Rozprawy doktorskie: „Neurodevelopment”

1

Dickinson, Amanda J. G. "Early molluscan neurodevelopment". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/mq24834.pdf.

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Lynex, Clare Nadine. "Genetic studies of neurodevelopment". Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410764.

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Pilecka, Izabela. "Nutrition, neurodevelopment and mental health". Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/nutrition-neurodevelopment-and-mental-health(aef2ac73-1610-41bf-9941-5e7bd44f3666).html.

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There is increasing awareness for the potential effects of nutrition on mental health. Specifically, researchers are interested in the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFA) and vitamin D on brain development and psychological well-being. The main objective of this thesis is to examine evidence for the relationship between nutritional intake, neurodevelopment, psychotic and depressive symptoms. This thesis consists of a series of studies designed to test several hypotheses. A review and meta-analysis tested the hypothesis that maternal fish oil intake/omega 3 supplementation during pregnancy is associated with better cognitive performance in offspring. Next, we used data from the Swedish Women's Lifestyle and Health Study, to test the hypothesis that low UV exposure is associated with more positive psychotic symptoms and with more severe depressive symptoms. For the purpose of this study we use UV exposure data as a primary index for vitamin D. Firstly, the results of meta-analysis showed that for the measure of overall cognitive ability the standardised difference in means (SMD) was estimated to 0.10 (95% CI, -0.01 to 0.20; p=0.07) and for memory functions the SMD was 0.21 (95% CI, 0.01 to 0.41; p=0.04). The observational studies showed better overall cognitive ability with pooled OR of 1.92 (95% CI, 1.61 to 2.30; p<0.001) and for the domain of language and verbal skills the OR was 1.93 (95% CI, 1.37 to 2.73; p<0.001) among children of mothers consuming 2 to 3 fish servings per week during pregnancy. Maternal intake of fish oil during pregnancy is associated with improved cognitive abilities in the offspring. Secondly, the association between sun exposure and psychotic experiences was evaluated by quantile regression models. 34 279 women were included in the analysis. Women who reported no sunbathing holidays and two or more weeks of sunbathing holidays scored higher on the Community Assessment of Psychic Experience (CAPE) scale than women exposed to one week of sunbathing holidays across the entire distribution, when adjusting for age and education. Similarly, compared with women who reported a history of a single sunburn, the women with none or two or more sunburns showed higher scores on the CAPE scale with more women in the right part of the distribution. Thirdly, women who reported a history of two or more sunburns showed positive association with depressive symptoms, compared to history of a single sunburn, when adjusting for age and education. The findings suggest that in a population based cohort of middle aged women, both low and high sun exposure is associated with increased level of positive psychotic experiences and high sun exposure is associated with an occurrence of depressive symptoms.

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Sun, Simon. "Planar Cell Polarity and Neurodevelopment". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3414.

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Planar cell polarity (PCP) is a developmental signaling mechanism that establishes a polarity within the plane of an epithelium. PCP has been shown to play a role in guiding numerous neurodevelopmental processes such as convergent extension, neuron migration, and axon pathfinding. Certain commissural neurons in the dorsal spinal cord make a series of guidance decisions en route to the brain: first, a ventral projection along the D-V axis, followed by a midline crossing, and after exiting the floorplate, a dorso-anterior turn along the A-P axis. Here, we provide in vivo evidence that the axons of the Commissural Primary Ascending (CoPAs) neurons in zebrafish require the PCP genes fzd3a, vangl2, and scribble for rostral pathfinding both before and after crossing the midline. Dorsoventral guidance of CoPA axons is unaltered in fzd3a, vangl2, and scribble mutants, suggesting that the PCP signaling pathway only controls A-P guidance of CoPAs. Our results have provided evidence for two potential non- mutually exclusive models: (i) A-P axon guidance is achieved by cell-autonomous Wnt-Frizzled signaling or that (ii) A-P axon guidance is achieved by non-cell-autonomous PCP signaling in the neuroepithelial environment. The single-cell nature of the CoPA axon system allows for simple genetic manipulation and visualization, which will potentially elucidate the validity of either model. Scribble (Scrib), a member of the LAP family, plays a critical role in establishing and regulating cell polarization in epithelia and during cell migration. In zebrafish, Scrib mutants have defects in convergent extension (CE) cell movements and facial branchiomotor neuron (FBMN) migration. Despite our understanding of Scrib’s genetic role in neurodevelopment, little is known about the subcellular localization of endogenous Scrib in vivo during CE and FBMN migration. We have generated a monoclonal antibody against the C-terminus of zebrafish Scrib and have shown that this antibody is specific against endogenous Scrib in both western blot and immunocytochemical applications. Confocal microscopy of Scrib immunocytochemistry shows that at various developmental stages, Scrib distinctly localizes to basolateral membranes of non polarized epithelium, to the membrane in mesodermal cells undergoing CE, and to the membrane of migrating FBMNs. Furthermore, the distribution of Scrib puncta along membranes of FBMN- FBMN contact is significantly altered in the PCP mutant pk1b. Further application of our newly generated Scrib antibody will potentially lead to new insight on Scrib’s role in neurodevelopment.

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López, Vicente Mònica 1988. "Physical activity and neurodevelopment in children". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/585877.

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This thesis aims to study the determinants and trajectories of cognitive development, as well as the role of physical activity on cognitive and brain development in children aged 4 to 14 years old. We used data from two Spanish cohorts (INMA and BREATHE) and one Dutch cohort (Generation R). Teachers reported Attention Deficit and Hyperactivity Disorder (ADHD) symptoms of the participants through questionnaires. Cognitive development, specifically of attention and working memory, was tested by using computerized-based tasks. Growth trajectories were constructed based on four repeated cognitive measurements during a 1-year period in 7- to 11-year-old children. Physical activity was reported by parents through questionnaires. Magnetic Resonance Imaging data was collected in Generation R when children were 6-to-10 years old. Age, gender and ADHD symptoms were identified as important determinants of cognitive development. The use of cognitive growth trajectories in epidemiological research was supported. Physical activity during childhood was positively associated with brain maturation and promoted cognitive development.
Aquesta tesi pretén estudiar els determinants i les trajectòries del desenvolupament cognitiu, així com el paper de l’activitat física en el desenvolupament cognitiu i cerebral en nens entre 4 i 14 anys. Vam utilitzar dades de dues cohorts espanyoles (INMA i BREATHE) i una cohort holandesa (Generation R). Els mestres van avaluar els símptomes de Trastorn per Dèficit d’Atenció i Hiperactivitat (TDAH) dels participants a través de qüestionaris. El desenvolupament cognitiu, en concret d’atenció i memòria de treball, es va avaluar amb tasques computeritzades. Les trajectòries de creixement es van generar a partir de quatre mesures cognitives repetides durant un període d’un any en nens de 7 a 11 anys. L’activitat física va ser informada pels pares a través de qüestionaris. Es van recollir dades de ressonància magnètica a Generation R quan els nens tenien de 6 a 10 anys. L’edat, el sexe i els símptomes de TDAH es van identificar com a determinants importants del desenvolupament cognitiu. L’ús de les trajectòries de creixement cognitiu en recerca epidemiològica va ser recolzat. L’activitat física durant la infantesa es va associar positivament amb la maduració del cervell i va promoure el desenvolupament cognitiu.

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6

Brandt, Brittany Lee. "Household environmental toxins and neurodevelopment in children". Montana State University, 2012. http://etd.lib.montana.edu/etd/2012/brandt/BrandtB0512.pdf.

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Neurodevelopmental disorders diagnosed in children, such as ADHD, autism, Tourette's syndrome, learning disabilities, dyslexia, mental retardation, and cerebral palsy, are thought to arise from complex interactions between genetic, social and environmental factors. The increasing prevalence of some of these disorders in children over the past thirty years has precipitated more research into preventable environmental causes. Environmental toxins, such as heavy metals and synthetic chemicals, are among the targets of investigation by researchers. This literature review examines what is known from current research about neurodevelopment and exposure to the following household environmental toxins: PBDEs, pesticides, mercury, lead, and bisphenol A. Variables reviewed include source, neurological effects, and ways to reduce exposure to each toxin. Relevant articles were retrieved through keyword search of Medline database. Online government databases were also utilized. Results of the literature review indicate adverse neurological effects of developmental exposure to PBDEs, pesticides, mercury, lead and bisphenol A are similar to diagnostic features of some neurodevelopmental disorders. Adverse effects associated with exposures include: hyperactivity, aggression, decreased IQ, and impairments in attention, memory, fine and gross motor skills, social behavior, and communication. Nurses are often the first and sometimes the only health care provider working with children and families. As such, they are in an ideal position to address possibly harmful environmental exposures. Including screening for toxic exposures and addressing prevention is recommended during all primary care visits with children and is increasingly considered an expected practice by leading health care institutions.

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Beaubien, Francois. "Role of Slitrk family members in neurodevelopment". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110496.

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The development of the nervous system is an extremely complex process where gene expression is tightly regulated, both spatially and temporally. Any gene disruption during neurodevelopment, from the complete non-transcription of the gene to a single nucleotide mutation, has the potential to lead to severe consequences in the organism. This situation is particularly well illustrated by the whole spectrum of neurological disorders affecting humans. Thanks to basic research at the gene and protein levels, some genetic causes for certain mental illness have been identified. This thesis focuses on a novel family of proteins termed the Slitrks. Initial characterization of the Slitrk family genes revealed that their expression is enriched in the central nervous system. Herein, I have performed a detailed analysis of the patterns of expression of the six members of the family in the mouse nervous system. I demonstrate that, despite some overlapping expression, several key brain regions express different combinations of Slitrks suggesting that the different family members may have distinct functions during nervous system development. I further demonstrate that members of the Slitrk family can regulate synapse formation in hippocampal neurons. More precisely, Slitrk1 is required for the formation of both excitatory and inhibitory synapses. Taken together, the results presented in my thesis indicate that Slitrks play an important role in the developing nervous system.
Le développement du système nerveux est un processus extrêmement complexe pendant lequel l'expression des gènes est contrôlée de façon précise temporellement et localement. Durant le neurodéveloppement, chaque dérégulation génétique, de l'arrêt complet de la transcription d'un gène jusqu'à la mutation d'un seul nucléotide, a le potentiel de mener à de graves conséquences pour l'organisme. Cette situation est particulièrement bien illustrée par l'ensemble des troubles neurologiques qui affectent l'humain.Cette thèse se concentre sur une nouvelle famille de protéines nommées Slitrks. La description préliminaire de cette famille a révélé que leur expression est enrichie dans le système nerveux central. Par conséquent, j'ai réalisé une analyse détaillée du patron d'expression des six membres de la famille dans le système nerveux de la souris. J'ai ainsi pu démontrer que malgré certains chevauchements d'expression, plusieurs régions du cerveau expriment différentes combinaisons de Slitrks. Cela laisse présager que certains membres de la famille Slitrks peuvent avoir des fonctions distinctes durant la formation du système nerveux. Au cours de mes travaux, j'ai aussi pu démontrer que les Slitrks peuvent réguler la formation des synapses dans les neurones de l'hippocampe. Plus précisément, Slitrk1 est requis à la fois pour la formation des synapses excitatrices et inhibitrices. Dans l'ensemble, les résultats présentés dans cette thèse indiquent que les Slitrks jouent un rôle important dans le développement du système nerveux.

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Baltussen, Lucas L. "Novel CDKL5 substrates and functions in neurodevelopment". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10052904/.

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Cyclin-Dependent Kinase-Like 5 (CDKL5) is a serine/threonine protein kinase important for neuronal development. Mutations in the CDKL5 gene are responsible for CDKL5 deficiency disorder, a rare neurodevelopmental disorder displaying a heterogeneous range of clinical phenotypes. CDKL5 is enriched in the brain during early postnatal development, and is known to be involved in the development of dendritic spines and synapses. However, direct downstream effectors of CDKL5 and its molecular mechanisms of action remain unknown. We have generated analogue-specific CDKL5 by mutating the gatekeeper residue in the ATP-binding pocket, and introduced a second-site mutation to rescue kinase activity. Based on the utilization of bulky ATP analogues by analogue-specific CDKL5, we used an unbiased chemical genetic screen to identify CDKL5 substrates and phosphorylation sites in mouse brain. In vitro validation of ARHGEF2, EB2 and two sites in MAP1S revealed RPxS as a common CDKL5 phosphorylation motif. We show that EB2 and MAP1S phosphorylation is strongly reduced in brains of Cdkl5 KO mice. In neurons derived from CDKL5 patient iPSCs, we observe similar reductions indicating that regulation of these phosphorylation sites is conserved in humans. By using CDKL5 substrate phosphorylation as a read-out, we have been able to show that CDKL5 activity is regulated during brain development and affected by neuronal activity. These novel CDKL5 substrates share microtubule binding properties, but only phosphorylation of MAP1S by CDKL5 is directly regulating its microtubule binding affinity. Attempts to identify a molecular function of EB2 phosphorylation did not lead to satisfying results. Both MAP1S and EB2 are known to be involved in microtubule dynamic instability, the process of constant growth and collapse of microtubule plus-ends. We show that primary cortical cultures of Cdkl5 KO mice have altered microtubule plus-end dynamics visualised by sparser, but longer EB3 comets. Knockdown of MAP1S, but not EB2, partially rescued this phenotype in Cdkl5 KO neurons, indicating a downstream function of MAP1S in the regulation of microtubule dynamics.

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Czerminski, Jan T. "Modeling Down Syndrome Neurodevelopment with Dosage Compensation". eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1037.

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Due to their underlying genetic complexity, chromosomal disorders such as Down syndrome (DS), which is caused by trisomy 21, have long been understudied and continue to lack effective treatments. With over 200 genes on the extra chromosome, even the specific cell pathologies and pathways impacted in DS are not known, and it has not been considered a viable target for the burgeoning field of gene therapy. Recently, our lab demonstrated that the natural mechanism of dosage compensation can be harnessed to silence the trisomic chromosome in pluripotent cells. Using an inducible XIST transgene allows us to study the effects of trisomy in a tightly controlled system by comparing the same cells with either two or three active copies of chromosome 21. In addition, it raises the prospect that insertion of a single gene into a trisomic chromosome could potentially be developed in the future for “chromosome therapy”. This thesis aims to utilize this inducible system for dosage compensation to study the neurodevelopmental effects of trisomy 21 in vitro, and to answer basic epigenetic questions critical to the viability of chromosome silencing as a therapeutic approach. Foremost, for XIST to have any prospect as a therapeutic, and to strengthen its experimental utility, it must be able to initiate chromosome silencing beyond its natural context of pluripotency. Here I demonstrate that, contrary to the current literature, XIST is capable of initiating chromosome silencing in differentiated cells and producing fully dosage compensated DS neurons. Additionally, I show that silencing of the trisomic chromosome in neural stem cells enhances their terminal differentiation to neurons, and transcriptome analysis provides evidence of a specific pathway involved. Separate experiments utilize novel three-dimensional organoid technology and transcriptome analysis to model DS neurodevelopment in relation to isogenic euploid cells. Overall, this work demonstrates that dosage compensation provides a powerful experimental tool to examine early DS neurodevelopment, and establishes that XIST function does not require pluripotency, thereby overcoming a perceived obstacle to the potential of XIST as a therapeutic strategy for trisomy.

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Bothma, Jó-Marié van der Merwe. "A neurodevelopmental movement programme for 4-8 year old hearing impaired children in the rural QwaQwa region of South Africa / Jó-Marié van der Merwe Bothma". Thesis, North-West University, 2012. http://hdl.handle.net/10394/9721.

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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.

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Riesgo, Victoria Rae. "Phthalate Exposure and Maternal Infection: Implications for Neurodevelopment". Bowling Green State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1619553601242514.

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Ivanochko, Danton. "ATRX Protects Cells Against Replication-Induced Genomic Instability". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35123.

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Expansive proliferation of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered cerebral cortex. NPC expansion places a heavy burden on proteins that regulate chromatin packaging and genome integrity, which is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. Accordingly, mutations in ATRX, a chromatin remodelling protein required for heterochromatin maintenance at telomeres and simple repeats, cause the ATR-X syndrome. Here, we demonstrate that proliferating ATRX-null cells accumulate DNA damage, while also exhibiting sensitivity to hydroxyurea-induced replication fork stalling. Specifically, PARP1 hyperactivation and replication-dependent double strand DNA breakage indicated replication fork protection defects, while DNA fiber assays confirmed that ATRX was required to protect replication forks from degradation. Interestingly, inhibition of the exonuclease MRE11 by the small molecule mirin could prevent degradation. Thus, ATRX is required to limit replication stress during NPC expansion.

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Weber, Ashley M. "Oxytocin: Biomarker of Affiliation and Neurodevelopment in Premature Infants". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461182484.

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Nidey, Nichole Lynn. "Depression during the perinatal period: rurality, opioids and neurodevelopment". Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/7001.

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Depression during the perinatal time period is the most common medical condition related to pregnancy and childbirth. Based on previous research, this condition can have negative sequelae for mothers, their offspring, families and the community. Therefore, studies are needed to better understand risk factors and health outcomes among women with depression and the health outcomes among children born to mothers with depression. We examined rurality as a risk factor for depression during the perinatal time period using data from the 2016 Pregnancy Risk Assessment Monitoring Survey (aim one). We found women who resided in rural communities, as defined by their individual states, had an increase in the odds of depression during the perinatal period by 21% (OR: 1.21; 95% CI 1.05,1.41) when compared to women who resided in urban communities. Based on the results from this study, future studies are warranted to examine mediators of this relationship to develop effective public health and clinical interventions. Next, we examined the association between perinatal mental health conditions and postpartum prescription opioid use using private insurance claims data of women who delivered a baby in the state of Iowa 2005 to 2016 (aim two). Overall 38.63% of the women in our study filled at least one opioid prescription and 5.88% filled at least two prescriptions in the first 90 days postpartum. A significant interaction of having a perinatal mental health condition and delivery mode was observed for at least one (p=.04) and at least two opioid fills (<.0001). The presence of a mental health condition among women who delivered vaginally increased their odds of filling at least one opioid fill by nearly 50% (OR: 1.48 95% CI 1.35, 1.63) and by almost 20% (OR: 1.19 95% CI: 1.00, 1.43) among women with a cesarean delivery. A mental health condition significantly increased the odds of filling at least two opioid prescriptions among women with a vaginal or cesarean delivery by 2.78 (95% CI: 2.32-3.33) and 1.66 (95% CI: 1.40,1.98). Based on findings from this study, more research is needed to improve our understanding of the relationship between perinatal mental health and prescription opioid use. Finally, the association between perinatal depression and attention deficit hyperactivity disorder (ADHD) use was examined using private insurance claims data from mother-child pairs from the state of Iowa (aim three). Children were born during years 2004 through 2015. In our study children born to mothers with perinatal depression were at an increased odds of ADHD diagnosis by 170% (OR: 2.70; 95% CI 2.06, 3.55). We also evaluated how timing of depression (during pregnancy vs. postpartum) influenced the odds of ADHD diagnosis. While we found children born to mothers with depression during pregnancy and postpartum had an increased risk of ADHD diagnosis, we observed children exposed to depression during fetal development had the greatest risk overall. Research is needed to better understand the mechanisms of risk between perinatal depression and ADHD risk in offspring. Additionally, due to low power we were not able to evaluate how treatment of depression during pregnancy or postpartum may influence childhood outcomes, therefore more studies are needed in this area. Overall, findings from each study illustrate the importance of maternal mental health and how a mental health condition during the perinatal period can influence maternal and child health outcomes. Future prospective population-based studies are needed to better understand the etiologies of perinatal mental health conditions and how such conditions can influence outcomes for maternal and child health. Results from future studies have the potential to shift clinical practice to improve prevention and intervention in turn improving overall maternal and child health outcomes.

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Masante, Linda. "The missing rings of neurodevelopment: circRNAs in brain wiring". Doctoral thesis, Università degli studi di Trento, 2022. http://hdl.handle.net/11572/338658.

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circRNAs are covalently closed RNA molecules recently re-discovered thanks to the advances in RNA-seq technology. They are produced by the canonical spliceosome in a non-canonical splicing process, named back-splicing. Heterogeneous in internal composition and highly stable, circRNAs regained the attention of neuronal biologists because of their enrichment in brain and neuronal compartments. Moreover, several pioneering studies revealed a fine orchestration of circRNA expression in crucial stages of neuronal development, such as synaptogenesis. The growing evidence of circRNA enrichment in synapses raises the intriguing question as to the yet unknown molecular mechanisms leading to this unique neuronal sub-compartmentalization. In addition, in which of the compartments composing the synapse – dendrites and axon – circRNAs preferentially localize, is still largely elusive. Here, I have focused specifically on the pre-synaptic compartment – the axon – during specific stages of neuronal development. The proper development of the axon is crucial to guarantee the correct synapse formation. Impairments in this process can lead to severe neurodevelopment diseases. I explored circRNA expression in the axonal compartment, shedding light on circRNA distribution in and trafficking to the neuronal distal compartment. To reach these goals, I used Xenopus laevis retinal ganglion cell (RGC) developing axons as a model. The results presented in this thesis highlight an abundant expression of circRNAs in the axonal compartment, where they are enriched compared to the somatic one. The enrichment in axons led me to deeper explore their preferential axonal sub localization, by investigating how they reach the neuronal distal compartment. circDDX17 was selected as reference model of axonal circRNAs. Its tracking within the axon revealed an heterogenous distribution and shape. circDDX17 trafficking along the axon displayed an anterograde preferential directionality and slow speed giving hints to uncover the molecular mechanisms of circRNA translocation to the axonal compartment. Bioinformatic analysis revealed that the RNA-RBP complex formation, the most common and described mechanism of axonal transport, could underlie circRNA intracellular translocation. Taken together, my data uncover the axonal circRNA population and characterize their localization in the neuronal distal compartment.

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BROCCHETTI, SILVIA. "HES CELLS TO STUDY EARLY NEURODEVELOPMENT IN HUNTINGTON'S DISEASE". Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/891498.

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La Corea di Huntington (MH) è una malattia neurodegenerativa genetica causata dall’espansione del tratto CAG nel gene codificante la proteina Huntingtina (HTT). La morte progressiva di specifici neuroni GABAergici striatali, chiamati Medium Spiny Neurons (MSNs) è responsabile delle disfunzioni motorie, cognitive e psichiatriche dei pazienti MH. Numerosi studi stanno evidenziando le cruciali funzioni dell'HTT durante le prime fasi dello sviluppo, sostenendo la presenza di una componente evolutiva della MH. Abbiamo quindi impiegato la serie isogenica di linee hES RUES2 HD per studiare gli effetti di diverse lunghezze CAG patologiche in un background genetico costante. Innanzitutto, esponendo la linea RUES2 al differenziamento telencefalico ventrale abbiamo osservato la propensione a differenziare verso l'eminenza gangliare mediale (MGE). Inoltre, la linea HD risulta incapace di acquisire un destino MGE. Queste linee inoltre ricapitolano fenotipi HD noti, come la ridotta espressione di BDNF e NEUROD1 e una maggiore scissione della proteina sinaptica N-cadherina. In particolare, è risultato alterato il passaggio dalla pluripotenza al destino neuroectodermico; poiché, le linee HD mostrano una persistente espressione di OCT4 insieme a ridotti livelli del marker neuroectodermico PAX6. Considerando il ruolo fondamentale delle proteine dei gruppi Polycomb (PcG) nella regolazione dell'identità cellulare e del differenziamento, abbiamo caratterizzato questi complessi nel nostro sistema cellulare. Sono emerse differenze nel numero e nella dimensione delle strutture tridimensionali dei PcG tra la linea controllo e HD, suggerendo un potenziale legame tra la proteina HTT e questi complessi epigenetici. Inoltre, le linee HD RUES2 presentano un’alterazione anche a livello della modificazione istonica H3K9me3 durante il differenziamento. In conclusione, questi dati preliminari hanno evidenziato modificazioni nella regolazione dell'eterocromatina costitutiva e facoltativa, suggerendo un possibile coinvolgimento della proteina HTT nella regolazione epigenetica. Questa ipotesi sarà ulteriormente verificata mediante analisi ChIP-seq, per identificare geni bersaglio la cui espressione potrebbe essere alterata durante le prime fasi dello sviluppo neurale.
Huntington Disease (HD) is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding for the Huntingtin (HTT) protein. The progressive death and atrophy of specific striatal GABAergic projection neurons named Medium Spiny Neurons (MSNs) lead to motor, cognitive and psychiatric dysfunctions in HD patients. Several studies are pointing to the crucial functions of HTT during early development, advocating to a developmental component of HD. Based on these observations, we employed the isogenic series of HD human embryonic stem cells (RUES2) to study the effects of mutant HTT on neuronal differentiation in a fixed genetic background. Firstly, by exposing the control RUES2 cell line to ventral telencephalic differentiation we observed the propensity of the cells to differentiate toward the medial ganglionic eminence (MGE) compared to other human embryonic stem cell (hESC) lines. Moreover, HD RUES2 displayed aberrant MGE cell fate acquisition. Also, these cells recapitulate known HD phenotypes, such as reduced expression of BDNF and NEUROD1, and increased cleavage of N-cadherin. In particular, HD lines exhibit a defect in the transition from pluripotency toward neuroectodermal fate as documented by the persistency of the pluripotent marker OCT4 and by reduced upregulation of the neuroectodermal marker PAX6. Considering the fundamental function of Polycomb group proteins (PcGs) in regulating cell fate identity and differentiation and the crucial role of epigenetics in HD pathogenesis, we started investigating whether these complexes were affected in our cell system. Differences in the number and size of the three-dimensional PcG foci structures emerged between control and HD lines, suggesting a potential link between HTT and these epigenetic complexes. Moreover, level of H3K9me3 histone modification was affected in HD lines during the differentiation. Overall, these preliminary data suggest that the presence of the mutation in the HD gene causes alterations in the regulation of both constitutive and facultative heterochromatin already in pluripotency. This hypothesis will be further tested through experiments of ChIP-seq analysis, in which we expect to identify target genes whose expression may be dysregulated in the early stages of neural development.

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FERRARA, SILVIA. "NEUROINFLAMMATION AND DEFECTIVE MYELINATION IN POLYMICROGYRIA". Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/543392.

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Polymicrogyria (PMG) is a condition characterized by abnormal prenatal brain development and excessive number of ectopic small gyri in the cerebral cortex. PMG patients present an excessive number of abnormally small gyri separated by shallow sulci, associated with fusion of the overlying molecular layer of the cerebral cortex. The topographic distribution of PMG may be focal, multifocal or diffuse; unilateral or bilateral; symmetric or asymmetric. Clinical manifestations have a large spectrum, ranging from isolated selective impairment of cognitive functions to severe encephalopathy and intractable epilepsy. The severity of neurological manifestations and the age at presentation are in part influenced by the extent and localization of the cortical malformations but may also depend on its specific aetiology. The pathogenesis is still poorly understood, several causative gene mutations have been recently found, but also other causes has been identified (prenatal infections, ipoxia). Experimentally, the mouse model of polymicrogyria (PMG) displays the formation of ectopic microgyri in the mouse cortex, enhanced excitatory and inhibitory synaptic transmission accompanied by increased connectivity in the paramicrogyral cortex and higher susceptibility to epilepsy in vitro. Besides the alteration in the cortical layering, the molecular, morphological and behavioural analysis of PMG mice reveal a significant astrogliosis and microglial activation, indicating the occurrence of an inflammatory process. In addition, a diffuse cortical hypomyelination is evident in brain slices stained for myelin basic protein (MBP). Furthermore, PMG mice displayed altered EEG profile and defective motor skills such as reduced brawn. All these features make PMG model suitable for the study of the pathology and to investigate possible therapeutic approaches. Here we found that transplantation of human neural stem cells (hNSCs), which has been demonstrated to exert positive effects on inherited or acquired myelination disorders and to dampen brain inflammation, plays a beneficial effect on the pathological condition of PMG ameliorating the myelination defect by promoting oligodendrocyte precursors proliferation and remodelling of myelin fibres. Our data also show that hNSC transplantation restores normal EEG brain activity and improves motor performances. Moreover, we tried a pharmacological blockade of IL-1R activation by the IL-1R antagonist: anakinra. We found that this treatment leads to a significant improvement of EEG and motor skills in adult PMG mice thus suggesting a possible role of inflammation at the root of the pathology and identifying a therapeutic time window for the treatment.

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Vernes, Sonja. "Investigation of the role of FOXP transcription factors in neurodevelopment". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497468.

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Cooper, H. "Neurodevelopment of children at risk of hearing and communication problems". Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1556534/.

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This thesis examines the neurodevelopment of two under-studied cohorts of children who are at risk of hearing and communication problems. Assessment methods included clinical and experimental tests of auditory function, speech discrimination and psychoacoustics evaluation, and the use of parental questionnaires. Advanced MRI methods were used to examine the effects of the two conditions on neurodevelopment and brain microstructure. The first group of children had all been diagnosed with auditory neuropathy spectrum disorder (ANSD). Difficulties with speech discrimination were seen in the ANSD group as expected, and associations were found with temporal processing abilities as well as with brain MRI measures. Children from the second group were diagnosed with congenital hypothyroidism (CH) through the Newborn Bloodspot Screening Programme. In the CH group, hearing and communication problems were found for some children along with evidence of structural white matter abnormalities in the brain and associations between white matter microstructure and hearing abilities. This thesis shows that children with ANSD and children with CH have variable outcomes for hearing and communication and provides evidence that advanced MRI methods can support our understanding of the development of children with these conditions.

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Durak, Omer. "Converging roles of neurodevelopment and Wnt signaling in neuropsychiatric disorders". Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/108880.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 158-173).
Neuropsychiatric Disorders are the leading category contributing to disability-adjusted life years (DALYs) in the U.S. according to the World Health Organization. These findings underline the vast burden caused by neuropsychiatric disorders on patients. However, effective treatments do not exist for many of the neuropsychiatric disorders mostly due to lack of understanding of disease pathology. Evidence from whole genome sequencing of psychiatric disorder patients increasingly suggest that Wnt signaling and cortical development - in addition to other perturbations - may underlie the pathophysiology of multiple disorders. Furthermore, besides autism spectrum disorder, contribution of neurodevelopmental dysregulations to disease etiology in late-onset disorder such as schizophrenia are becoming widely accepted. Therefore, a better understanding of cortical development and functions of Wnt signaling could prove critical in determining the cellular and molecular mechanisms underlying the causes of psychiatric disorders. The work presented in this thesis aims to understand the functions of multiple neuropsychiatric disorder risk genes in brain development, and the converging role of Wnt signaling in neurodevelopment. First, we determined ASD risk gene Chd8 to be a positive regulator neural progenitor proliferation in the developing mouse brain through its transcriptional regulation of cell cycle and Wnt signaling genes. Surprisingly, Chd8 exhibits a cell type-specific modulation of Wnt signaling. Furthermore, knockdown of Chd8 in the upper cortical layer neurons caused ASD-related behavioral abnormalities in adult mice, which could be rescued via induction of Wnt signaling. Secondly, we made the novel observation that bipolar disorder risk gene Ank3 (ankyrin-G) plays a crucial role in cortical neurogenesis through regulation of subcellular localization of [beta]-catenin, which is an essential component of Wnt signaling. Finally, the effects of brain-specific deletion of BcI9 on brain development and behavior were characterized using a heterozygous BcI9 deletion transgenic mouse line. Behavioral and brain development defects associated with BcI9 were shown to mimic some of the clinical symptoms observed in patients. Collectively, our results demonstrate a central role for Wnt signaling and cortical development in pathophysiology of neurodevelopmental and neuropsychiatric disorders.
by Omer Durak.
Ph. D.

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Anyanwu, Ulunma Nneka. "Characterising the role of GPR50 in neurodevelopment and lipid metabolism". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/10064.

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G-protein coupled receptor 50 (GPR50) is a genetic risk factor for psychiatric illness. It is a member of the melatonin receptor family, which includes the well characterised melatonin receptors 1 and 2 (MT1 and MT2). However, the ligand for GPR50 remains elusive and little is known about GPR50 signalling pathways. Despite this, GPR50 is known to enhance neurite outgrowth and inhibit the actions of the neurite outgrowth inhibitor NOGO-A. Existing evidence also indicates a role in lipid metabolism; GPR50 knockout mice displayed abnormalities in energy homeostasis and weight control, whilst sequence variants are associated with altered lipid levels in humans. Further, a yeast-2-hybrid screen identified SREBF2 and ABCA2, regulators of lipid homeostasis, as GPR50 interactors. This thesis explores the role of GPR50 in neuronal development and lipid metabolism. The work presented in this thesis shows that GPR50 promotes neuronal differentiation. Overexpression significantly increased the number of neurites per cell in SH-SY5Y cells. Further, dendritic branching was enhanced by GPR50 transfection in hippocampal and cortical neurons (DIV 14). In hippocampal neurons, GPR50 transfection also lead to a shift towards spine maturity although it had no effect on spine morphology, suggesting GPR50 enhances spine development but may not alter synaptic strength. The effect of GPR50 on neuronal morphology may be driven by actin remodelling. Immunocytochemistry showed an enrichment of GPR50 in highly dynamic regions of the membrane, i.e. the lamellipodia and dendritic spines. Overexpression in SH-SY5Y cells also resulted in an increase in WAVE-2 and phosphorylated RAC1/CDC42, key modulators of actin dynamics. Additionally, GPR50 transfection altered the protein level and localisation of α- catenin, another regulator of actin organisation, in HEK293 and SH-SY5Y cells respectively. An involvement of GPR50 in lipid metabolism has also been demonstrated in this thesis. Verification of the Y2H study suggested GPR50 does not physically interact with SREBF2 or ABCA2. However, ABCA2 appears to induce the intracellular localisation of GPR50 in several cell lines. In SH-SY5Y cells, this was mimicked by the inhibition of cholesterol trafficking, suggesting the translocation of GPR50 to the plasma membrane is dependent on cholesterol transport. Further, the depletion of lipoproteins resulted in the downregulation of GPR50, indicating a responsiveness to lipid levels. Finally, GPR50 increased lipid metabolism, as seen by a decrease in intracellular lipid droplets upon GPR50 overexpression. The data presented here extends previous work indicating a role of GPR50 in neurodevelopment. It also highlights a potential mechanism by which GPR50 regulates neuronal morphology, i.e. via actin remodelling. Reports that GPR50 is involved in energy homeostasis is also supported in this thesis, further, results presented here suggest GPR50 is specifically involved in lipid metabolism. These processes are often disrupted in mental illness, thus this work may provide a functional link between GPR50 and psychiatric disorders.

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Murray, Elizabeth. "The association between impaired fetal growth and neurodevelopment in childhood". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:f3a12dd8-868b-4e13-99f6-20b8f4b5adba.

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Impaired fetal growth is associated with an increased risk of negative neurodevelopmental outcomes. The majority of research to date, however, has relied on birth weight as an index of fetal growth impairment. Furthermore, few studies have included samples from low- and middle-income countries (LMICs). The objective of this thesis was to examine the association between impaired fetal growth, using a range of birth indices, and neurodevelopment in childhood. A systematic review showed that cognitive development and attention are two domains particularly affected by impaired fetal growth and thus was the focus of this thesis. Cognitive development and attention were assessed in three large, prospective birth cohorts drawn from high-, middle- and low-income countries: Pelotas (Brazil) 2004 (N=3579), ALSPAC (UK) (N=7354) and INTERGROWTH-21st (UK, Italy, Brazil, India and Kenya) (N=1073). INTERGROWTH-21st only enrolled low-risk mothers, whereas Pelotas and ALSPAC were not selective. In all three cohorts, indices of birth weight, stunting, wasting and asymmetry were collected at birth. Attention was assessed using subscales of the Child Behaviour Checklist or the Strengths and Difficulties Questionnaire; and cognition was assessed using the Wechsler Preschool and Primary Scales of Intelligence-Revised or INTERGROWTH-21st Neurodevelopmental Assessment (INTER-NDA). Each cohort measured these outcomes at one time point (range = 2-6 years of age). As part of this thesis the INTER-NDA was validated against the Bayley Scales of Infant Development. Associations between birth anthropometric indices and both cognitive and attention outcomes were assessed using hierarchical ordinal logistic regression. Attention impairment was associated with stunted birth length (BL) but only in females (OR=1.21-1.69, p < .05), across cohorts drawn from high-, middle- and low-income countries. In contrast, cognitive impairment was associated with stunted head circumference (HC) and low ponderal index (PI) in both sexes, although predominantly in LMIC settings (HC: OR=1.73-1.91, p < .05; PI: OR=1.46-4.91, p < .05). Identification of a female-specific association between stunted BL and poor attention across cohorts from different settings, suggests the association is robust to differential confounding effects. In contrast, the stronger association in LMICs between cognitive impairment and stunted HC and low PI suggests confounding structures (e.g. maternal and neonatal health care) may modify the effect of fetal growth on cognitive development. Birth indices (specifically BL, HC and PI) may be particularly helpful in identifying children at risk of neurodevelopmental impairment for early intervention.

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Jay, Taylor Reagan. "The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment". Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1560181547156823.

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DeProto, Jamin. "Elucidating transcription factor driven molecular cascades involved in embryonic neurodevelopment". Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559854.

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The brain is an incredibly complex organ composed of many cell types with intricate morphology, connectivity, and electrophysiological properties. Transcription factors orchestrate this elaboration by regulating numerous sets of genes and, in effect, the initial partitioning of gross functional areas of the brain and the eventual terminal differentiation of individual cells. Much is known about the expression patterns of individual transcription , factors, however, elucidating the exact mechanisms of transcription factor function has been , difficult because of their indirect regulatory relationship with genetic targets. '. I There are a few established methods for detecting direct transcription factor genetic targets. Chromatin immunoprecipitation and conditional knock-out mouse models are the most commonly utilized methods. Although there are advantages to such methods, they are challenging to implement, expensive, and prone to artifact. Over-expression of an electroporated transcription factor in cultured brain is shown to be an effective alternative. Tbr2 and Er81 were studied using over-expression in embryonic mouse. Subsequent expression changes were detected using gene micro array. Tbr2 appears to primarily target genes involved with cell cycle and metabolism (i.e. AgI, Uspll, Cdk-l, and Hes) while Er81 notably regulated genes associated with terminal differentiation (i.e. SIc18a3, Layn, and K v3.1). These findings fit with suspected functional significance of these transcription factors. However, some surprising results suggested other, unexpected roles. Tbr2 appears to interact with a few prominent angiogenic genes (Fgfr1, Sema6D, Mapk6, Epha3, and Ctnnb1). It was found that Tbr2 expressing neuroprogenitors tend to associate with blood vessels and is suggestive of a novel relationship establishing a neurovascular-neuroprogenitor niche at least partly regulated by Tbr2 regulated genes. Additionally, Er81 appears to down- regulate Ctip2 and up-regulate Tshz2. Taken together, a mechanism begins to take shape where axonal projections within the cerebral hemispheres are increased by way of Er81 regulation of Ctip2 and Tshz2. Overall, these results show that the method can identify genetic targets of transcription factors and a useful tool for understanding mechanisms of development, including novel relationships between seemingly disparate cell types.

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FONTANA, CAMILLA BARBARA. "EARLY INTERVENTION IN PRETERM INFANTS: EFFECTS ON NUTRITION AND NEURODEVELOPMENT". Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/546903.

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Background: Preterm infants are at high risk for neurodevelopmental disorders, even in the absence of overt brain lesions. NICU stressful environment, inadequate nutritional support and paucity of parental contact seem to negatively impact early brain development. In this context, mother milk feeding, could play a beneficial role although it is known to be challenging. Recent studies have shown how early interventions can reduce stress exposure with a positive effect on mother-infant relationship and subsequent neurodevelopment in preterm infants. Aims: To determine the effectiveness, in preterm infants, of an Early Intervention program on: i) visual function at term equivalent age (TEA) as an early emerging cognitive function; ii) infant’s feeding behavior and in particular on mother milk assumption at discharge; iii) epigenetic changes in DNA methylation status at TEA; iv) brain growth and maturation assessed by advanced Magnetic Resonance Imaging (MRI) at TEA. Methods: We conducted a parallel-group, randomized controlled trial (Trial Registration Number: NCT02983513). We included preterm infants born between 25+0 and 29+6 weeks of gestational age (GA) without severe morbidities and their families. Infants were recruited and randomized to either receiving Early intervention (EI) or Standard Care (SC). EI program included PremieStart, based on parental involvement, together with a multisensory stimulation (both tactile – through infant massage - and visual stimulation). SC, delivered according to NICU protocols, included Kangaroo Mother Care and minimal handling. Infants with major neonatal morbidities (i.e. surgical NEC; severe brain injuries as GMH-IVH>2°, cPVL) were excluded. The following evaluation were performed: i) Visual ability were assessed at TEA according to the protocol developed by Ricci et al. ii) Infants’ human milk intake at discharge was calculated from the infants’ computerized medical chart, as well as time of acquisition of full-oral feeding iii) As a proxy of DNA methylation we explored LINE-1 methylation status. The analyses were conducted using two blood samples: a cord blood sample, collected at birth, and a peripheral blood sample, harvested at TEA. iv) To calculate brain growth automated segmentation was conducted on each neonatal Axial T2 2 mm scan, in conjunction with the T1 scan. Volumetric measures of the structures were extracted from each segmentation. Results: Seventy preterm (EI n=34, SC n=36) infants were enrolled. According to the protocol 3 infants allocated to EI did not receive treatment. All babies in the SC group received allocated treatment as part of routine clinical practice. Main results include: i) Visual abilities: in total, 59% of infants in the EI group achieved the highest score possible in all 9 items of the visual assessment compared to 17% in the SC group (p=0.001). All infants in both groups showed complete maturation in four items, but EI infants showed more mature findings also in the other 5 items (ocular motility both spontaneous and with target, tracking arc, visual acuity and attention at distance). ii) Infant’s feeding behavior: a significantly higher rate of infants fed with any human milk was observed in the EI group (75.9%) compared to SC group (32.1%) (p=0.001) and EI infants were four times more likely to be fed exclusively with human milk at NICU discharge. Full oral feeding was achieved almost one week before in EI infants (mean postmenstrual age 36.8±1.6 vs 37.9±2.4 weeks in EI vs SC, p=0.04). iii) Epigenetic changes: LINE-1 methylation status increased from preterm birth to TEA for both group but was more pronounced in the EI group (p=0.0077) especially when looking at single CpG sites. iv) Brain growth: no differences were observed between the two groups in terms of regional brain volumes for the 48 areas analyzed. Conclusions: The present work provides further insights in the field of EI. Combining parental involvement and multisensory stimulation, our EI strategy showed an overall beneficial effect for preterm infants. This study, despite far to be conclusive, concur with recent evidence that the quality of early experiences influences neurodevelopment in preterm infants.

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Cabré-Riera, Alba 1991. "Radiofequency electromagnetic fields exposure, sleep, and neurodevelopment in preadolescents and adolescents". Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/670279.

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The use of mobile communication devices (e.g. mobile phones, tablets, and laptops) increased during the last few years, especially in preadolescents and adolescents. In order to function, mobile communication devices require a constant exchange of information achieved using radiofrequency electromagnetic fields (RF-EMF). Evidence is limited for potential effects of RF-EMF exposure to the brain and epidemiological studies that assessed RF-EMF exposure and its relationship with sleep and neurodevelopment are scarce. This thesis aimed to better understand the potential association between RF-EMF exposure and sleep, and RF-EMF exposure and neurodevelopment by: i) using a comprehensive RF-EMF exposure assessment (i.e. distinguish between sources with different patterns of RF-EMF exposure to the brain such as phone calls, screen activities, and environmental sources, ii) estimating the amount of RF-EMF the brain absorbs from each source and overall, ii) assessing sleep using objective measures collected with actigraphy, and iii) assessing neurodevelopment as cognitive function and brain volumes. The use of some mobile communication devices such as the tablet and problematic mobile phone use were associated with poorer sleep quality and less favourable objective sleep measures. Moreover, evening whole-brain RF-EMF dose from phone calls was associated with less favourable objective sleep measures. Regarding neurodevelopment, overall whole-brain RF-EMF dose and whole-brain RF-EMF dose from phone calls were not associated with brain volumes but whole-brain RF-EMF dose from screen activities was associated with smaller caudate volume. Finally, overall whole-brain RF-EMF dose and whole-brain RF-EMF dose from phone calls was associated with non-verbal intelligence. Given that the biological mechanism behind the observed associations between RF-EMF exposure and sleep, and RF-EMF exposure and neurodevelopment is unknown, that we found small effects sizes, and that we could not entirely disentangle between minutes of use and RF-EMF dose, our results should be interpreted with caution. We cannot discard chance finding, reverse causality, or that other non-RF-EMF factors related to the use of mobile communication devices are behind the observed associations (e.g. blue light, addiction, mental arousal or sleep displacement).
El uso de dispositivos móviles de comunicación como los teléfonos móviles, tabletas y ordenadores portátiles ha aumentado en los últimos años, especialmente en preadolescentes y adolescentes. Los dispositivos móviles de comunicación utilizan los campos electromagnéticos de radiofrecuencia (CEM-RF) para el intercambio constante de información necesario para su funcionamiento. La evidencia científica de los efectos que tiene la exposición a CEM-RF al cerebro es limitada y los estudios epidemiológicos que evalúan la exposición de CEM-RF y su relación con el sueño y el neurodesarrollo son escasos. Esta tesis tiene como objetivo entender mejor las asociaciones entre la exposición a CEM-RF y el sueño y la exposición a CEM-RF y el neurodesarrollo: i) haciendo una evaluación completa de la exposición de CEM-RF al cerebro, es decir, distinguiendo entre fuentes de CEM-RF con diferentes patrones de exposición al cerebro como las llamadas telefónicas, el uso de aparatos móviles de comunicación para actividades con pantalla y las fuentes ambientales, ii) estimando la cantidad de CEM- RF que el cerebro absorbe de cada fuente y en total, iii) evaluando el sueño utilizando medidas objetivas recogidas con actigrafia y iv) evaluando el neurodesarrollo como función cognitiva y volúmenes cerebrales. El uso de algunos dispositivos móviles de comunicación como por ejemplo la tableta y el uso problemático del teléfono móvil están associados con peor calidad y medidas objetivas del sueño. Además, hemos observado una asociación entre la dosis de CEM-RF al cerebro proveniente de las llamadas telefónicas por la tarde y peores medidas objetivas del sueño. En cuanto al neurodesarrollo, la dosis total de CEM-RF al cerebro y la dosis de CEM-RF al cerebro proveniente de las llamadas telefónicas no están asociadas con los volúmenes cerebrales, en cambio, la dosis de CEM-RF al cerebro proveniente de usos de aparatos móviles de comunicación para actividades con pantalla está asociada con un volumen más pequeño del núcleo caudado. Finalmente, la dosis total de CEM-RF al cerebro y la dosis de CEM-RF al cerebro proveniente de las llamadas telefónicas están asociadas con peor inteligencia no verbal. Teniendo en cuenta que se desconoce el mecanismo biológico que hay detrás de las asociaciones observadas entre la exposición a CEM-RF y el sueño y la exposición a CEM-RF y el neurodesarrollo, que los efectos que hemos encontrado son pequeños y que no hemos podido separar completamente entre los minutos de uso y la dosis de CEM-RF, nuestros resultados deben interpretarse con precaución. No podemos descartar hallazgo casual, causalidad inversa o que otros factores relacionados con el uso de dispositivos móviles de comunicación estén detrás de las asociaciones observadas. Por ejemplo, exposición a la luz azul, adicción a los dispositivos móviles de comunicación, excitación mental o desplazamiento del sueño.
L’ús de dispositius mòbils de comunicació com els telèfons mòbils, tauletes i ordinadors portàtils ha augmentat els darrers anys, especialment en preadolescents i adolescents. Els dispositius mòbils de comunicació utilitzen els camps electromagnètics de radiofreqüència (CEM-RF) per l’intercanvi constant d’informació necessari pel seu funcionament. L’evidència científica dels efectes que té l’exposició de CEM-RF al cervell és limitada i els estudis epidemiològics que avaluaven l’exposició de CEM-RF i la seva relació amb el son i el neurodesenvolupament són escassos. Aquesta tesi té com a objectiu entendre millor les associacions entre l’exposició a CEM-RF i el son i l’exposició a CEM-RF i el neurodesenvolupament. Per fer-ho: i) hem fet una avaluació completa de l’exposició de CEM-RF al cervell, és a dir, distingint entre fonts de CEM-RF amb diferents patrons d’exposició al cervell com les trucades telefòniques, l’ús d’aparells mòbils de comunicació per activitats amb pantalla i les fonts ambientals, ii) hem estimat la quantitat de CEM-RF que el cervell absorbeix de cada font i en total, iii) hem avaluat el son utilitzant mesures objectives recollides amb actigrafia i iv) hem avaluat el neurodesenvolupament com a funció cognitiva i volums cerebrals. L’ús d’alguns dispositius mòbils de comunicació com per exemple la tauleta i l’ús problemàtic del telèfon mòbil estan associats amb pitjor qualitat i mesures objectives del son. A més a més, hem trobat una associació entre la dosi de CEM-RF al cervell provinent de les trucades telefòniques al vespre i pitjors mesures objectives del son. En relació amb el neurodesenvolupament, la dosi total de CEM-RF al cervell i la dosi de CEM-RF al cervell provinent de les trucades telefòniques no estan associades amb els volums cerebrals, en canvi, la dosi de CEM-RF al cervell provinent d’usos d’aparells mòbils de comunicaió per activitats amb pantalla està associada amb un volum més petit del nucli caudat. Finalment, la dosi total de CEM-RF al cervell i la dosi de CEM-RF al cervell provinent de les trucades telefòniques estan associades amb pitjor la intel·ligència no verbal. Tenint en compte que es desconeix el mecanisme biològic que hi ha darrere de les associacions observades entre l'exposició a CEM-RF i el son i l'exposició a CEM-RF i el neurodesenvolupament, que els efectes que hem trobat són petits i que no hem pogut separar completament entre els minuts d'ús dels dispositius mòbils de comunicació i la dosi de CEM-RF al cervell, els nostres resultats s’han d’interpretar amb precaució. No podem descartar que les troballes siguin casuals, causalitat inversa o que altres factors relacionats amb l’ús de dispositius mòbils de comunicació estiguin darrere de les associacions observades. Per exemple, exposició a la llum blava, addicció als aparells mòbils de comunicació, excitació mental o desplaçament del son.

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Bartish, Margarita. "Establishing iPSCs as a method to model neurodevelopment in Down’s syndrome". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182353.

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The derivation of pluripotent stem cells (now termed induced pluripotent stem cells, iPSC) from mature somatic cells was a finding of seminal importance to fundamental cell biology. Thus established iPSC technology has been predicted to advance fields that previously relied on the ethically disputed use of embryonic stem cells. Being pluripotent (able to differentiate into every cell type present in the human body) and sharing most other characteristics with embryonic stem cells, but being much readier obtainable and their derivation free from ethical restraints, human induced pluripotent stem cells (hiPSC) provide access to cell types and insights into cell processes previously unattainable to researches. For this thesis, a hiPSC line was established from a skin biopsy donated by a Down’s syndrome patient. Most of what is known today about the molecular neurobiology behind this disease has been gathered from mice models or human post mortem studies, but this has a limited extrapolation potential to early human brain development in DS patients, as Down’s syndrome is an inherently human disease whose defining phenotype is established early during embryonic development. Having access to human pluripotent cells able to recapitulate the events of early neurogenesis is thus invaluable to the understanding of the mechanisms of this disorder. In parallel, work has been performed on optimizing iPSC reprogramming protocol. By exchanging one of the transcription factors used for reprogramming with a reporter gene, genomic integration of reprogramming factors has become possible to be traced visually, enabling more efficient selection of reprogrammed iPSC colonies.

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Mulder, Kelly Ann. "The complex relationship between omega-3 fatty acids and early neurodevelopment". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54842.

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Docosahexaenoic acid (DHA, 22:6ω-3) is an omega-3 fatty acid that is an important component of neural lipids accumulating in neural tissue during development. Decreased brain DHA is accompanied by increased 22:4ω-6 and 22:5ω-6, which has been shown to lead to deficits in neural function. However, dietary and other variables may impact DHA status and the potential for early deficiency to have lasting adverse effects on neurodevelopment remains unclear. Therefore, the effect of prenatal DHA and children’s DHA intake and status on neurodevelopment was examined. Pregnant women, n=271, were enrolled at 16 wk gestation and randomized to 400 mg/day DHA or placebo until delivery. Infant neurodevelopment was assessed at multiple time-points until 18 mo. Children returned for follow-up between 5-6 y (n=98). An additional group of 187 children (5-6 y) was enrolled at the same time to increase the sample size. Venous blood was collected, diet was assessed by food frequency questionnaire, and neurodevelopment was assessed. Infants from the placebo group were less likely to achieve high neurodevelopmental test scores up to 18 mo than infants from the DHA group (OR=2.23-3.22, P<0.05), suggesting that fetal DHA inadequacy occurred in our population. No differences were detected in children (5-6 y, n=98) from the placebo and DHA groups achieving a high neurodevelopment test score (P>0.05). However, child DHA intake and status (n=98) were related to the mother’s intake and status during pregnancy. For all children (n=285), DHA intake was positively associated with erythrocyte DHA. Child DHA status was associated with neurodevelopment test scores, but only short-term memory was associated with dietary DHA. These results suggest that DHA low enough to constrain infant neurodevelopment to 18 mo does occur among pregnant women in Vancouver, but the long-term effects remain unclear. We also provide evidence that DHA status is related to cognitive performance in young children. However, the association of maternal and child DHA intake and status limits the interpretation of whether DHA before or after birth is important. Finally, the variability in erythrocyte DHA was high, raising questions about the relationship between DHA intake and other fatty acids, DHA status, and neural function.
Land and Food Systems, Faculty of
Graduate

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Radomska, Katarzyna. "Functional studies of the Quaking gene : Focus on astroglia and neurodevelopment". Doctoral thesis, Uppsala universitet, Evolution och utvecklingsbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223332.

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The RNA-binding protein Quaking (QKI) plays a fundamental role in post-transcriptional gene regulation during mammalian nervous system development. QKI is well known for advancing oligodendroglia differentiation and myelination, however, its functions in astrocytes and embryonic central nervous system (CNS) development remain poorly understood. Uncovering the complete spectrum of QKI molecular and functional repertoire is of additional importance in light of growing evidence linking QKI dysfunction with human disease, including schizophrenia and glioma. This thesis summarizes my contribution to fill this gap of knowledge. In a first attempt to identify the QKI-mediated molecular pathways in astroglia, we studied the effects of QKI depletion on global gene expression in the human astrocytoma cell line. This work revealed a previously unknown role of QKI in regulating immune-related pathways. In particular, we identified several putative mRNA targets of QKI involved in interferon signaling, with possible implications in innate cellular antiviral defense, as well as tumor suppression. We next extended these investigations to human primary astrocytes, in order to more accurately model normal brain astrocytes. One of the most interesting outcomes of this analysis was that QKI regulates expression of transcripts encoding the Glial Fibrillary Acidic Protein, an intermediate filament protein that mediates diverse biological functions of astrocytes and is implicated in numerous CNS pathologies. We also characterized QKI splice variant composition and subcellular expression of encoded protein isoforms in human astrocytes. Finally, we explored the potential use of zebrafish as a model system to study neurodevelopmental functions of QKI in vivo. Two zebrafish orthologs, qkib and qki2, were identified and found to be widely expressed in the CNS neural progenitor cell domains. Furthermore, we showed that a knockdown of qkib perturbs the development of both neuronal and glial populations, and propose neural progenitor dysfunction as the primary cause of the observed phenotypes. To conclude, the work presented in this thesis provides the first insight into understanding the functional significance of the human QKI in astroglia, and introduces zebrafish as a novel tool with which to further investigate the importance of this gene in neural development.

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Hunter, Matthew. "NEUROPROFILES : NEUROdevelopment in PReschool children Of FIfe and Lothian Epilepsy Study". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28870.

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Neurobehavioural problems (i.e. cognitive impairment/behaviour problems) are common in childhood epilepsy. There are very limited data in children with early-onset epilepsy (CWEOE; onset ≤4 years). This study: (1) estimated the incidence of early-onset epilepsy, (2) described the spectrum and prevalence of neurobehavioural problems in CWEOE, and their risk factors, and (3) explored eye-gaze behaviour as a marker of neurobehavioural problems. This two year, prospective, population-based, case-controlled study identified newly diagnosed CWEOE in South East Scotland using active multi-source capture-recapture surveillance. CWEOE and controls completed detailed age-appropriate neuropsychological assessment - including Bayley III/WPPSI III, NEPSY II and social-emotional behaviour questionnaires. Children completed five eye-tracking tasks which assessed memory, attention, and social cognition. 59 CWEOE were identified (36M:23F); ascertainment-adjusted incidence 62/100,000 ≤4yrs/yr (95%CI 40-88). Asian and White-European children were at increased risk of epilepsy. 46 CWEOE (95%CI 62-84, 27M:19F) and 37 sex-age matched controls (18M:19F) underwent neuropsychological assessment. CWEOE had poorer general cognitive ability (p < .001, η²=.24), and increased parent reports of abnormal behaviour – significantly so in adaptive behaviour, ASD behaviours, hyperactivity/inattention, and atypical social behaviour. Overall 63% of CWEOE met criteria for neurobehavioural problems across multiple domains, vs 27% of controls (p < .001). Risk factors varied by domain. Prematurity and symptomatic/cryptogenic aetiology were common risk factors but other seizure-related variables were not. CWEOE with social problems exhibited abnormal eye-gaze behaviour toward social stimuli. Subtle atypicalities in sustained attention were noted in CWEOE, and an unexpected absence of antisaccade production was seen in all children. This is the first population-based study to describe the neurobehavioural profile, and explore eye-gaze behaviour, in CWEOE. Neurobehavioural problems are present, detectable, and highly prevalent in CWEOE, with implications for medical, psychosocial and educational resource provision, and provides an argument for early intervention. Eye-tracking may be a viable marker of neurobehavioural problems, and this study provides impetus for future eye-tracking investigations in CWEOE. Lastly, certain ethnic groups may be at increased risk of early-onset epilepsy in Scotland, providing opportunity for targeted intervention.

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Xu, Yingying. "Low-level Methyl-mercury Exposure from Fish Consumption and Child Neurodevelopment". University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505211195518167.

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Nist, Marliese Dion. "Inflammatory Mediators of Stress Exposure and Neurodevelopment in Very Preterm Infants". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1565718071063954.

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33

Evans, Matt. "The Structure and Function of the TACC Protein Family in Neurodevelopment". Thesis, Boston College, 2015. http://hdl.handle.net/2345/bc-ir:104021.

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Thesis advisor: Laura Anne Lowery
Thesis advisor: Eric Folker
In order to form the exact synaptic connection required for proper neurological function, the growing tip of the neuron hosts an orchestra of hundreds of different proteins interacting with extracellular cues to steer neuron growth in the right direction. The goal of our current research is to study several of the components of this pathway, known as the TACC family. Here, we present a detailed structure/function analysis of the TACC family in regards to binding and activity with other proteins in the growth cone. We investigate the function of TACC3 in mediating neuron outgrowth and guidance in vivo. We have found structural elements of the TACC family that enable their activity. Studying these conserved structures and functions of the TACC family will enable greater understanding of the entire process of cytoskeletal regulation and neurodevelopment
Thesis (BS) — Boston College, 2015
Submitted to: Boston College. College of Arts and Sciences
Discipline: Scholar of the College
Discipline: Biology

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34

Andrew, Morag Jane. "Neurodevelopmental and visual outcomes of infants at risk of neurodevelopmental disability following dietary supplementation in infancy". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:2c4a24e3-4924-4085-bad0-fb054622cb7f.

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Background: Docosahexaenoic acid (DHA), choline and uridine-5-monophosphate (UMP) are important brain nutrients which form phosphatidylcholine, the most abundant brain membrane phospholipid. DHA, choline and UMP supplementation increases rodent brain phospholipids, synaptic components, functional brain connectivity and cognitive performance. This novel pilot study supplemented infants at risk of neurological impairment (ARNI) with a nutrient combination containing these neurotrophic compounds. Aims: 1) In a double blind randomised control trial (RCT), investigate if intake of a specific nutrient combination improves neurodevelopmental and visual outcome in infants ARNI. 2) Using novel measures of cortical visual function, investigate the effect of perinatal brain injury severity, gestational age at birth and sex upon visuocognitive development in infants at risk of neurodevelopmental impairment. Method: Recruitment was from UK neonatal units. Eligibility: ≤ 31 weeks, weight < 9th percentile; < 31 weeks with ≥ Grade II intraventricular haemorrhage (IVH) or preterm white matter injury (PWMI); 31-40 weeks with ≥ Grade II IVH or PWMI, ≥ Sarnat Grade II HIE or defined brain MRI abnormalities. Stratification was by sex, gestation and brain injury severity. Randomised infants received neurotrophic supplementation or placebo, for 2 years. Primary outcome was Bayley Scales of Infant Development III (BSID III) composite cognitive score (CCS) after 2 years. Secondary outcomes included BSID III composite language score (CLS) and BSID III composite motor score (CMS). Cortical visual measures were pattern reversal visual event related potential (PR-VERP) latency (transient and calculated), orientation reversal visual event related potentials (OR-VERP), and the Fixation Shift test (FS). Functional behavioural vision was assessed using the Atkinson Battery of Child Development for Examining Functional Vision (ABCDEFV). Local Ethics Committee approval was granted. Results: 62 neonates were recruited. After 2 years, mean CCS in the intervention group was 87.7 (SD 20.4) and 81.6 (SD 18.5) in the placebo group (mean difference = 2.28, p=0.13; -0.2, 18.2). Mean CLS in the intervention group was 91.5 (SD 20.1) and 83.2 (SD 19.6) in the placebo group (mean difference = 2.74, p=0.1; -2.4, 18.3). CMS was similar in both groups. In relation to trial visual outcome measures, more infants in the placebo group gave a statistically significant OR-VERP response than in the intervention group (p=0.03). There were no statistically significant differences between the placebo and intervention on any other trial visual outcome measure. Cohort analyses indicate that transient PR-VERP latency is prolonged in children at risk of neurodevelopmental disability compared to typically developing infants (mean difference = -23.3, p=0.015, 95% CI -42.10 - -4.54). Calculated PR-VERP latency is prolonged to an even greater extent in children at risk of neurodevelopmental disability compared to typically developing infants (mean difference -148.6, p=0.000, 95% CI -179.7- -117.43), and remains prolonged across the age range tested. Conclusions: 1) The difference in CCS and CLS between intervention and placebo groups represents a clinically significant effect size. Use of neurotrophic micronutrient supplementation in infants ARNI warrants exploration in a large multicentre RCT. 2) Calculated PR-VERP latency may be a more appropriate outcome measure of cortical visual function than transient PR-VERP latency in infants at risk of neurodevelopmental disability.

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McCleery, Joseph Paul. "Examinations of social and non-social factors in the neurodevelopment of autism". Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3222058.

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Thesis (Ph. D.)--University of California, San Diego, 2006.
Title from first page of PDF file (viewed September 20, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

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Ouellette, Julie. "Role of Cerebrovascular Abnormalities in the 16p11.2 Deletion Autism Syndrome". Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38740.

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Brain development and function rely on vascular features that ensure adequate supply of oxygen and nutrients from the blood stream. These features consist of a well-established vascular network, a functional blood-brain barrier, as well as cerebral blood flow regulation. Early life impairments in these features can lead to neurodevelopmental defects. Very few studies have considered the contribution of the brain vasculature to autism spectrum disorders (ASD). A recent postmortem study in young ASD brains suggested an impairment in angiogenesis, a process through which new vessels are formed. A possible link between ASD and altered cerebral perfusion has also been suggested by functional imaging studies. Yet, contribution of cerebrovascular deficits to ASD physiopathology remains elusive, hence a detailed analysis of these deficits is needed. ASD are viewed as neurodevelopmental conditions associated with genetic origins. Mutations identified as a possible cause for ASD include the common 16p11.2 deletion, which leads to the haploinsufficiency of approximately 30 highly-conserved genes. In this thesis, we are using a multidisciplinary approach in order to decipher the cerebrovascular underpinnings of ASD in a mouse model of the 16p11.2 deletion syndrome (16p11.2df/+ mice). We have identified functional and structural cerebrovascular deficits during postnatal development in constitutive 16p11.2df/+ mutants. In particular, 16p11.2df/+ mice display a significant decrease in microvascular branching and density in the cerebral cortex at P14 when compared to age-matched WT littermates. In addition, 16p11.2df/+ mice display a collection of functional abnormalities at P50 when compared to WT mice, such as altered neurovascular coupling in vivo and altered vascular reactivity ex vivo. Notably, we demonstrated a defective endothelium-dependent vasodilation in 16p11.2df/+ mice, while smooth muscle function is unaffected. Furthermore, we generated mice harboring the endothelial-specific 16p11.2 haploinsufficiency (Cdh5-Cretg/+;16p11.2flox/+) in order to dissect the endothelial contribution to ASD phenotypes. These mice underwent behavioral testing to assess whether they display 16p11.2 syndrome -related characteristics. We demonstrated that these conditional mutant mice show home cage hyperactivity in the beam break test, repetitive behaviors in the marble burying test, as well as motor coordination deficits in the rotarod test. Our findings thus establish endothelial cells as key contributors to the pathophysiology of the 16p11.2 deletion syndrome, and provide novel insight into how the cerebral endothelium fine-tunes brain maturation.

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Smith, Alexandra. "The IgSF protein MDGA1 regulates morphology during a defined stage of placode-derived neuron maturation in developing chick cranial sensory ganglia". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:5ab9a049-31c9-4236-bd5b-a2cb83b7c9c3.

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The developing distal cranial sensory ganglia of the chick present an interesting and tractable model for the study of general processes of neural development. While the early stages of placodal neurogenesis, including induction of the placodes and initiation of the neurogenic programme, have been extensively studied, little is known about the molecular mechanisms that regulate migration of placode-derived neuroblasts and their aggregation to form ganglia. These questions have been addressed in the context of the trigeminal ganglion, however it remains unclear whether these principles apply to the epibranchial ganglia, on which the work presented here is focussed. Molecules potentially involved in controlling placodal neuroblast migration in the epibranchial ganglia were identified through a comparative microarray screen carried out in the Begbie lab. A list of candidate genes implicated in a variety of different cellular was validated by determining expression patterns in the region of the epibranchial CSG by in situ hybridisation. These expression patterns showed that different genes were expressed by different populations within the migratory stream. This question was further addressed through the detailed analysis of the expression patterns of a panel of neuronal and neurogenic markers, leading to the finding that placodal neuroblasts appear to sequentially upregulate different groups of genes as they migrate away from the placode. Neuroblasts within the migratory stream can further be subdivided according to cell morphology, which was assessed through high resolution imaging of GFP-labelled placodal cells. Multipolar and bipolar cells were concentrated around two different regions of the migratory stream with multipolar cells localised near the placode and bipolar cells localised closer to the neural tube. Together these findings support the hypothesis that placodal neuroblasts mature as they migrate towards the site of ganglion aggregation. With this detailed description of the system in mind, the question of molecular control was addressed through the functional characterisation of a candidate gene identified in the original microarray screen. MDGA1, a GPI-anchored IgSF molecule that has been implicated in controlling radial migration of cortical neurons, was specifically expressed in the chick CSG at the relevant stages. RNAi-mediated knockdown and overexpression were used to test the function of MDGA1 in migrating placodal neuroblasts. These experiments showed that MDGA1 negatively regulates the formation and extension of neuronal projections in bipolar neuroblasts. With the mechanisms of MDGA1 function relying entirely on protein-protein interactions at the cell-surface, we then set out to identify and characterise potential MDGA1 binding partners. SPR binding experiments carried out in collaboration with the Aricescu lab revealed that MDGA1 interacts with the Neuroligin family of synaptic proteins. Recent evidence has shown that MDGA1 interacts in cis with NLGN2 in rat hippocampal neurons where it disrupts its interaction in trans with Neurexin1. Neuroligins and Neurexins function to stabilise dendritic filopodia by creating trans-synaptic adhesions and recruiting the synaptic apparatus. Having determined that both NLGN2 and NRXN1 are expressed in placode-derived neuroblasts of the CSG, we propose that these molecules play a role in the stabilisation and extension of neuronal projections in this system and that this function in modulated by MDGA1 function.

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Mah, Kar Men. "Unique roles for the C3 gamma-protocadherin isoform in WNT signaling and dendrite arborization". Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5964.

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A key component of neural circuit formation is the elaboration of complex dendritic arbors, the pattern of which constrains inputs to the neuron and thus, the information it processes. As such, many neurodevelopmental disorders such as autism and Down, Rett, and Fragile X Syndromes are associated with reduced forebrain dendrite arborization. Identifying molecules involved in regulating dendrite arborization and neural circuitry formation therefore, is a start to understanding these disorders. Nearly 70 cadherin superfamily adhesion molecules are encoded by the Pcdha, Pcdhb, and Pcdhg gene clusters. These so-called clustered protocadherins (Pcdhs) are broadly expressed throughout the nervous system, with lower levels found in a few non-neuronal tissues. Each neuron expresses a limited repertoire of clustered Pcdh genes, a complicated process controlled by differential methylation and promoter choice. The clustered Pcdh proteins interact homophilically in trans as cis-multimers, which has the potential to generate a combinatorially explosive number of distinct adhesive interfaces that may give neurons unique molecular identities important for circuit formation. Functional studies of animals in which clustered Pcdhs have been deleted or disrupted demonstrate that these proteins play critical roles in neuronal survival, axon and dendrite arborization, and synaptogenesis. Additionally, they have been implicated in the progression of several cancers, suggesting that basic studies of their function and signaling pathways will have important future clinical applications. Recent work has shown that γ-Pcdhs can regulate the Wnt signaling pathway, a common tumorigenic pathway which also play roles in neurodevelopment, but the molecular mechanisms remain unknown. I determined that γ-Pcdhs differentially regulate Wnt signaling: the C3 isoform uniquely inhibits the pathway while 13 other isoforms upregulate Wnt signaling. Focusing on γ-Pcdh-C3, I show that the variable cytoplasmic domain (VCD) is critical for Wnt signaling inhibition. γ-Pcdh-C3, but not other isoforms, physically interacts with Axin1, a key component of the canonical Wnt pathway. The C3 VCD competes with Dishevelled for binding to the DIX domain of Axin1, which stabilizes Axin1 at the membrane and leads to reduced phosphorylation of Wnt co-receptor Lrp6. I also present evidence that the Wnt pathway can be modulated up (by γ-Pcdh-A1) or down (by γ-Pcdh-C3) in the cerebral cortex in vivo, using conditional transgenic alleles. Studies have implicated γ-Pcdhs as a whole, in many neurodevelopmental processes but little is known if distinct roles exists for individual isoforms. By using a specific C3-isoform knockout mouse line engineered in collaboration with Dr. Robert Burgess of The Jackson Laboratory, I was able to uncover a unique role for the C3-isoform in the regulation of dendrite arborization. Mice without γ-Pcdh-C3 exhibit significantly reduced dendrite complexity in cortical neurons. This phenotype was recapitulated in cultured cortical neurons in vitro, which can be rescued by reintroducing the C3-isoform. The ability of γ-Pcdh-C3 to promote dendrite arborization cell-autonomously was abrogated when Axin1 was depleted with an shRNA, indicating that this process by which γ-Pcdh-C3 regulates dendrite arborization is mediated by its interaction with Axin1, which I had previously demonstrated. Together, these data suggest that γ-Pcdh-C3 has unique roles distinct from other γ-Pcdhs, in the regulation of Wnt signaling and dendrite arborization, both of which are mediated by interaction with Axin1.

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Fuller, Tyson David. "Insights into neurodevelopmental disorders: molecular and behavioral studies using the zebrafish". Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6945.

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Neurodevelopmental disorders (ND) present a significant burden on society as over 5% of the US population is diagnosed with a ND. While environmental and biological factors have been associated with some cases of NDs, many still have unknown etiology. Strong comorbidities of NDs have been shown suggesting common biological processes of disease development. Sequencing technologies have allowed for the unprecedented identification of new candidate genes associated with NDs and many genes have been linked to multiple NDs. Developing robust methods to functionally validate these candidates is a critical next step for aiding patients with NDs. Using the zebrafish (Danio rerio), we characterized the developmental requirement of epilepsy candidate genes in the context of gene knockdown (KD). We demonstrated three different larval responses to pentylenetetrazol (PTZ) (hyperactive, hypoactive, or the same as control). We characterized the two genes resulting in a hyperactive response, Zinc Finger Homeobox 3 (ZFHX3) and Spectrin Repeat Domain Containing Nuclear Envelope Protein 1 (SYNE1), in greater detail. ZFHX3 is expressed in distinct brain regions during development and shows strong expression along nerve fiber tracts. SYNE1 shows broad expression during development that is enriched in the brain. Using CRISPR/Cas9 we generated a predicted null SYNE1 allele and recapitulated the seizure sensitivity phenotype in mutant larvae. Using a 60-hour behavioral assay we also demonstrate a generalized daytime hyperactivity in SYNE1 mutants. Our studies confirm ZFHX3 and SYNE1 as strong candidates for further study in epilepsy and suggest a role for SYNE1 in multiple NDs such as autism and attention-deficit/hyperactivity disorder.

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DESIATO, GENNI. "Regulation of the GABA switch by immunomodulatory signals". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199045.

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L'acido Gamma Amino butirrico, noto come GABA, rappresenta il principale neurotrasmettitore inibitorio del Sistema Nervoso nell'individuo adulto. Tuttavia, durante le precoci fasi di sviluppo, il GABA ha attività depolarizzante ed eccitatoria, fondamentale per il successivo e corretto sviluppo della rete. Il "GABA switch" rappresenta quindi un evento critico dello sviluppo neuronale, caratterizzato da uno shift funzionale della trasmissione GABAergica, da eccitatoria a inibitoria, le cui alterazioni sono comuni caratteristiche dei disordini del neurosviluppo, solitamente associati a disabilità cognitive e deficit comportamentali. Anche se i meccanismi molecolari del switch del GABA sono stati ampiamente descritti, nuovi regolatori di questo evento sono continuamente individuati e caratterizzati. È noto che le Cellule Staminali Mesenchimali (MSC) rappresentano buoni candidati a fini terapeutici, data la loro influenza positiva nella neuroprotezione verso le malattie neurologiche e immuno-mediate. Tuttavia, sempre più crescenti evidenze stanno dimostrando che le vescicole extracellulari (EVs) derivate da MSCs potrebbero rappresentare delle candidate migliori rispetto all'utilizzo di cellule per possibili applicazioni cliniche, mostrando un miglior profilo di sicurezza e utilizzo, e minori effetti collaterali. Tra le molecole immunomodulatorie, notevoli studi considerano l'Interleuchina 6 (IL-6) come un nuovo fattore neurotrofico, nonostante il suo ruolo ben descritto nelle malattie dello sviluppo neurologico, come l'autismo. Combinando tecniche funzionali (imaging di calcio e cloro) e approcci molecolari (RT-PCR), abbiamo osservato che le MSC-EVs, ma non le MSCs promuovono il GABA switch e aumentano l'espressione dei marcatori sinaptici inibitori del GABA. Allo stesso modo, l'esposizione precoce di IL-6 nei neuroni ippocampali, accelera il GABA switch modulando la trasmissione GABAergica e sovraregolando l'espressione di KCC2, in modo STAT-3- dipendente. Studi in letteratura suggeriscono la presenza di citochine come IL-6 all'interno delle MSC-MVs, ed è per questo possibile speculare sull'azione sinergica di questi due fattori, se combinati insieme. ILe evidenze osservate in questo lavoro aprono la possibilità di sfruttare tale sistema come nuovo approccio terapeutico, per veicolare molecule immunomodulanti tramite organelli sicuri e non tossici, in quelle condizioni patologiche caratterizzate da un ritardato GABA switch, come nel caso dei disordini dello neurosviluppo.
The neuronal “GABAergic switch” represents a critical event that occurs early in life before birth, during brain development, characterized by the excitatory-to-inhibitory transition of the GABAergic transmission. Impairments in the accomplishment of this event have been associated to a remarkable excitation/inhibition network imbalance, usually linked to cognitive disabilities and behavioural deficits, typical hallmarks of neurodevelopmental disorders. Even though molecular mechanisms of the GABA switch have been widely described, novel regulators of this event are being continuously characterized. It is well known that mesenchymal stem cells (MSCs) represent good candidates for therapeutic interventions, given their positive roles in neuroprotection against immune-mediated and neurological diseases. However, raising evidences are considering MSC-derived extracellular vesicles (EVs) better candidates than the whole cells for clinical applications, bearing more safety and less side effects. Among the immunomodulatory molecules, increasing studies consider the cytokine Interleukin 6 (IL-6) as a novel trophic factor, despite its well described role in neurodevelopmental diseases, such as autism. By taking advantage of a combination of functional (calcium and chloride imaging) and molecular approaches (RT-PCRs), we found that MSC-EVs but not MSCs accelerated the timing of the GABA switch and boosted the expression of the GABA inhibitory synaptic markers. Likewise, IL-6 early exposure in neurons accelerated the timing of the GABA switch by enhancing the GABAergic transmission and upregulating the expression of KCC2, in a STAT3- dependent manner. Given several evidences suggesting the presence of IL-6 within the MSC-MV cargo it is possible to speculate about their synergistic action when combined. All these data open the possibility to harness such system as a new therapeutical approach, for delivering safe and nontoxic organelles to those pathological conditions characterized by a delayed GABA switch, such as neurodevelopmental disorders.

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Birks, Laura Ellen 1983. "Pre- and post-natal exposure to radiofrequency electromagnetic fields and neurodevelopment in children". Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/665301.

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With the recent evolution of mobile communication, there is a lack of understanding of increased radiofrequency (RF) exposure from these new technologies, especially among children. Little is known about the amount of RF exposure children experience day-to-day and its main sources. Furthermore, there is little understanding of RF dose during fetal life or RF dose to the brain during childhood. This thesis assessed environmental RF exposure and RF brain and body dose in children in several large, population-based cohort studies through personal exposure measurement studies and integrated exposure models. This thesis also evaluated whether maternal mobile phone use during pregnancy or RF dose to the brain in childhood was associated with neurodevelopmental outcomes, specifically, behavioral problems. In Europe, measured environmental RF in children and estimated dose to children’s brains was found to be far below recommended limits. Maternal mobile phone use during pregnancy was associated with hyperactivity/inattention problems in young children (ages 5-7) while RF dose to the brain during childhood was associated with behavioral problems, particularly in older children (ages 14-18). Uncontrolled confounding, reverse causality, and effects of mobile device use, apart from RF dose to the brain, could not be entirely excluded as possible explanations for these results. In the meantime, pregnant women could reduce RF exposure to the fetus by keeping mobile devices away from the belly, while children can reduce RF dose by limiting calls, limiting high resolution video streaming, or keeping mobile devices away from the body.
Con la reciente evolución de la comunicación, existe una falta de comprensión del aumento de la exposición a la radiofrecuencia (RF) de estas nuevas tecnologías, especialmente entre los niños. Se sabe poco sobre la cantidad de exposición a RF que experimentan los niños día a día y sus principales fuentes. Además, hay poca comprensión de la cantidad de RF durante la vida fetal o la cantidad de RF en el cerebro durante la infancia. Esta tesis ha evaluado la exposición ambiental a RFs y la cantidad de RF en el cerebro y cuerpo en niños en varios estudios de cohorte de gran tamaño a través de estudios de medición de exposición personal y modelos de exposición integrados. Esta tesis también evaluó si el uso del teléfono móvil materno durante el embarazo o la cantidad de RF al cerebro en la infancia se asoció con problemas del desarrollo neurológico, específicamente, problemas de comportamiento. En Europa, la RF ambiental medida en niños y la cantidad estimada en el cerebro de los niños se encontraron muy por debajo de los límites recomendados. El uso del teléfono móvil materno durante el embarazo se asoció con problemas de hiperactividad/falta de atención en niños pequeños (entre 5 y 7 años) mientras que la cantidad de RF al cerebro durante la infancia se asoció con problemas de conducta, particularmente en niños mayores (14-18 años). Los factores de confusión no controlados, la causalidad inversa y los efectos del uso de dispositivos móviles, aparte de la cantidad de RF al cerebro, no podrían excluirse como posibles explicaciones para estos resultados. Además, las mujeres embarazadas podrían reducir la exposición a RF al feto manteniendo los dispositivos móviles alejados del estómago, mientras que los niños pueden reducir la cantidad de RF limitando las llamadas, limitando la transmisión de video de alta resolución o manteniendo los dispositivos móviles alejados del cuerpo.

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Dharmaraj, Sandeep Timothy. "Postnatal growth retardation in preterm infants : relationship with neurodevelopment and post-discharge morbidity". Thesis, University of Newcastle upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435550.

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Gibertoni, Dino <1966&gt. "Trajectories and predictors of growth and neurodevelopment in Very Low Birth Weight infants". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6380/.

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Neurodevelopment of preterm children has become an outcome of major interest since the improvement in survival due to advances in neonatal care. Many studies focused on the relationships among prenatal characteristics and neurodevelopmental outcome in order to identify the higher risk preterms’ subgroups. The aim of this study is to analyze and put in relation growth and development trajectories to investigate their association. 346 children born at the S.Orsola Hospital in Bologna from 01/01/2005 to 30/06/2011 with a birth weight of <1500 grams were followed up in a longitudinal study at different intervals from 3 to 24 months of corrected age. During follow-up visits, preterms’ main biometrical characteristics were measured and the Griffiths Mental Development Scale was administered to assess neurodevelopment. Latent Curve Models were developed to estimate the trajectories of length and of neurodevelopment, both separately and combined in a single model, and to assess the influence of clinical and socio-economic variables. Neurodevelopment trajectory was stepwise declining over time and length trajectory showed a steep increase until 12 months and was flat afterwards. Higher initial values of length were correlated with higher initial values of neurodevelopment and predicted a more declining neurodevelopment. SGA preterms and those from families with higher status had a less declining neurodevelopment slope, while being born from a migrant mother proved negative on neurodevelopment through the mediating effect of a being taller at 3 months. A longer stay in NICU used as a proxy of preterms’ morbidity) was predictive of lower initial neurodevelopment levels. At 24 months, neurodevelopment is more similar among preterms and is more accurately evaluated. The association among preterms’ neurodevelopment and physiological growth may provide further insights on the determinants of preterms’ outcomes. Sound statistical methods, exploiting all the information collected in a longitudinal study, may be more appropriate to the analysis.

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Ubhi, Kirenjeet. "The POU-domain transcription factor, POU3f1, in neurodevelopment, psychiatric disorders and brain injury". Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431674.

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Gaertner, Bryn, i Bryn Gaertner. "The Neurodevelopmental and Genetic Basis to Natural Variation in Thermal Preference Behavior in Caenorhabditis elegans". Thesis, University of Oregon, 2012. http://hdl.handle.net/1794/12385.

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In a heterogeneous environment where temperature influences fitness, individuals must navigate to a thermal optimum to maximize reproductive output and minimize physiological stress. However, the optimal temperature varies among individuals due to genetic and environmental contributions. The neural and genetic basis to such natural variation in behavior has remained elusive in most cases, as the high-throughput genomic, neurodevelopmental, and behavioral techniques were not developed. Using the nematode
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Schmitt, James Eric. "The Quantitative Genetics of Neurodevelopment: A Magnetic Resonance Imaging Study of Childhood and Adolescence". VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd/1042.

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Understanding the causes of individual differences in brain structure may give clues about the etiology of cognition, personality, and psychopathology, and also may identify endophenotypes for molecular genetic studies on brain development. We performed a comprehensive statistical genetic study of anatomic neuroimaging data from a large pediatric sample (N=600+) of twins and family members from the Child Psychiatry Branch at the NIMH. These analyses included variance decomposition of structural volumetric endophenotypes at several levels of resolution, voxel-level analysis of cortical thickness, assessment of gene by age interaction, several multivariate genetic analyses, and a search for genetically-mediated brain-behavioral relationships. These analyses found strong evidence for a genetic role in the generation of individual differences in brain volumes, with the exception of the cerebellum and the lateral ventricles. Subsequent multivariate analyses demonstrated that most of the genetic variance in large volumes shares a common source. More subtle analyses suggest that although this global genetic factor is the principal determinant of neuroanatomic variability, genetic factors also mediate regional variability in cortical thickness and are different for gray and white matter volumes. Models using graph theory show that brain structure follows small-world architectural rules, and that these relationships are genetically-determined. Structural homologues appeared to be strongly related genetically, which was further confirmed using novel methods for semi-multivariate quantitative genetic analysis at the voxel level. Studies on interactions with age were mixed. We found evidence of gene by age interaction on frontal and temporal lobar volumes, indicating that the role of genetic factors on these structures is dynamic during childhood. Analyses on cortical thickness at a finer scale, however, showed that environmental factors are more important in childhood, and environmental changes were responsible for most of the changes in heritability over this age range. When assessing the relationship between brain and behavior, we found weak negative genetic correlations and positive environmental correlations between IQ and cortical thickness, which appear to partially cancel each other out. More complex models allowing for age interactions suggest that high and low IQ groups have different patterns of gene by age interactions in concordance with prior literature on cortical phenotypes.

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Chaudhury, Sumona. "The Neurodevelopment and Mental Health of Children Affected by HIV in Sub-Saharan Africa". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:32644536.

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This dissertation assesses neurodevelopment in children affected by HIV in Botswana, by examining associations between a range of factors and neurodevelopmental outcomes at 24 months of age and adjusting for potential confounders through linear regression. We followed children from birth to approximately 24 months to assess their neurodevelopment with an adapted version of Bayley Scales of Infant Development third edition (BSIDIII: cognitive, gross motor, fine motor, expressive and receptive language domains) and with the Development Milestones Checklist (DMC: locomotor, fine motor, language and personal-social domains), a parent-completed questionnaire. Chapter I compares neurodevelopment between HIV-exposed uninfected (HEU) children whose mothers took antenatal 3-drug combination antiretroviral therapy (ART) vs. zidovudine (ZDV) within a prospective study, nested within two cohorts of HIV-infected mothers and their children in Botswana (one observational, one interventional). We observed that neurodevelopmental outcomes at 24 months of age were generally at least as good among HEU children exposed in utero to ART when compared to those exposed in utero to ZDV. Chapter II compares neurodevelopment between HEU vs. HIV-unexposed uninfected (HUU) children in Botswana, within a prospective observational study. We observed that neurodevelopmental outcomes at 24 months among HEU children were generally as good as those among unexposed children. Results from Chapter I and II provide reassurance, easing concerns that HIV or ARV-exposure may detrimentally affect neurodevelopment in young children. Chapter III examines the potential of a family-based intervention for use in reducing harmful alcohol use and intimate partner violence, to protect and promote child mental health, within families affected by HIV in Rwanda. Quantitative data from a randomized controlled trial (RCT) were analyzed to demonstrate significant reductions in alcohol-use and intimate partner violence within HIV-affected families receiving the intervention, when compared to control families. Quantitative and qualitative data from the RCT, were integrated using a mixed-method approach, and support the potential of family-based interventions to reduce adverse caregiver behaviors as a major mechanism for improving child well-being, for families affected by HIV in Sub-Saharan Africa.

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Eamegdool, Steven Suprakit. "Human neural precursor cells and iron-oxide nanoparticles: relevance to neurodevelopment and neural repair". Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13570.

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We were able to identify neuroblasts as one of the main candidates involved in phagocytosing apoptotic cells which occurs during the peak of programmed-cell death in early neurogenesis. This biological phenomenon was found to be regulated through the P2X7 scavenger receptor, thus contributing towards a better understanding of the processes involved in the regulation of embryonic neurogenesis. Furthermore, we studied the interactions between nanoparticles and neural precursor cells in order to provide clinically relevant data for future cell transplantation studies and possible use in stem cell therapies. Nanoparticles at low concentrations proved to be viable contrast agents for labelling cells prior to MRI visualisation, however at higher concentrations the cells underwent apoptosis through the ablation of mitochondria function, offering a dual role as an MRI contrast agent or as a target-specific drug delivery vehicle. The biological impacts that nanoparticles had on neural precursor cell mitochondrial function suggests potential mechanisms involved in the pathogenesis of CNS-related diseases and damage, and hence possible therapeutic targets and treatment regimens. Overall, this thesis was able to enhance our understanding of neurodevelopment and neurodegeneration, as well as provide valuable information for future for cell tracking and transplantation studies.

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Geider, Kirsten [Verfasser], Bodo [Akademischer Betreuer] Laube i Ralf [Akademischer Betreuer] Galuske. "Ionotropic glutamate receptor dysfunction in pediatric neurodevelopment / Kirsten Geider. Betreuer: Bodo Laube ; Ralf Galuske". Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2015. http://d-nb.info/1110981228/34.

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Brown, Stephanie Sian Gabriella. "Functional MRI in FMR1 premutation carriers : a cross-sectional study of neurodegeneration and neurodevelopment". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28806.

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Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the FMR1 premutation. Carriers of the FMR1 premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS), which involves progressive symptoms of tremor, ataxia and cognitive decline. Evidence also suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. The present study aimed to investigate and delineate neurodegenerative and neurodevelopmental aspects of the premutation utilising primarily fMRI, clinical assessments and molecular measurements in 17 premutation carrier participants and 17 age-matched control participants, aged between 20 and 70 years. The functional imaging protocol included a motor task and an emotional processing task. A battery of clinical and neuropsychological tests outside of the scanner and blood-based measurements of FMR1 CGG repeat length, FMRP levels and FMR1 mRNA levels were also carried out. In the motor task, premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Quantative real-time PCR analysis revealed that mean age-matched FMR1 mRNA levels display a trend towards being higher in carriers and clinical testing of motor skills additionally showed significantly worse tremor and co-ordination scores in non-FXTAS carriers. No significant associations were seen between these measurements and neuroimaging data. During the emotional processing task, carriers exhibited significantly lower activation compared to controls (FWEcorr < 0.001) at the bilateral superior parietal lobe, bilateral Brodmann Area (BA) 17 (V1), right intraparietal area and right BA18 (V2) when comparing high arousal and low arousal conditions. Group by age interaction analyses indicated no significant between group differences at a whole brain level. Clinical assessment revealed that carriers displayed significantly worse symptoms of obsessive-compulsiveness, anxiety, global severity of psychiatric symptoms, facial emotion recognition and autistic traits compared to controls and FMRP levels were comparable between groups. No significant associations were seen between these measurements and neuroimaging data. Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability. Additionally, we show significantly altered emotional processing at neuropsychological, clinical and functional neuroimaging levels in carriers compared to controls, which appear to display stability over age. Overall, we present new evidence in keeping with possible neurodegenerative and neurodevelopmental traits in FMR1 premutation carriers.

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