<p>The relationship between gene copy number and protein expression levels has not thoroughly been examined in humans or mouse models of Down syndrome (DS) in relationship to developmental changes in the trisomic brain. Found on human chromosome 21 (Hsa21) and triplicated in DS, Dual-specificity tyrosine-phosphorylated regulated kinase 1A (<i>DYRK1A)</i> has been linked in DS to neurological deficits by restricting cell growth and proliferation. Little information exists regarding DYRK1A during perinatal development and how its expression may lead to cognitive deficits, and none exists that explores the gene-to-protein relationship during these critical time periods. This study aims to 1) Quantify variable DYRK1A expression across development as a function of age, sex, and brain region in trisomic Ts65Dn mice compared to euploid counterparts and 2) establish that the spatiotemporal pattern of developmental DYRK1A in the brain is not influenced solely by gene copy number, and that reduction of <i>Dyrk1a</i> in euploid and trisomic mice does not result in a corresponding global reduction of DYRK1A expression. DYRK1A was quantified in three areas of the postnatal brain at seven ages using the Ts65Dn mouse, the most studied model of DS, and found that trisomic expression is significantly increased on postnatal day ([P]6), declining by the third week to near euploid levels. We also uncovered a sexual dimorphic expression of DYRK1A when comparing animals of different sexes within the same genotype. Data from <i>Dyrk1a</i> knockdown mice indicated that reducing only <i>Dyrk1a</i> in euploid and in otherwise trisomic animals yields highly variable levels of DYRK1A, dependent on sex and tissue type, supporting the non-intuitive relationship between gene dosage and protein expression. These data emphasize the need to understand the age-dependent regulation of antecedent conditions that are causing changes in <i>Dyrk1a</i> expression in the brain.</p>

Part 1 - Background: Maternal prenatal adversity often results in changes to the hypothalamic- pituitary-adrenal axis (HPA axis) function, such as greater cortisol secretion. Recent evidence suggests that fetal exposure to elevated cortisol levels may cause structural changes to key limbic regions integral to regulation of the HPA axis such as the amydala and hippocampus in children. In the early postnatal months these same structures are particularly vulnerable to the quality of maternal care and parenting styles. However, the relative impact and interaction of such factors is still underreported. Methods: 24 healthy 7-8 year old children (male:female=13:11) underwent an MRI. Amygdala and hippocampal volumes were assessed and used in multiple regression models to determine the impact of prenatal cortisol and postnatal maternal sensitivity. Results: Larger right hippocampal volumes were associated with increases in late gestation cortisol levels (4.6 mm3/nmol of cortisol; FDR corrected p<0.005). Increases in 6th month maternal sensitivity predicted a decrease in right hippocampal volumes at a trend level (FDR corrected p=0.09). There was no interaction effect between cortisol and sensitivity. There were no significant effects on left hippocampus or bilateral amygdala volumes. No sex differences were noted. Discussion: Given previous work we had expected greater amygdala volume and reduced hippocampal volumes to associate with increases in cortisol and decreases in sensitivity. Our results suggest that there may indeed be a programming effect on children’s hippocampi by prenatal cortisol. Findings may be reflective of a positive adaptive response or resilience to adverse prenatal environments. Part 2 - Introduction: Emotion regulation (ER) is an integral component to mental health. ER is thought to incorporate limbic as well prefrontal regions in several cognitive top-down circuits to utilize higher-order executive functions to adequately monitor and inhibit emotion when necessary. However, only recently has research targeted the developmental trajectories of these circuits from childhood. Methods: 29 healthy children aged 7-8 years (mean 7.34 ± 0.48) underwent functional magnetic resonance imaging (fMRI) with an implicit emotion go/nogo cognitive task to assess the developmental state and interaction between cognitive and emotional circuitry using functional connectivity (FC) in this age group. Results: Central executive networks (CEN) and salience networks (SN) showed more diffuse FC than mature networks, with greater inter-network connectivity. During exposure to fearful stimuli, there was greater connectivity within CEN and SN during go trials. Nogo trials were associated with more limbic-cognitive network interaction during concurrent exposure to fearful stimuli than neutral stimuli, Connectivity with the dACC was found to be common between limbic and CEN seeded networks. Discussion: Results indicate that cognitive networks are present but generally less mature than previous results from adult populations. Particularly, diffuse connectivity between the insula and PCC was negatively correlated indicating a developing switch between resting and salience networks. Additionally, greater connectivity for response inhibition tasks (nogo) during fearful stimuli exposure in the dACC, amygdala, anterior prefrontal, and DLPFC, suggests a maturing emotion regulation network, capable of managing cognitive tasks during emotional stimuli presentation. / Thesis / Master of Science (MSc)

Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as Influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain's susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies. / Thesis / Master of Science (MSc) / Viral infections, like Influenza and SARS-CoV-2, vary in severity based on a person's age and sex. Generally, older men suffer severe immediate symptoms such as stroke and seizures, while women endure long-term effects, including brain inflammation and cognitive issues. Recent research suggests even non-brain-related infections can lead to changes within the brain. Yet, our understanding of how our brains' viral receptors - key to infection - change with age and between sexes is limited. We used a public database to explore these changes, studying receptor-related genes in different brain areas across various ages and sexes. Our analysis revealed unique patterns of gene expression, grouping the brain into different regions based on development and sex. We noticed many differences between men and women during childhood, potentially influencing how their brains respond to viruses. This research aids our understanding of why viral infections impact individuals differently based on age and sex, offering insights that could help develop personalized treatments.

No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24985号 / 生博第514号 / 新制||生||68(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 北島 智也, 教授 見学 美根子, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

This dissertation focuses on the effects of lead (Pb) on the expression of thyroid hormone distributor proteins and how that affects the developing brain in Xenopus laevis tadpoles. Previous work has shown that Pb has the ability to dysregulate thyroid hormone (TH)-signaling in vertebrates and that Pb can impair brain development. This dissertation reports results for a series of Pb-treatment experiments conducted in Xenopus laevis tadpoles. The first primary hypothesis of this dissertation is that Pb impairs TH-dependent mechanisms of brain development. The second primary hypothesis of this dissertation is that Pb-induced impairments of brain development happen via dysregulation of thyroid hormone distributor proteins (THDPs) transthyretin (TTR) and β-trace. Analyses of the effects of Pb on overall body growth showed dose-dependent decreases in body length with increasing concentrations. Evaluation of the effect of Pb on tectal size and cell death in the developing brain yielded bimodal changes that depended upon Pb concentration in both features. Furthermore, Pb impaired TH-induced changes in brain development, including neurogenesis and brain volume. Pb abolished the T4-mediated increase in proliferating cell nuclear antigen (PCNA) expression, while having only marginal effects on neuronal regeneration related protein (NREP) and Krueppel-like factor 9 (klf9). Analyses of the effects of Pb on TTR and β-trace expression yielded results demonstrating a significant decrease in expression of both proteins in response to Pb-treatment. Contrary to prior studies in the literature, I demonstrate here that TTR is present in the brains of Xenopus. While electroporation of TTR morpholino did result in fewer TTR puncta, electroporation with morpholinos for TTR and β-trace knock down did not mimic the effects of Pb on neurogenesis. However, overexpression of these proteins in the choroid plexus (CP) of these animals was sufficient to produce an increase in neurogenesis. Finally, overexpression of these proteins was sufficient to ameliorate the effects of Pb-treatment on neurogenesis. The results affirm both the primary and secondary hypotheses, illustrating that Pb does, indeed, impair TH-mediated mechanisms of brain development and that these impairments are mitigated by dysregulation of TTR and β-trace. / Doctor of Philosophy / This dissertation focuses on the effects of lead (Pb) poisoning on thyroid hormone (TH)-mediated mechanisms of brain development in Xenopus laevis tadpoles. The work detailed here seeks to shine a light on the effects of Pb on brain development and one mechanism by which those effects may be mediated. This dissertation details experiments done in Xenopus laevis tadpoles, which are a prime animal model for studying environmental toxicants, especially those that disrupt TH physiology. This dissertation focuses on two primary hypotheses within a two journal manuscript format. The first primary hypothesis of this dissertation is that Pb impairs TH-dependent mechanisms of brain development. The second primary hypothesis of this dissertation is that Pb-induced impairments of brain development happen via dysregulation of thyroid hormone distributor proteins (THDPs) TTR and β-trace. The results found in this dissertation are consistent with the conclusions that Pb impairs TH-mediated mechanisms of brain development and that those impairments are mitigated by dysregulation of THDPs in the brain and body.

No description available.

School and learning readiness are continually being placed under the spotlight in an attempt to protect the grade 1 learner from possible learning failures, since unsuccessful learning experiences have negative effects even on a person's adult life. A factor that plays a significant role in the current teaching situation in the RSA is the fact that many grade 1 leamers are not instructed in their mother tongue and that they are not familiar with the concepts which are used in the language of learning and teaching. Another important factor is the fact that since 2004 learners may enrol as grade 1 learners at primary schools if they are five and a half years old and did not attend a grade R class. In this study the problems experienced by grade 1 leamers in primary schools since the implementation of Outcomes-based Education in the RSA in 1998, were determined by means of a pilot study. It was followed up by a literature study on the brain and factors that influence the working of the brain among young learners, as well as learning and factors that cannot only promote learning among this age group, but also disadvantage it. The literature was also consulted to look at stimulation of the child's development in the early development stage (0-9 years). As cross control for the study, the influence of the implementation of the RNCS was determined by means of a Likert-type questionnaire that was sent to grade1 teachers. As a result of factors that were identified from the above-named literature study and from the information acquired from the pilot project and Likert-type questionnaire, a conceptual stimulation programme for multicultural grade 1 classes was developed to provide in the shortcomings that currently occur among grade 1 learners. The Aptitude Test for School beginners (ASB), a standarised school readiness test of the HSRC, was used as a measuring instrument to acquire a differentiated image in a scientific way of the grade 1 learners (n = 39) for the purpose of this study. Thereafter, the learners were divided into an experimental and a control group. The conceptual stimulation programme was presented to the experimental group for ten consecutive weeks. The AS6 test was then conducted again with all the grade 1 learners involved. Both the first and final tests were marked according to the prescribed marking keys, interpreted according to the norm tables and statistically processed. The pre and post test scores of the two groups were compared and the experimental group improved in all 8 sections of the test battery, namely perception, spatial, reasoning, numerical, Gestalt, co-ordination , memory and verbal comprehension. In each of these categories there was an increase of d = 0.5 and more which according to Cohen's d-values, can be regarded as practically meaningful. The above-mentioned results indicate that the effective presentation of a conceptual stimulation programme to a group of multicultural grade 1 learners provides positive results and that the didactical methods used during the presentation can be recommended to grade 1 teachers in the current multicultural schools in the RSA. The programme can serve as a prototype to adress the shortcomings identified in the practise (questionnaires) and the literature study. Keywords for indexing are: stimulation programme, schoolreadiness, schoolreadiness programme, cognitive development, learning theories, conceptual learning, brain development. / Thesis (Ph.D. (Education))--North-West University, Potchefstroom Campus, 2006.

Few studies have explored emotion processing abilities in children following Acquired Brain Injury (ABI). This study develops previous research in this area by exploring emotion processing skills in children with focal ABI, using eye tracking technology. It was hypothesised that children with focal ABI would demonstrate impaired emotion recognition abilities relative to a control group and that, similar to adult eye tracking studies, they would show an atypical pattern of eye moments when viewing faces. Sixteen participants with focal ABI (10-16 years) and 27 healthy controls (10-16 years) completed one novel and one adapted visual emotion processing task, presented using a T120 Tobii eye-tracker. The eye-tracker measured eye-movement fixations in three areas of interest (AOIs; eyes, nose, mouth), as participants viewed the stimuli. Emotion perception accuracy was recorded. All participants from the ABI group also completed neuropsychological assessment of their immediate visual memory, visual attention, visuospatial abilities, and everyday executive function. The results of the study showed no significant difference in accuracy between the ABI and control groups. However, on average children with ABI appeared slightly less accurate than the control group in both emotion recognition tasks. Within-subjects analysis revealed no effect of lesion location and laterality or age at lesion onset upon emotion recognition accuracy. Eye tracking analysis showed that children within the ABI group presented with an atypical pattern of eye movements relative to the control group, demonstrating significantly greater fixation times within the eye region, when viewing disgusted, fearful angry and happy faces. The ABI group also showed reduced mean percentage fixation duration within the nose and mouth regions, relative to controls. Furthermore, it was observed that the ABI group took longer on average to give an accurate response to sad, disgusted, happy and surprised faces and this difference reached statistical significance for the accurate recognition of happy and surprised faces. It is suggested that the atypical fixation patterns noted within the ABI group, may represent a difficulty with dividing visual attention rapidly across the whole of the face. This slowing may have an impact upon functioning in everyday social situations, where rapid processing and appraisal of emotion is thought to be particularly important. It is therefore suggested that eye tracking technology may be a valuable method for the identification of subtle difficulties in facial emotion processing, following focal ABI in childhood, and may also have an application in the rehabilitation of these difficulties in future.