Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.

Syftet med detta examensarbete är att undersöka hur skolkuratorer kan kategorisera och beskriva de insatser som kan erbjudas till grundskoleelever med neuropsykiatriska funktionsvariationer. Det finns flera lagstiftningar som pekar på barns rättigheter till skolgång samt att alla barn har rätt till anpassningar utifrån deras individuella behov för att forma deras vardag och göra den likvärdig andra barns skolgång. Tidigare forskning indikerar att det finns flera olika typer av insatser till barn med neuropsykiatriska funktionsvariationer som används världen över. De olika typerna av insatser kategoriserar på olika sätt, antingen utifrån diagnos eller problemområde så som akademiska eller beteende-insatser.    För att besvara våra frågeställningar har fyra semistrukturerade intervjuer genomförts med skolkuratorer som arbetar på grundskolor runtom i Sverige. Insamlad data har analyserats utifrån tematisk analysmetod för att förstå hur informanterna kategoriserar de aktuella insatserna. Vidare har data också analyserats utifrån stigmateorin, framställd av Goffman (1963), och stämplingsteorin, framställd av Goldberg (1980), för att skapa förståelse för hur insatserna kan beskrivas och tolkas ur såväl ett samhällsperspektiv som individperspektiv.    Slutsatserna i denna studie visar på att informanterna kategoriserade insatserna utifrån främst två kategorier: individuella insatser och generella insatser. Informanterna valde att försöka anpassa insatserna utifrån de specifika svårigheter som följde diagnoserna så som koncentrationssvårigheter eller anpassningar kring det mänskliga mötet, i stället för att anpassa insatserna utifrån de specifika diagnoserna. Olika typer av insatser manade till en inkluderande miljö och normalisering av extra anpassningar, medan vissa insatser exkluderade och särskilde elever från den gemensamma klassrumsmiljön. Ytterligare slutsatser är att insatserna kan påverka klassrumsmiljön, samt att informanterna i studien genom sitt arbete försökte normalisera behovet av extra anpassningar och därmed motverka stigmatiseringen av neuropsykiatriska funktionsvariationer.

Quelque 30 % de la population neuronale du cortex mammalien est composée d’une population très hétérogène d’interneurones GABAergiques. Ces interneurones diffèrent quant à leur morphologie, leur expression génique, leurs propriétés électrophysiologiques et leurs cibles subcellulaires, formant une riche diversité. Après leur naissance dans les éminences ganglioniques, ces cellules migrent vers les différentes couches corticales. Les interneurones GABAergiques corticaux exprimant la parvalbumin (PV), lesquels constituent le sous-type majeur des interneurones GABAergiques, ciblent spécifiquement le soma et les dendrites proximales des neurones principaux et des neurones PV+. Ces interneurones sont nommés cellules à panier (Basket Cells –BCs) en raison de la complexité morphologique de leur axone. La maturation de la connectivité distincte des BCs PV+, caractérisée par une augmentation de la complexité de l’axone et de la densité synaptique, se déroule graduellement chez la souris juvénile. Des travaux précédents ont commencé à élucider les mécanismes contrôlant ce processus de maturation, identifiant des facteurs génétiques, l’activité neuronale ainsi que l’expérience sensorielle. Cette augmentation marquante de la complexité axonale et de la synaptogénèse durant cette phase de maturation suggère la nécessité d’une synthèse de protéines élevée. La voie de signalisation de la cible mécanistique de la rapamycine (Mechanistic Target Of Rapamycin -mTOR) a été impliquée dans le contrôle de plusieurs aspects neurodéveloppementaux en régulant la synthèse de protéines. Des mutations des régulateurs Tsc1 et Tsc2 du complexe mTOR1 causent la sclérose tubéreuse (TSC) chez l’humain. La majorité des patients TSC développent des problèmes neurologiques incluant des crises épileptiques, des retards mentaux et l’autisme. D’études récentes ont investigué le rôle de la dérégulation de la voie de signalisation de mTOR dans les neurones corticaux excitateurs. Toutefois, son rôle dans le développement des interneurones GABAergiques corticaux et la contribution spécifique de ces interneurones GABAergiques altérés dans les manifestations de la maladie demeurent largement inconnus. Ici, nous avons investigué si et comment l’ablation du gène Tsc1 perturbe le développement de la connectivité GABAergique, autant in vitro que in vivo. Pour investiguer le rôle de l’activation de mTORC1 dans le développement d’une BC unique, nous avons délété le gène Tsc1 en transfectant CRE-GFP dirigé par un promoteur spécifique aux BCs dans des cultures organotypiques provenant de souris Tsc1lox. Le knockdown in vitro de Tsc1 a causé une augmentation précoce de la densité des boutons et des embranchements terminaux formés par les BCs mutantes, augmentation renversée par le traitement à la rapamycine. Ces données suggèrent que l’hyperactivation de la voie de signalisation de mTOR affecte le rythme de la maturation des synapses des BCs. Pour investiguer le rôle de mTORC1 dans les interneurones GABAergiques in vivo, nous avons croisé les souris Tsc1lox avec les souris Nkx2.1-Cre et PV-Cre. À P18, les souris Tg(Nkx2.1-Cre);Tsc1flox/flox ont montré une hyperactivation de mTORC1 et une hypertrophie somatique des BCs de même qu’une augmentation de l’expression de PV dans la région périsomatique des neurones pyramidaux. Au contraire, à P45 nous avons découvert une réduction de la densité des punctas périsomatiques PV-gephyrin (un marqueur post-synaptique GABAergique). L’étude de la morphologie des BCs en cultures organotypiques provenant du knock-out conditionnel Nkx2.1-Cre a confirmé l’augmentation initiale du rythme de maturation, lequel s’effondre ensuite aux étapes développementales tardives. De plus, les souris Tg(Nkx2.1Cre);Tsc1flox/flox montrent des déficits dans la mémoire de travail et le comportement social et ce d’une façon dose-dépendante. En somme, ces résultats suggèrent que l’activation contrôlée de mTOR régule le déroulement de la maturation et la maintenance des synapses des BCs. Des dysfonctions de la neurotransmission GABAergique ont été impliquées dans des maladies telles que l’épilepsie et chez certains patients, elles sont associées avec des mutations du récepteur GABAA. De quelle façon ces mutations affectent le processus de maturation des BCs demeuret toutefois inconnu. Pour adresser cette question, nous avons utilisé la stratégie Cre-lox pour déléter le gène GABRA1, codant pour la sous-unité alpha-1 du récepteur GABAA dans une unique BC en culture organotypique. La perte de GABRA1 réduit l’étendue du champ d’innervation des BCs, suggérant que des variations dans les entrées inhibitrices en raison de l’absence de la sous-unité GABAAR α1 peuvent affecter le développement des BCs. La surexpression des sous-unités GABAAR α1 contenant des mutations identifiées chez des patients épileptiques ont montré des effets similaires en termes d’étendue du champ d’innervation des BCs. Pour approfondir, nous avons investigué les effets de ces mutations identifiées chez l’humain dans le développement des épines des neurones pyramidaux, lesquelles sont l’endroit privilégié pour la formation des synapses excitatrices. Somme toute, ces données montrent pour la première fois que différentes mutations de GABRA1 associées à des syndromes épileptiques peuvent affecter les épines dendritiques et la formation des boutons GABAergiques d’une façon mutation-spécifique. / About 30% of the total neuronal population in the mammalian cortex is composed by a very heterogeneous population of GABAergic interneurons. These interneurons differ in their morphology, gene expression, electrophysiological properties and subcellular targets, thus establishing a rich diversity. After birth in the ganglionic eminences these cells migrate to distinct cortical layers. Parvalbumin (PV) expressing cortical GABAergic cells which constitute the major GABAergic subtype specifically targets the soma and proximal dendrites of principal neurons and PV+ cells. These cells are often referred as Basket cells (BCs) because of the intricate morphological complexity of their axons. The maturation of the distinct connectivity of PV+ BCs, characterized by an increase of axon complexity and synapse density, occurs gradually in juvenile mice. Previous studies started to elucidate the mechanisms controlling this maturation process, including genetic factors, neuronal activity and sensory experiences. The striking increase in axonal complexity and synaptogenesis occurring during the maturation phase suggests the requirement for elevated proteins synthesis in order to sustain the developmental process. The Mechanistic Target Of Rapamycin (mTOR) pathway has been implicated in controlling several aspects of neurodevelopment by regulating protein synthesis. Mutations in the regulatory components Tsc1 and Tsc2 of mTOR-Complex1 (mTORC1) cause the disease Tuberous Sclerosis (TSC) in humans. The majority of TSC patients develop neurological problems including seizures, mental retardation and autism. Recent studies investigated the role of mTOR pathway dys-regulation in excitatory cortical cells, however its role in the development of cortical GABAergic interneurons and the specific contribution of altered GABAergic cells in disease manifestation remain largely unknown. Here, we investigated whether and how Tsc1 knockout perturbs GABAergic circuit development, both in vitro and in vivo. To investigate the role of mTORC1 activation in BC development, we knocked out Tsc1 expression, by transfecting Cre-GFP driven by a promoter specific for BCs in cortical organotypic cultures prepared from Tsc1lox mice. Tsc1 knockdown in vitro caused a precocious increase in bouton density and terminal branching formed by mutant BCs, which was reversed by Rapamycin treatment. These data suggest that mTOR pathway hyperactivation affects the timing of BC synapse maturation. To investigate the role of mTORC1 in GABAergic cells in vivo, we bred Tsc1lox mice with Nkx2.1-Cre and PV-Cre mice. At P18, Tg(Nkx2.1Cre),Tsc1flox/flox mice showed both mTORC1 hyperactivation and somatic hypertrophy in BCs along with increased expression of PV in the perisomatic region of pyramidal neurons. In contrast, by P45 we found a reduction of PV-gephyrin (post-synaptic GABAergic marker) perisomatic puncta density. Study of BC morphology in organotypic cultures from the Nkx2.1-Cre conditional knockout confirmed the occurrence of a faster maturation rate initially which however collapsed at later stages. Additionally Tg(Nkx2.1Cre),Tsc1flox/flox mice exhibit Tsc1 dose-dependent deficits in working memory and social behaviour. All together, these results suggest that controlled mTOR activation regulates both the time course and the maintenance of BC synapses. Dysfunction of GABAergic neurotransmission has been implicated in several disease states like epilepsy and in some patients it is associated with mutations in the GABAA receptor. How these mutations affect the BC cell maturation process remains largely unknown. To address this question, we used the Cre-lox strategy to knockout the endogenous GABRA1 gene coding for the GABAA-receptor alpha-1 subunit in single PV-expressing basket cells (BCs) in organotypic cultures. Cell-autonomous loss of GABRA1 reduced the extent of BC innervation field suggesting changes in inhibitory inputs caused by the absence of GABAAR α1 subunit may alter BC development. Over-expression of mutant GABAAR α1 subunits (found in patients diagnosed with epilepsy) show similar effects in terms of BC target coverage. Further studies involved the effect of these human mutations in the development of Pyramidal cell dendritic spines, which are the preferential site for excitatory synapse formation. Altogether, this data show for the first time that different GABRA1 mutations associated with genetic epilepsy syndromes can affect dendritic spine and GABAergic bouton formation in a mutation-specific manner.

Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death. Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI) MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white matter injury is multifactorial and several clinical risk and resilience factors have been identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life experience to later life disease and is associated with normal brain development, neuronal processes and neurological disease. Several studies have shown DNAm is altered by the perinatal environment, however its role in preterm white mater injury is yet to be investigated. Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To investigate the effect of neuroprotective treatments and deleterious clinical states on white matter integrity in preterm infants 3. To assess the best DTI method of quantifying white matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA methylation and 5. To determine the clinical and imaging factors that contribute to the variance in DNA Methylation caused by preterm birth Methods: DTI data was acquired from preterm infants (< 32 weeks' gestation or < 1500 grams at birth) at term equivalent age (TEA) and term controls (> 37 weeks' gestation at birth). Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk factors on white matter integrity were analysed. 8 major white matter tracts were segmented using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also allowed the calculation of tract shape. The two DTI techniques were compared to evaluate agreement between results. DNA was collected from preterm infants and term controls at TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic neighborhood tractography (PNT) methodology and clinical risk and resilience factors were used to inform a principal components analysis to investigate the contribution of white matter integrity and clinical variables to variance in DNAm. Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition, DTI parameters were affected by clinical factors that included antenatal magnesium sulphate, histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI methodology revealed good accuracy in repeated ROI measurements but limited agreement with tract-averaged values. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants, compared with controls. 10 of these genes have a documented association with neural function or neurological disease. Differences detected in the array were validated with pyrosequencing which captured additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Conclusions: Preterm birth is associated with alterations in white matter integrity which is modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide sufficient representation of white matter tracts in their entirety. Prematurity is related to alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for future work and contributed to the understanding of the pathogenesis of preterm brain injury.

Dyslexia is a neurodevelopmental disorder that affects between 5% and 12% of school-aged children. Individuals with dyslexia have difficulties in learning to read despite normal IQ levels and adequate socio-economical and educational opportunities. Dyslexia has a strong genetic component, but only a few candidate genes have been characterized to date. The KIAA0319 gene is a strong dyslexia candidate found to be associated with dyslexia in independent studies. The KIAA0319 genetic variants associated with dyslexia reside in a regulatory region. Studies in rat suggested that this gene is required for neuronal migration during early cortex formation. The KIAA0319-like (KIAA0319L) is a KIAA0319 homolog in structure and has recently been shown to play a role in dyslexia. I used zebrafish as a model organism both to study the effects of non-coding variants and to characterise kiaa0319 gene function. I used Gateway Tol2 technology to study the role of regulatory sequences. While these experiments led to inconclusive results, they highlighted some of the challenges but also the feasibility of using zebrafish as model organism to study genetic associations. In parallel, I studied the kiaa0319 function with knockout and knockdown experiments. Additionally, I conducted a detailed gene expression analysis with different in situ hybridisation protocols showing kiaa0319 ubiquitous expression in the whole embryo before 12 hours post fertilisation, with later specification to the eyes, brain, otic vesicle and notochord. Additionally, I have tested for the expression of kiaa0319l and showed similar expression pattern to the kiaa0319, but with significantly lower expression of kiaa0319l in zebrafish notochord. My data show, for the first time, that kiaa0319 has stage-specific expression in the brain and notochord during zebrafish early development, suggesting kiaa0319 specific role in the development of these structures. These results are in line with recent mouse studies. With this project I support the idea of kiaa0319 role being extended beyond the brain function and propose a role for kiaa03019 in the visual system and in the notochord.

Abstract Understanding how modern technology plays a role in our children’s early development is especially crucial in this era of technological advancement. Never in human history have we seen such an exponential shift in the human experience than we have with the rise of the internet and the subsequent mass integration of technology into our daily lives. Put simply, times have changed, and our understanding of early childhood development must follow suit. This thesis explores the impact digital technologies have on the neurodevelopment of children, with regard to different critical periods in early childhood development. The apparent impacts on attention, memory, and focus, as well as the behavioral manifestations that result from these childhood interactions depend greatly on the critical period of neurodevelopment they occur. This thesis provides evidence and recommendations for parents and caretakers alike, advising parents on the perils associated with overexposure to sensory stimuli in infants, while demanding a more tailored approach technology mediation in adolescents, as the advent of social media presents its own unique perils and potentials for early neurodevelopment. Keywords: neurodevelopment, technology, infancy, adolescence

<p>Background: Silver nanoparticles (AgNPs) act as antimicrobials by releasing monovalent silver (Ag+) and are increasingly used in consumer products, thus elevating exposures in human and environmental populations. Materials and Methods: We evaluated Ag+ in a standard model of neuronal cell replication and differentiation, and then determined whether there were similar effects of the ion in vivo using zebrafish. Next, we compared Ag+ and AgNP exposures in the same two models and incorporated the effects of particle coating, size and composition. Conclusions: This work is the first to show that both Ag+ and AgNPs are developmental neurotoxicants in vitro and in vivo. Moreover, although both the soluble ion and the particles impair measures of neurodevelopment, the outcomes and underlying mechanisms of each toxicant are often wholly distinct. Superimposed on the dichotomies between Ag+ and AgNP exposures are clear effects of particle coating, size and composition that will necessitate evaluation of individual AgNP types when considering potential environmental and human health effects. The results presented here provide hazard identification that can help isolate the models and endpoints necessary for developing a risk assessment framework for the growing use of AgNPs.</p> / Dissertation

Clinical and preclinical research both indicate that early life adversities alter sensitivity to stress well into adulthood. Although clinical research identifies infancy, childhood, and adolescence as periods of heightened vulnerability, the majority of preclinical research experiments have examined the enduring impact of stressors delivered either prenatally or prior to weaning. It was recently shown that exposing rats to intermittent stressors across the childhood/ adolescent period (PD 21-51) increased their behavioural and endocrine sensitivity to stress in adulthood. The purpose of the current project was to determine whether specific developmental periods are differentially sensitive to the lasting effects of intermittent stress. Male and female Long-Evans rats were exposed to three stressors (foot shock, elevated platform exposure, and cold water emersion) two times each, randomly over a twelve day period (childhood: PD 22-33 vs. adolescence: PD 35-46). Age-matched controls were briefly handled on each of the stressor application days. After completion of the stress exposure period, rats were left undisturbed for 27 days and behavioural testing commenced in adulthood. Intermittent physical stress exposure during the childhood period increased anxiety-like behaviours in adulthood, as indexed by the Elevated-Plus Maze (EPM) and Shock Probe Burying Test (SPBT). This also increased depression-like behaviour in adult male rats and decreased depression-like behaviour in adult female rats, as indexed by the Forced Swim Test (FST). Intermittent physical stress exposure in the adolescent period increased open-arm activity, increased burying behaviour and increased immobility in the forced swim test, in both male and female rats. Stress during either developmental period, failed to alter corticosterone (CORT) reactivity to restraint stress in adulthood. Thus, it appears that the long lasting behavioural impact of early-life adversity can vary, according to the developmental period the stressors are experienced in, but this is further modified by sex and the type of test used to evaluate adult behaviour. / Thesis (Master, Psychology) -- Queen's University, 2010-08-25 18:53:24.136

Methylmercury (MeHg) is an environmental toxin to which we are exposed through the consumption of seafood. Reactive oxygen species (ROS) have been implicated in the mechanism of toxicity, and in vitro studies in our laboratory have implicated DNA oxidation, particularly the DNA repair enzyme oxoguanine glycosylase 1 (OGG1). My studies determined the effects of in utero exposure to MeHg on fetal brain DNA oxidation and postnatal neurodevelopmental deficits, and the role of ROS-mediated oxidative DNA damage using the free radical spin trap, α-phenyl-N-tert-butylnitrone (PBN), and DNA repair-deficient ogg1 knockout mice. While neither MeHg nor PBN altered DNA oxidation in fetal brain, MeHg caused cognitive deficits in passive avoidance and novel object recognition, the latter of which was blocked by PBN pretreatment, suggesting ROS involvement. Preliminary longevity studies following one litter from each treatment group to 16 months suggest that in utero MeHg treatment may shorten lifespan. Endogenous DNA oxidation was increased in the brains of ogg1 knockout fetuses compared to wild-type littermates, although this was not enhanced by MeHg. However, OGG1-deficient animals exhibited cognitive deficits in passive avoidance after MeHg treatment, suggesting a role for DNA damage. Furthermore, ogg1 knockout female mice exhibited a passive avoidance deficit compared to wild-type females regardless of treatment, corroborating a role for oxidative DNA damage in neurodevelopmental deficits. MeHg increased apoptosis in the hippocampal region of fetal brain, and may cause DNA double-strand breaks (DSBs), evidenced by enhanced phosphorylation of histone 2AX (γH2AX). Ogg1 knockout progeny exhibited increased cellular proliferation or migration in the developing hippocampal region, which was blocked by MeHg. My results provide the first evidence that: (1) MeHg may decrease lifespan; (2) PBN protects against some postnatal neurodevelopmental deficits caused by in utero exposure to MeHg; and (3) DNA repair-deficient progeny are more susceptible to postnatal cognitive deficits caused by in utero MeHg exposure, suggesting that ROS-mediated DNA oxidation plays a role in MeHg-initiated neurodevelopmental deficits.

Being hearing impaired does not only affect a child’s academic performance, but can also influence a child’s overall development and ability to succeed academically. Evidence suggests that the outlay in early childhood has a large impact on a child’s readiness to learn. Neurodevelopmental movement programmes are generally not accepted as evidenced-based practice and their effect on academic performance is often underrated. Movement, however, is regarded by many as essential to learning and there seems to be a positive interchange between the brain and the body. This study reports on the influence of a neurodevelopmental movement programme on the development, behaviour and performance on a neurodevelopmental evaluation scale of four to eight year-old children with hearing impairment children. The study furthermore provides a report of the results of the psychometric assessment in the form of a neurodevelopmental profile for this specific sample. Children were selected from a special needs school in the rural QwaQwa Free State area of South Africa. Two groups of children (an experimental and comparison group) were used in this study, with both groups undergoing a pretest and posttest phase using three test batteries (Griffiths Mental Developmental Scales- Extended Revised, Child Behaviour Checklist, and a neurodevelopmental evaluation scale). The experimental group was subjected to a fourteen-week neurodevelopmental movement programme. The comparison group underwent a placebo intervention. The results indicate that the children in the experimental group showed an improvement in some aspects of specific development following the intervention (locomotor functioning, performance related abilities, and practical reasoning skills). General developmental age showed significant improvement in both the experimental group and the comparison group. No behavioural aspects showed significant improvements following the intervention, whereas some neurodevelopmental aspects, such as the vestibular system (Tandem Walk and One Leg Stand) and the reflex system (TLR – reflex) showed significant improvements. The results of this empirical investigation aid in understanding the impact of movement programmes on a child with hearing disability’s general development and neurodevelopmental development. / Thesis (PhD (Psychology))--North-West University, Potchefstroom Campus, 2013.