sirt1, which we showed to be required for Bcl6-dependent neurogenesis in vitro. The resulting epigenetic silencing of Hes5 leads to neuronal differentiation despite active Notch signalling. These findings thus suggest a role for Bcl6 as a novel proneurogenic factor and uncover Notch-Bcl6-Sirt1 interactions that may affect other aspects of physiology and disease (Tiberi et al. 2012a). <p><p>A subsequent yet unpublished part of this Phd-project focused on unraveling roles for Bcl6 in regionalization of the cerebral cortex. In all mammals, the three major areas of the neocortex are the motor, somatosensory and visual areas, each subdivided in secondary domains and complemented with species-specific additional areas. All these domains comprise of neurons with different functionality, molecular profiles, electrical activity and connectivity. Spatial patterning of the cortex is mainly under the control of diffusible molecules produced by organizing centers, but is also regulated by intrinsic, cell-autonomous programs (Tiberi et al. 2012b). <p>Since Bcl6 expression is confined to frontal and parietal regions of the developing cerebral cortex and remains high in postmitotic neurons, also after completion of neurogenesis, we hypothesized it would be involved in acquisition of motor and somatosensory identity. As expected from the neurogenesis defect in these regions, we observed a trend towards a reduced size of the frontal areas in the Bcl6 mutant cortex. Preliminary data from cDNA microarray profiling after gain- and loss-of-function of Bcl6 and from in situ hybridization on mouse cortex however do not show dramatic changes in molecular markers of different cortical areas. Similarly, the coarse-grained pattern of thalamocortical and efferent projections of motor and somatosensory neurons appears to be spared. These preliminary findings thus suggest that Bcl6 is not strictly required for proper acquisition of motor and somatosensory areal identity. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

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.

O presente estudo comparou o efeito do tratamento crônico com lítio em doses subterapêuticas (0,02mM e 0,2mM) e dose terapêutica (2mM) em cultura primária de neurônios corticais e hipocampais. As amostras foram analisadas e comparadas com o grupo controle (sem tratamento) tanto para os neurônios corticais, como para os neurônios hipocampais. O objetivo do estudo foi: 1) avaliar, nessas culturas celulares, a atividade de diferentes quinases (PKA, CaMKII, AKT e GSK3beta), diferentes sítio de fosforilação da Tau (Ser, 199, 205, 214, 396, C-terminal e seis isoformas), a partir da inibição da PLA2 pelo lítio; 2) Investigar as vias de sinalização envolvidas na modulação do estado de fosforilação da proteína tau a partir da inibição da PLA2 em culturas primárias de neurônios; 3) avaliar, simultaneamente, a expressão de fatores neurotróficos (BDNF) e citocinas (GM-CSF, IL-1b, IL-2, IL-4, IL-5, IL6, IL-10, IL-12, IFN-y e TNF-alfa) mediante o tratamento de neurônios primários com lítio e 4) avaliar expressão gênica por microarray das culturas tratadas com diferentes doses, subterapêuticas e terapêutica, de cloreto de lítio. Nossos resultados sugerem uma dissociação de efeitos em neurônios corticais dos observados em neurônios hipocampais. O lítio aumentou a atividade enzimática da iPLA2 e da cPLA2, tanto em neurônios corticais como em neurônios hipocampais. A atividade da GSK3beta foi inibida pelo tratamento crônico com lítio em neurônios hipocampais e apresentou efeito contrário em neurônios corticais. Observamos comportamentos diferentes das diferentes proteínas analisadas em culturas de neurônios corticais e hipocampais, e não tivemos significância estatística para as alterações na proteína tau. O tratamento nas doses subterapêuticas aumentou a secreção de citocinas pró-inflamatórias tanto em neurônios corticais quanto em neurônios hipocampais / The present study compared the effect of lithium chronic treatment with subtherapeutic doses (0.02mM and 0.2mM) and therapeutic dose (2mM) in primary cortical and hippocampal neurons cell culture. This samples were analyzed and compared with the control group (no treatment). The study\'s goal was: 1) to evaluate in these Cell Culture a different activity kinases (PKA, CaMKII, AKT and GSK3beta), different phosphorylation site of the Tau (199, 205, 214, 396, C-terminal and Six isoforms) and PLA2 inhibition; 2) To investigate how signaling pathways involved in modulation of tau phosphorylation from the inhibition of PLA2 in primary cultures of neurons; 3) analyze an expression of neurotrophic factors (BDNF) and cytokines (GM-CSF, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IFNy TNFalfa 4) to evaluate gene expression via microarray with different doses of lithium treatment. Our results suggest a dissociation effects on cortical and hippocampal neurons cell culture. Lithium increased the enzyme activity of iPLA2 and cPLA2, in both cortical and hippocampal neurons. The GSK3beta the activity was inhibited by chronic treatment with lithium in hippocampal neurons and presented contrary effect on cortical neurons. We observe not statistics significance on tau protein. The treatment at subtherapeutic and therapeutic doses increased the secretion of pro and anti-inflammatory cytokines both in cortical and hippocampal neurons

Alterações morfométricas cerebrais em pacientes com esquizofrenia têm sido descritas em muitos estudos utilizando ressonância magnética estrutural, sendo as mais consistentes o aumento ventricular e a redução do volume de substância cinzenta em neocórtex pré-frontal e temporal, ínsula, tálamo e no hipocampo/giro parahipocampal. No entanto, a natureza e o curso dessas alterações ainda não foram esclarecidos. Embora a principal hipótese a respeito da etiopatogenia da esquizofrenia sugira a presença de alterações anatômicas de início precoce e estáveis ao longo da doença, estudos longitudinais de ressonância magnética estrutural a partir do primeiro episódio psicótico têm indicado que, apesar de observáveis já no início da doença, ou mesmo antes do surgimento da mesma, algumas alterações podem ser progressivas, principalmente nos primeiros anos. Neste trabalho, foi comparado, transversal e longitudinalmente, o volume de substância cinzenta entre pacientes com esquizofrenia e transtorno esquizofreniforme após o primeiro contato com serviços de saúde e controles não psicóticos. As imagens de ressonância magnética estrutural de 62 pacientes e 94 controles procedentes da mesma área de captação, recrutados a partir de um estudo epidemiológico na cidade de São Paulo, foram adquiridas em um aparelho de 1,5 Tesla. Após um intervalo médio de 16 meses, 39 pacientes e 52 controles foram reexaminados. As imagens foram analisadas pelo método de morfometria voxel-a-voxel com o uso do programa Statistical Parametric Mapping e a significância estatística foi estabelecida em p<0,05, corrigido para comparações múltiplas. A comparação inicial entre os grupos evidenciou áreas de redução de substância cinzenta nos pacientes em córtex pré-frontal direito e esquerdo, córtex temporal superior esquerdo, ínsula bilateral e hipocampo e giro parahipocampal direitos. A análise longitudinal evidenciou maior grau de preservação de substância cinzenta no grupo dos pacientes em córtex temporal superior esquerdo e em hipocampo/giro parahipocampal direitos. Não houve áreas de perda significativamente maior de substância cinzenta em pacientes comparados aos controles na análise longitudinal. Não foi encontrada diferença de volume de substância cinzenta entre pacientes com maior ou menor tempo de exposição aos antipsicóticos, tanto à análise inicial, quanto à análise longitudinal. Os resultados da análise transversal estão de acordo com a literatura sobre alterações cerebrais estruturais em primeiro episódio psicótico. Os achados da investigação longitudinal estão de acordo com alguns estudos de seguimento e apontam para a possibilidade de que essas alterações surgiriam antes do primeiro episódio psicótico. Além disso, tais resultados sugerem que, pelo menos durante o intervalo pesquisado, tais alterações não são progressivas. As diferenças volumétricas entre pacientes e controles não foram causadas pelo uso de antipsicóticos / Morphometric brain abnormalities have been extensively described in subjects with schizophrenia in many structural magnetic resonance imaging studies, the most consistent findings being ventricular enlargement and gray matter reductions in frontal and temporal neocortices, insula, thalamus and hippocampus/parahippocampal gyri. However, the nature and course of these abnormalities have not yet been clarified. Although the main hypothesis regarding the etiopathology of schizophrenia implies the presence of early and stable anatomical brains abnormalities, longitudinal magnetic resonance imaging studies have suggested that, despite being present at the first episode of psychosis, or even before its onset, some brain abnormalities may be progressive, especially at the first few years of the disorder. In the present study, gray matter volumes were compared, at baseline and longitudinally, between first-episode patients with schizophrenia or schizophreniform disorder and non-psychotic controls. Structural magnetic resonance images from 62 patients and 94 controls, recruited from the same catchment area for an epidemiological study in the city of São Paulo, were acquired using a 1.5 Tesla scanner. After a mean period of 16 months, 39 patients and 52 controls were rescanned. Images were analyzed by voxel-based morphometry with the Statistical Parametric Mapping software and statistical significance was set at p<0.05, corrected for multiple comparisons. The initial betweengroup comparison revealed gray matter reductions in patients, when compared to controls, in the right and left prefrontal cortices, left superior temporal cortex, bilateral insula and right hippocampus and parahipocampal gyrus. Longitudinally, patients exhibited significantly greater gray matter preservation in left superior temporal cortex and right hippocampus/ parahipocampal gyrus. There were no areas showing significantly greater gray matter loss in patients relative to controls in the longitudinal analysis. There were no gray matter differences between medicated and unmedicated patients, neither at baseline nor at follow-up. The findings of the baseline comparison are in accordance with previous studies that reported brain abnormalities in association with first episode psychosis. The longitudinal results are in accordance with some of the follow-up neuroimaging studies conducted to date and support the hypothesis that the described abnormalities could have been present before the onset of illness. Also, these findings suggest that, at least considering the follow-up interval of our study, such brain changes are not progressive. The volumetric differences between patients and controls observed in our study were not caused by antipsychotic medication effects

Em modelos de redes corticais com neuronios pulsantes, os mecanismos responsaveis pela emergencia e impacto de flutuacoes de atividade neuronal ainda nao estao completamente entendidos. Neste trabalho, modelos computacionais de redes corticais foram utilizados para investigar como flutuacoes ritmicas e nao-ritmicas surgem e suas possiveis consequencias. Foram estudadas redes com dois tipos de topologia: aleatoria e hierarquica modular, esta ultima inspirada em evidencias experimentais para a arquitetura cortical. Foram utilizados tres diferentes modelos simplificados de neuronios: integra-e-dispara, Izhikevich e integra-e-dispara exponencial com adaptacao. Primeiramente, estudou-se a ocorrencia de atividade auto-sustentada em redes hierarquicas modulares compostas por populacoes de neuronios de classes eletrofisiologicas distintas. Nesses modelos, os padroes de atividade auto-sustentada de longa duracao sao oscilatorios e seu tempo de vida depende do nivel hierarquico e da mistura de neuronios na rede. Em seguida, estudou-se o efeito da introducao de ruido sinaptico em modelos de redes aleatorias. Observou-se o aparecimento de alternancia intermitente entre atividade ritmica e nao-ritmica com caracteristicas similares a estados corticais sincronos e assincronos, respectivamente. Desenvolveu-se a extensao de uma abordagem reducionista para redes neuronais homogeneas, em que um esquema iterativo auto-consistente e usado para que um unico neuronio gere trens de disparo com propriedades estatisticas de segunda ordem similares as de uma rede, para o caso de redes neuronais heterogeneas. Mostrou-se que essa abordagem captura situacoes em que flutuacoes de atividade lentas emergem. Finalmente, utilizou-se o esquema reducionista e ferramentas de teoria de informacao para estudar a emergencia de flutuacoes de atividade lentas e sua propagacao em redes hierarquicas modulares. Os resultados mostram que a propagacao de informacao pela rede depende do numero de modulos, sugerindo que ha um nivel hierarquico otimo para a propagacao de informacao. Os estudos feitos contribuem para aprofundar o entendimento da relacao entre estrutura e composicao neuronal em modelos de redes corticais e indicam mecanismos de emergencia e manutencao de flutuacoes de atividade nessas redes / In cortical network models with spiking neurons, the mechanisms responsible for the emergence and impact of neuronal activity fluctuations are not yet completely understood. In this work, computational models of cortical networks were used to investigate how rhythmic and non-rhythmic fluctuations arise and their possible consequences. Networks with two types of topology were studied: random and hierarchical modular, this latter inspired on experimental evidence about cortical architecture. Three different simplified spiking neuron models were used: integrate-and-fire, Izhikevich, and integrate-and-fire with adaptation. Initially, the types of self-sustained activity patterns that emerge in hierarchical modular networks with mixtures of electrophysiological neuronal classes were studied. In these models, the long-duration self-sustained activity patterns are oscillatory and their lifetime depend on the hierarchical level of the network and its neuronal composition. Next, the effect of the introduction of synaptic noise in random networks was studied. These networks displayed intermittent alternations between rhythmic and non-rhythmic activity patterns with characteristics similar to synchronous and asynchronous cortical states, respectively. A reductionist approach for homogeneous neuronal networks, in which an iterative self-consistent scheme is used so that a single neuron spike train generates second-order statistical properties similar to the ones of a network, was extended to heterogeneous networks. It was shown that this reductionist scheme captures situations in which slow activity fluctuations emerge. Finally, the reductionist scheme and information theoretical tools were used to study the emergence of slow activity fluctuations and their propagation through hierarchical modular networks. The results show that the information propagation in the network depends on the number of modules, suggesting an optimal hierarchical level for information propagation. The studies done contribute to deepen the understanding of the relationship between structure and neuronal composition in cortical network models, and point to mechanisms of emergence and maintenance of activity fluctuations in these networks