O sistema nervoso central é o mais complexo de todos os sistemas de órgãos dos vertebrados. Células progenitoras neurais ao se diferenciarem em neurônios e outros tipos celulares, desenvolvem um padrão altamente organizado de conexões, criando uma rede neuronal que forma o cérebro e o restante do sistema nervoso. Para que se possa gerar os diferentes tipos de neurônios e glias deste sistema, as células embrionárias proliferam-se e diferenciam-se através de processos altamente controlados. Este estudo visou avaliar a importância do receptor B2BkR durante o desenvolvimento encefálico do camundongo. Como modelo estudo, foram utilizados animais knockout (B2BkR-/-) para o gene do receptor B2BKR como modelo para avaliação do padrão de expressão de proteínas marcadoras neurais e dos sistemas purinérgicos e de cininas durante o desenvolvimento encefálico de camundongos B2BkR-/-. Há evidências que mostram que o sistema nervoso de mamíferos contém todos os componentes do sistema calicreína-cininas e que as cininas podem atuar como neuromediadores. Os transcritos do receptor B2BkR foram encontrados em células localizadas em regiões neurogênicas a partir do dia 9.5 do desenvolvimento, esta expressão ampliou-se para toda a extensão do sistema nervoso a partir do dia 12,5 do desenvolvimento. A deleção do gene que codificado para o receptor B2BkR levou a um aumento na expressão relativa do receptor B1BkR. No animal knockout foi também observado um aumento nos níveis de expressão dos cininogênios 1 e 2, sugerindo a ativação de mecanismos compensatórios devido a falta do gene codificado para o receptor B2BkR. De acordo com resultados obtidos com modelos de diferenciação in vitro, também os padrões de expressão de marcadores neurais foram alterados ao longo do desenvolvimento de animais knockout, nos quais houve a diminuição da expressão dos marcadores β3-tubulina e MAP2, confirmando o papel do receptor B2BkR na neurogênese. O marcador glial GFAP teve sua expressão relativa significativamente aumentada nos animais knockout B2BkR-/-, confirmando que a inibição deste receptor favorece a gliogênese. A deleção do receptor B2BkR alterou o perfil de expressão dos receptores purinérgicos do subtipo P2X. Os subtipos P2X2 e P2X3 apresentaram níveis de expressão maiores nos animais selvagens. As subunidades P2X4, P2X5, P2X6 e P2X7 apresentam uma expressão maior nos animais B2BkR-/-. Efeitos semelhantes a estes já haviam sido observados na expressão gênica durante a diferenciação d e neuroesferas do telencéfalo de ratos tratados com antagonistas do B2BkR. No entanto, este trabalho é o primeiro a demonstrar os efeitos da delação do B2BkR sob a expressão do receptor B1BkR; de marcadores neurais e gliais; dos cininogênios 1 e 2; e receptores purinérgicos do suptipo P2X in vivo. Deste modo, estes resultados servem como incentivo para estudos adicionais visando elucidar a participação do receptor B2BkR e do sistema calicrína-cininas na determinação de fenótipos neurais utilizando modelos in vivo, bem como os mecanismos envolvidos e o papel do receptor B2BkR na terapia de doenças neurodegenerativas. / The central nervous system (CNS) is the most complex one of all vertebrate organs. Neural stem and progenitor cells differentiate into neurons and other neural cell types such as glia, originating a highly coordinated network characterizing the brain and the remaining nervous system in strictly controlled processes. It is known that the mammalian nervous system expresses all components of the kallikrein-kinin system, and several functions in the brain have been attributed to bradykinin including neurotransmission, neuroprotection and also lately neurogenesis. The present work aimed at studying the importance of the kinin-B2 receptor (B2BKR) during mouse brain development. A B2BKR knock-out model was used for characterizing changes in the expression patterns of neural marker protein and of the purinergic and kininergic systems. Transcripts of B2BkR-coding sequences were detected in neurogenic regions from embryonic day 9.5 (E9.5) on. Expression of the receptor augmented to the whole extension of the CNS beginning from E12.5. Deletion of the B2BKR-coding gene resulted in increased B1BkR gene expression together with augmented kininogen-1 and -2 expression levels. In agreement with results obtained with in vitro models, expression patterns of neural marker proteins also suffered alterations during neural development of B2BKR(-/-) mice when compared to wild-type animals. Reduction of neuronal protein β3-tubulina e MAP2 expression was observed in B2BKR(-/-) mice, while at the same time glial GFAP expression was enhanced, indicating that activation of the B2BKR promotes neurogenesis, while its inhibition favors gliogenesis. Deletion of the B2BkR-coding gene also lets to changes in expression patterns of purinergic P2X receptors. P2X2 and P2X3 subunits were higher expressed in wild-type animals, while P2X4, P2X5, P2X6 e P2X7 subunits revealed increased expression patterns in B2BkR-/- animals. These results are in line with previous ones of our group obtained in differentiating neurospheres from embryonic rat telencephalons. In summary, the present work is the first to demonstrate the effects of B2BKR deletion on expression patterns of neural marker proteins, the B1BKR and several purinergic receptor subunits. Additional studies will be incentivized for elucidation of functions and underlying mechanism of B2BKR actions in vivo, with applications in cell therapy of neurodegenerative diseases.

No description available.

Die Adoleszenz beschreibt die entwicklungspsychologische Phase zwischen der Kindheit und des Erwachsenenalters, die durch rapide Veränderungen in der Physiologie, im Hormonhaushalt und Verhalten charakterisiert ist. Typische jugendliche Verhaltenstendenzen wie risikohaftes Verhalten und Impulsivität werden einer erheblichen biologischen Umstrukturierung des jugendlichen Gehirns attribuiert. Unklar ist jedoch, wie sich diese massiven biologischen Veränderungen auf spezifische Prozesse auswirken, welche in ein erhöhtes risikohaftes und impulsives Entscheidungsverhalten in der Adoleszenz resultieren. Die vorliegende Dissertation setzt sich zum Ziel, die kognitiven, affektiven und neuronalen Mechanismen der jugendlichen Impulsivität zu untersuchen. Hier wird der Pubertät eine besondere Rolle zugeschrieben und unterschiedliche Analyseebenen wie kognitive und affektive Maße mit biologischen Maßen wie Hormonen kombiniert, sowie Methoden der funktionellen Magnetresonanztomographie (fMRT) und kognitiven Modellierung angewandt. Die vorliegende Dissertation ist publikationsorientiert und besteht aus vier Projekten. Zum Zeitpunkt der Abgabe der Dissertation sind Kapitel I und Kapitel II erschienen, und Kapitel III und IV sind als vollständige Manuskripte bei unterschiedlichen peer-reviewed Journals eingereicht. Kapitel I gibt eine generelle Übersicht zum aktuellen Forschungsstand über den Zusammenhang zwischen Hormonen in der Pubertät, affektiver Verarbeitung und erhöhter Impulsivität und Risikobereitschaft in der Adoleszenz. Es werden Befunde von empirischen Studien mit Menschen und Tieren diskutiert, welche sich mit jugendlichen Verhalten, sowie Gehirnentwicklung während der Pubertät befassen, sowie zukünftige neue Forschungsschwerpunkte formuliert. Die folgenden drei weiteren Kapitel sind empirische Studien, welche sich mit den offenen Punkten aus dem ersten Kapitel befassen. Alle drei Studien untersuchen Ungeduld, da diese als eine spezifische Subkomponente von dem eher allgemein gefassten psychologischen Konstrukt der Impulsivität definiert ist (Romer, 2010). Während sich alle drei Studien auf die ungeduldige Entscheidungsfindung fokussieren, entscheiden sie sich dennoch in den untersuchten Mechanismen: Kapitel II fokussiert sich auf die Pubertät, speziell auf Testosteron und seinen Zusammenhang mit ungeduldiger Entscheidungsfindung. Konsistent mit früheren Studien ist das chronologische Alter (und nicht Testosteron) assoziiert mit einer generellen Abnahme der Diskontierung in der frühen Adoleszenz, während hingegen Testosteron (und nicht das Alter) mit einer erhöhten Sensitivität für sofortige Belohnungen einhergeht. Kapitel III untersucht die neuronalen Mechanismen, die der Beziehung zwischen Testosteron in der Pubertät und ungeduldigem Entscheidungsverhalten (dargestellt im vorherigen zweiten Kapitel) unterliegen. Ergebnisse dieser Studie zeigen, dass Testosteron in der Pubertät speziell das dorsale, nicht jedoch das ventrale Striatum beeinflusst, welches mit der Entscheidung für kleinere, aber zeitlich früherer Belohnungen einhergeht. Die letzte Studie in Kapitel IV befasst sich mit der Frage, wie der affektive Inhalt einer Belohnung ungeduldige Entscheidungsfindung beeinflusst. Zwei unabhängige Studien haben gezeigt, dass erhöhte Levels an positiven Affekt mit einer Zunahme an ungeduldigen Entscheidungen assoziiert waren. Ein möglicher Mechanismus, der dieses Ergebnis erklären kann, ist eine Veränderung der Zeitwahrnehmung. Zusammenfassend untersucht die vorliegende Dissertation in sehr umfangreicher Art und Weise die zugrundeliegenden Mechanismen von ungeduldiger Entscheidungsfindung und kombiniert in einem multi Modell Ansatz Maße von Affekt und Hormonen mit Methoden, wie der fMRT und kognitiver Modellierung von aufgabenbezogenen Verhalten. Ergebnisse früherer Studien über jugendliches Verhalten und Gehirnentwicklung werden durch die vorliegende Doktorarbeit erweitert, indem Hormone in der Pubertät eine besondere Hervorhebung genießen und in diesem Zusammenhang spezifische Prozesse, die der impulsiven Entscheidungsfindung unterliegen, auf neuronaler und verhaltensbasierter Ebene umfangreich und sorgfältig analysiert werden. Schließlich wird die Rolle von Testosteron in der Pubertät neu definiert und es wird ein neues Framework vorgeschlagen, welches den Einfluss von Testosteron auf die kognitive Kontrolle in der Pubertät besonders hervorhebt und somit neuartige, spannende Ideen für die zukünftige Forschung darbietet / Adolescence describes the developmental phase between childhood and adulthood and is characterized by rapid changes in physiology, hormones and behavior. Typical adolescent behavioral tendencies such as risk taking and impulsivity are thought to evolve from a major biological reorganization of the adolescent brain. However, it remains unclear how these large scale biological changes impact specific processes that result in increases in risky and impulsive decision-making in adolescence. The current dissertation aims at elucidating the cognitive, affective and neural mechanisms of adolescent impulsivity by 1) highlighting the role of puberty and 2) combining different levels of analyses, including cognitive or affective measures, with biological measures such as pubertal hormones and functional magnetic resonance imaging (fMRI), in combination with cognitive modeling techniques. The dissertation is publication-oriented and consists of four pieces of work. At the time of submitting this dissertation, Paper I and Paper II have been published, and Paper III and Paper IV exist as complete drafts that have been submitted for publication. Paper I gives a general overview of the current state of the art on the relationship between pubertal hormones, affective processing and increased impulsive and risky decision-making in adolescence. It discusses findings of empirical studies focusing on both adolescent behavior and the brain in the light of pubertal maturation in humans and animals and formulates new research directions. The following three papers are empirical studies that tackle the questions made in Paper I, examining specifically impatience, which is defined as one subcomponent of the more broader construct of impulsivity (Romer, 2010). While each paper focuses on impatient decision-making, they differ in terms of the mechanism being investigated: Paper II focuses on puberty, in particular testosterone and its relationship to impatient decision making. Consistent with previous studies, age, but not testosterone is associated with an overall decline in discounting in early adolescence, while testosterone but not age is associated with increased sensitivity to immediate rewards. Paper III investigates the neural mechanisms underlying the relationship between pubertal testosterone and impatient decision making previously described in Paper II. Here, results indicated that testosterone specifically impacts the dorsal, but not the ventral striatum, which in turn lead to behavior that was biased towards choosing smaller sooner rewards. Finally, Paper IV focuses on affective processing, specifically on how the affective content of a reward impacts impatient decision-making. In two independent studies, increased levels of positive affect were consistently associated with an increase in impatient decisions. The underlying mechanism that may explain this increased impatient behavior is a shift in time judgment. In summary, this dissertation thoroughly investigated the underlying mechanisms of impatient decision-making by using a multimodal approach with measures of affect, fMRI, and hormonal assessment combined with cognitive modeling of task-related behavior. It extends previous findings on adolescent behavior and brain development by elucidating the role of pubertal hormones with regard to specific processes underlying impatient decision making, both on a behavioral and neural level. Finally, it redefines the role of pubertal testosterone by proposing a novel framework that highlights its impact on executive control, thus offering novel, exciting directions for future research.

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To form complex organisms characterized by different tissues with specialized functions, cells must acquire distinct identities during development. Yet, all the cells of an organism are equipped with the same genomic information. Elucidating the mechanisms that regulate the determination of a cell identity, i.e. the cell-fate commitment, is a main purpose in developmental biology. Numerous studies focused on genes that are activated or repressed at each stage of differentiation, identifying several key regulators of development. However, this approach ignores the transcript variability derived from alternative splicing, the transcriptional process by which different gene coding segments, i.e. exons, are combined giving rise to multiple transcripts and proteins from the same gene. With the advent of novel sequencing technologies, it is becoming clear that alternative splicing is widespread in higher organisms, regulates several processes and presents tissue- and cell-specificity. In mammals, the brain shows the highest degree of alternative splicing, with neurons expressing a high variety of splice variants. In this project I investigated whether and how alternative splicing could regulate cell-fate determination in the context of the embryonic development of the mouse neocortex, a highly complex structure presenting several different neuronal subtypes generated at specific time points. For this purpose, I analyzed transcriptome data of cells of the neurogenic lineage isolated from the developing mouse neocortex at subsequent stages of differentiation. I showed that the expression pattern of the proteins regulating splicing, i.e. the splicing factors, changes during neocortical development. By employing several bioinformatic tools, I described the splicing profile that characterizes each differentiation stage and, for the first time, I identified the splicing events that mark cell-fate commitment to a neurogenic identity. Alternative splicing mostly involved genes with a role in nervous system development, cell growth and signaling, mainly leading to the production of alternative protein isoforms. Splicing choices taken during the neurogenic commitment were kept throughout neurogenesis. Thus, exons that start to be included during cell-fate determination are always included in post-mitotic neurons. Exons gained during neurogenic commitment were characterized by strong features in their upstream intron, presented a general short length with an overrepresentation of microexons in the 3-27 nucleotides length range and showed an enrichment for binding motifs of the neural splicing factor nSR100. In vivo manipulation in the embryonic mouse neocortex highlighted isoform-specific effects on neocortical development, strongly suggesting a causal relationship between alternative splicing choices and cell-fate commitment. Moreover, the higher cell-specificity offered by the present dataset, compared to similar studies, allowed a better understanding of previously identified splicing events that characterize the nervous system and the relationships between neural-specific splicing factors.:Table of Contents Abstract I Zusammenfassung III Table of Contents V List of Figures VII List of Tables IX Abbreviations X Gene abbreviations XII 1 Introduction 1 1.1 Neurogenesis during embryonic development 2 1.1.1 Formation and patterning of the neural tube 2 1.1.2 Neural progenitors in the dorsal telencephalon 6 1.1.3 Neurogenesis 8 1.1.4 Regulation of neurogenesis 10 1.1.5 A novel tool to investigate cell-fate determination in the central nervous system: the Btg2RFP/Tubb3GFP mouse line 13 1.2 Alternative splicing: an additional level of genomic regulation 15 1.2.1 The splicing reaction 16 1.2.2 What makes splicing alternative? 18 1.2.3 Regulation of alternative splicing 19 1.2.4 The challenge to detect splicing 23 1.2.5 New sequencing technologies reveal a high transcriptome complexity 29 1.2.6 Splicing in nervous system development 31 1.2.7 Aims of the project 36 2 Materials and methods 38 2.1 Materials 38 2.1.1 Bacteria, cells, mouse strains 38 2.1.2 Vector 38 2.1.3 Primers 38 2.1.4 Chemicals and buffers 41 2.1.5 Antibodies 42 2.1.6 Kits and enzymes 42 2.2 Methods 43 2.2.1 Animal experiments 43 2.2.2 Molecular biology 44 2.2.3 Immunohistochemistry 46 2.2.4 Bioinformatics 47 3 Results 53 3.1 Splicing factors are differentially expressed during neurogenic commitment and neurogenesis 53 3.2 Detection of alternative splicing 55 3.2.1 Isoform-switching 55 3.2.2 Exon usage and splicing events 57 3.3 Validation 62 3.3.1 The isoform switching method has a poor validation rate 62 3.3.2 Analysis at the exon level has a high rate of validation 65 3.4 Pattern and representation of splicing events 67 3.4.1 Splicing choices during neurogenic commitment define the splicing profiles of neurons 67 3.4.2 Splicing events: microexon inclusion characterizes neurogenic commitment 69 3.5 Alternative splicing changes the protein output of genes involved in neurogenesis 75 3.5.1 Spliced genes are involved in neurogenesis and signaling 75 3.5.2 Impact of alternative splicing on the proteome 77 3.6 Splicing regulation: neural exon features and splicing factor binding 79 3.6.1 Included neural exons are short and preceded by strong exon-definition features 79 3.6.2 Early included exons are enriched for nSR100 binding sites 85 3.7 The Btg2RFP/Tubb3GFP mouse line outperforms previous models for the study of cell-type-specific splicing in the brain 88 3.8 In vivo manipulation of splice variants 90 4 Discussion 94 4.1 The combination of different bioinformatic approaches allows an accurate identification of splicing events at the exon-level 95 4.2 Splicing choices during neurogenic commitment establish a neural signature characterized by microexon inclusion 97 4.3 Splicing during neocortical development leads to the generation of alternative protein isoforms in genes involved in neurogenesis and signaling 98 4.4 Neural exons are short and present strong features facilitating inclusion 101 4.5 Neural exons are prevalently regulated by nSR100 during neurogenic commitment 102 4.6 In vivo overexpression of splice variants highlights isoform-specific functions in neurogenic commitment 105 4.7 Concluding remarks and future perspectives 108 5 Supplementary figures 110 6 References 118 Acknowledgments 137 Anlange I 138 Anlange II 139

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human prefrontal cortex of individuals across the lifespan to describe changes in cellular programs and their regulation by epigenetic mechanisms. The analysis considers previous knowledge in terms of functional gene signatures and chromatin states derived from independent studies, aging profiles of a battery of chromatin modifying enzymes, and data of gliomas and neuropsychological disorders for a holistic view on the development and aging of the brain. Expression and methylation changes from babies to elderly adults decompose into different modes associated with the serial activation of (brain) developmental, learning, metabolic and inflammatory functions, where methylation in gene promoters mostly represses transcription. Expression of genes encoding methylome modifying enzymes is very diverse reflecting complex regulations during lifetime which also associates with the marked remodeling of chromatin between permissive and restrictive states. Data of brain cancer and psychotic disorders reveal footprints of pathophysiologies related to brain development and aging. Comparison of aging brains with gliomas supports the view that glioblastoma-like and astrocytoma-like tumors exhibit higher cellular plasticity activated in the developing healthy brain while oligodendrogliomas have a more stable differentiation hierarchy more resembling the aged brain. The balance and specific shifts between volatile and stable and between more irreversible and more plastic epigenomic networks govern the development and aging of healthy and diseased brain.

During evolution, the mammalian cerebral cortex has undergone a considerable increase in size and complexity. The emergence of the cortical structure begins during embryonic development when neural stem cells initially undergo proliferative division to expand their pool and then switch to neurogenic division, generating differentiating progenitors that will give rise to neurons. Although the intrinsic molecular mechanisms instructing the switch from proliferative to neurogenic division have been well-studied, most work to date has focused on gene expression. However, as a consequence of transcriptional and post-transcriptional regulation, different transcripts can arise from a single gene. In particular, the process of alternative splicing occurs at a high frequency in the nervous system and can lead to changes in protein output regardless of gene expression. In the past years, the role of post- transcriptional mechanisms in neuronal maturation and function have been extensively investigated, mostly focusing on the function of specific isoforms or RNA binding proteins. Yet, the role of alternative splicing in generating transcript and protein diversity during neurogenic commitment is still unknown. Therefore, I used a combination of different RNA sequencing technologies and bioinformatic tools to reveal the transcript and protein diversity of proliferating progenitors, differentiating progenitors, and neurons isolated from double reporter mouse line. I identified widespread isoform diversity and many novel transcripts amongst expressed genes in the developing cortex. To date, this analysis represents the most comprehensive characterization of full-length transcript diversity at different stages of the neurogenic lineage in the developing mouse cortex. The resulting transcriptome annotation was used to quantify changes in exon inclusion across cells of the neurogenic lineage and identified alternative splicing events potentially involved in neurogenic commitment. These alternative splicing events were enriched in the coding sequence of isoforms, indicating that they might be relevant for protein diversity generation in the developing cortex. During neurogenesis, alternative splicing events were less enriched in regions that could disrupt or strongly affect protein structure and function, such as transmembrane regions, active sites, and domains. Interestingly, my results indicated that alternative splicing enables increased functional diversity by modulating protein-protein interaction sites and signaling properties of proteins. Still, further studies are required to delineate the causal relationship between these alternative splicing choices and cell-fate commitment. Applying a similar approach to other mammalian species, including humans, has the potential to uncover species-specific innovations and conserved features that underlie evolutionary cortex expansion. Moreover, understanding the function of isoforms during neural development could provide important insights into the molecular mechanisms involved in the onset of neurodevelopmental disorders. Therefore, the higher cell-specificity offered by the present dataset, compared to similar studies, allowed not only a better understanding of transcript and protein diversity generated by alternative splicing in the nervous system and highlighted potential functional consequences, but also shed light on the advantages of applying such strategy to address different biological questions.

Summaries in Afrikaans and English / Text in Afrikaans / Vanaf geboorte is die ouers en die omgewing wat hulle vir die kind skep van die uiterste belang. Ouers behoort 'n ruimte te skep waar die kind intellektueel gestimuleer kan word, begeleide leerervaringe kan ontvang en waar hy veiligheid en geborgenheid kan beleef Dit is in hierdie voorskoolse jare waar die grondslag gele word vir latere leer. Waar vroee stimulering en bemiddeling ontbreek is dit later baie moeilik om met insette dieselfde positiewe resultate te bereik. Begeleide leerervaringe is 'n essensiele komponent van en voorwaarde vir optimale ontwikkeling. Wanneer die kind aan geletterdheidervaringe blootgestel word in sy voorskoolse jare, kan hy, wanneer hy skool toe gaan, die insette en konsepte as "bekend" ervaar, omdat hy reeds vroeg al daarmee kennisgemaak het. Die ouers kan die kind se voorskoolse jare s6 ontwerp dat die kind se potensiaal optimaal verwesenlik kan word. In die empiriese ondersoek is onderhoude met ouers gevoer sodat hulle hul ervarings met hul kinders wat hulle voorskools gestimuleer het, kon weergee. Volgens die resultate blyk dit dat vroee stimulering waarskynlik 'n belangrike faktor is ten opsigte van latere prestasie. / Parents should create an atmosphere where the child can be stimulated intellectually, can receive mediated learning experiences (MLE) and where he can experience safety and security. It is in the preschool years that the foundation is laid to make learning easier later on. Where early stimulation and mediation is lacking it is very difficult later on to achieve positive results with the same inputs. When the child is exposed to literacy experiences in his pre-school years, he can experience the inputs and concepts as "known" when he attends school, as he was already acquainted with them. The parents can shape the pre-school years of the child in such a manner that the potential of the child can be realised optimally. In the empirical investigation parents were interviewed in order to determine the extent to which they supplied intellectual stimulation to their pre-school children. According to the results it appears that early stimulation is probably an important factor with regard to achievement in later years. / Psychology of Education / M. Ed. (Psychology of Education)

Crime is as old as mankind. It started with an incident of theft inside Paradise and a murder outside. In order to understand the phenomenon of crime several theories were formulated over time. One fact should be recognized: All forms of trauma can be reduced to a single common factor: Control – or better said: a lack of control. A lack of personal control causes tension; tension leads to desperation; desperation leads to irresponsibility. Then the door to crime is unlocked. Fortunately all irresponsibilities doesn’t lead to crime. In order to understand the offender it is imperative to understand his background. The relationship between childhood trauma and crime cannot be denied. It is a fact that childhood traumas can lead to abnormal brain development in early childhood. For this reason special attention is paid to the processes involved in brain development, both in normal children and in maltreated ones. If not identified and intervened in time, it can lead to a situation where the cycle of frustration and desperation, and eventually crime, cannot be interrupted - not even by prisonization. Management of change (rehabilitation) must reckon with the influence of said traumas on the brain development of children. Efforts to rehabilitate the offender becomes senseless if applied for an hour once a week. Such efforts cannot repair the damage done by negative influences repeated thousands of times over many years. In the same vein it is fruitless to aim therapeutic interventions on the reason of man hoping to repair the emotional damage of his childhood. For this reason the Neurosequential Method of Therapeutics holds promise in the quest for the rehabilitation of the offender and in the fight against crime. / Penology / D. Litt. et Phil. (Penology)

Résumé : Le trouble de l’acquisition de la coordination (TAC), d’étiologie encore indéterminée, est une anomalie neurologique affectant environ 6% des enfants de l'âge scolaire. Le TAC se manifeste essentiellement par un déficit au niveau des exécutions motrices. Le présent travail de recherche comporte deux volets portant sur le TAC. Premièrement, une étude clinique sur 129 sujets âgés de 4 à 18 ans a permis de classifier les caractéristiques du TAC en sous-groupes cliniques. Trente-trois caractéristiques du TAC, les plus fréquemment rapportées dans la littérature, ont été recensées chez nos sujets. L'application d'évaluations statistiques a permis de faire ressortir trois classes essentielles. Le deuxième volet consistait à identifier les régions cérébrales impliquées dans une tâche motrice à l'aide de l'imagerie par la tomographie d'émission par positrons (TEP). Deux sujets avec TAC et deux sujets normaux ont été étudiés en deux séances d'imagerie TEP dont l'une au repos et l'autre en tapotant du pouce sur les doigts de la main gauche non-dominante. Les analyses du premier volet ont montré, entre autres, que le TAC touchait 3.17 garçons pour une fille, que tous les sujets étaient lents, que 47% des sujets étaient gauchers ou ambidextres alors que seulement 10% sont gauchers dans la population générale, que 26% avaient une dyspraxie verbale, et que 83% avaient été diagnostiqués anxieux. Les sujets ont été classés en trois sous-groupes: 1- maladroits et autres caractéristiques, sans problème de langage; 2- trouble de l’estime de soi et relation avec les pairs; 3- difficulté de langage. En imagerie, les structures cérébrales ont été classées selon leur captation du 18F-fluorodesoxyglucose (FDG) dans les hémisphères droit et gauche, avant et après l'activation, et en comparaison avec les sujets normaux. Trois types de structures cérébrales sont ressortis avec les statistiques: des structures activées, celles relativement non sollicitées et des structures désactivées. Il y avait plus de variations dans la captation du FDG chez les sujets avec TAC que chez les normaux. En conclusion, la caractérisation des sujets avec TAC par le diagnostic clinique et par l'imagerie peut procurer un plan de thérapie adéquat et ciblé étant donné que le TAC a un large spectre et pourrait coexister avec d'autres déficits cérébraux. / Abstract : Developmental Coordination Disorder (DCD) is a neurological abnormality affecting approximately 6% of children of school age. DCD is essentially manifested by deficit in motor executions. The present research aims two parts of DCD. First, a clinical study on 129 subjects aged 4 to 18 years old allowed to classify DCD characteristics (subtyping) in three classes. Thirty-three features of DCD, the most frequently reported in literature, have been identified in our subjects. The application of statistical clustering produced three essential classes. The second part was to identify the brain regions involved in a motor task using positron emission tomography (PET) imaging. Subjects with DCD and control subjects were studied in two PET imaging sessions at rest and then by tapping the thumb on each finger of the left non-dominant hand. The results showed, that DCD concerned 3.17 boys for one girl, all subjects were slow, 47% of the subjects were left-handed or ambidextrous while only 10% are left-handed in general population, 26% had a verbal dyspraxia, and 83% had been diagnosed with anxiety. Subjects were classified into three groups: 1- clumsy and other features without language problem; 2- self-esteem and peer relationships concern; 3- difficulty of spoken language. With PET imaging, the brain structures were classified according to their uptake of 18F-fluorodeoxyglucose (FDG) in the right and left hemispheres before and after activation, and compared with normal subjects. Three types of brain structures statistically emerged: activated structures, those relatively unsolicited and those disabled. There was more variation in uptake of FDG in patients with DCD than in control subjects. In conclusion, the characterization of subjects with DCD for clinical diagnostic and imaging can provide adequate and focused treatment plan since DCD has a broad spectrum and could coexist with other brain deficits.