This study examined the effects of bilateral and unilateral deafness by measuring cortical auditory evoked potential (CAEP) responses in children at initial stages of bilateral cochlear implant (CI) use. We recorded cortical responses evoked by right and left CI stimulation in 127 children with early onset (< 12 months) deafness, with 72 children receiving the two devices in the same surgery (simultaneously implanted) and 55 children receiving the devices in separate procedures (sequentially implanted). Three different types of responses were identified in children with bilateral CIs. No significant effects of duration of deafness, age at implantation, or duration of unilateral CI use were found on response latencies and amplitudes within each type of cortical response, but there were clear differences in responses types between groups and ears. In the context of these findings, the effects of bilateral and unilateral deafness to the auditory pathways were discussed.

The neural cell adhesion molecule L1 is a member of the immunoglobulin superfamily and it mediates many adhesive interactions during brain development. Mutations in the L1 gene are associated with a spectrum of X-linked neurological disorders known as CRASH or L1 syndrome. The objective of this thesis was to use the zebrafish model to investigate the molecular mechanisms of L1 functions and the pathological effects of its mutations. Zebrafish has two L1 homologs, L1.1 and L1.2. Inhibition of L1.1 expression by antisense morpholino oligonucleotides resulted in phenotypes that showed resemblances to L1 patients. However, knockdown of L1.2 expression did not result in notable neural defects. Furthermore, analysis of the expression pattern of L1.1 has led to the discovery of a novel soluble L1.1 isoform, L1.1s. L1.1s is an alternatively spliced form of L1.1, consisting of the first four Ig-like domains and thus a soluble secreted protein. L1.1 morphants exhibited disorganized brain structures with many having an enlarged fourth/hindbrain ventricle. Further characterization revealed aberrations in ventricular polarity, cell patterning and proliferation and helped differentiate the functions of L1.1 and L1.1s. While L1.1 plays a pivotal role in axonal outgrowth and guidance, L1.1s is crucial to brain ventricle formation. Significantly, L1.1s mRNA rescued many anomalies in the morphant brain, but not the trunk phenotypes. Receptor analysis confirmed that L1.1 undergoes heterophilic interactions with neuropilin-1a (Nrp1a). Peptide inhibition studies demonstrated further the involvement of L1.1s in neuroepithelial cell migration during ventricle formation. In the spinal cord, spinal primary motoneurons expressed exclusively the full-length L1.1, and abnormalities in axonal projections of morphants could be rescued only by L1.1 mRNA. Further studies showed that a novel interaction between the Ig3 domain of L1.1 and Unplugged, the zebrafish muscle specific kinase (MuSK), is crucial to motor axonal growth. Together, these results demonstrate that the different parts of L1.1 contribute to the diverse functions of L1.1 in neural development.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurodevelopmental disorders and is characterized by excessive inattention and/or hyperactivity and impulsivity. There is evidence that many children with ADHD experience emotion dysregulation, but little is known about the mechanisms by which children with ADHD develop difficulties with emotion dysregulation. The goal of the present study is to identify early neural and environmental predictors of emotion dysregulation and determine whether these factors interact in contributing to later emotion dysregulation. In this study, children (aged 4-7) with ADHD symptoms and typically developing children participated. Measures of emotion socialization and neural measures of emotion reactivity and regulation were completed at the first visit. Follow-up was conducted 18 months later, and emotion dysregulation was assessed using parent report, child self-report, and observed affect during a frustration task. Supportive and unsupportive emotion socialization, distress reactions, and neural markers of reactivity and regulation (P1, N2, and P3) predicted later emotion dysregulation. Additionally, emotion socialization and neural markers during reactivity interacted in predicting later emotion dysregulation, such that neural markers predicted later emotion dysregulation in the context of low but not high quality emotion socialization. This study has implications for understanding mechanisms by which emotion dysregulation develops in children with ADHD symptoms and will aid in the development of targeted interventions for children with ADHD.

abstract: The WNT signaling pathway plays numerous roles in development and maintenance of adult homeostasis. In concordance with it’s numerous roles, dysfunction of WNT signaling leads to a variety of human diseases ranging from developmental disorders to cancer. WNT signaling is composed of a family of 19 WNT soluble secreted glycoproteins, which are evolutionarily conserved across all phyla of the animal kingdom. WNT ligands interact most commonly with a family of receptors known as frizzled (FZ) receptors, composed of 10 independent genes. Specific interactions between WNT proteins and FZ receptors are not well characterized and are known to be promiscuous, Traditionally canonical WNT signaling is described as a binary system in which WNT signaling is either off or on. In the ‘off’ state, in the absence of a WNT ligand, cytoplasmic β-catenin is continuously degraded by the action of the APC/Axin/GSK-3β destruction complex. In the ‘on’ state, when WNT binds to its Frizzled (Fz) receptor and LRP coreceptor, this protein destruction complex is disrupted, allowing β-catenin to translocate into the nucleus where it interacts with the DNA-bound T cell factor/lymphoid factor (TCF/LEF) family of proteins to regulate target gene expression. However in a variety of systems in development and disease canonical WNT signaling acts in a gradient fashion, suggesting more complex regulation of β-catenin transcriptional activity. As such, the traditional ‘binary’ view of WNT signaling does not clearly explain how this graded signal is transmitted intracellularly to control concentration-dependent changes in gene expression and cell identity. I have developed an in vitro human pluripotent stem cell (hPSC)-based model that recapitulates the same in vivo developmental effects of the WNT signaling gradient on the anterior-posterior (A/P) patterning of the neural tube observed during early development. Using RNA-seq and ChIP-seq I have characterized β-catenin binding at different levels of WNT signaling and identified different classes of β-catenin peaks that bind cis-regulatory elements to influence neural cell fate. This work expands the traditional binary view of canonical WNT signaling and illuminates WNT/β-catenin activity in other developmental and diseased contexts. / Dissertation/Thesis / Doctoral Dissertation Biomedical Engineering 2019

Down syndrome (DS) is a developmental disorder caused by a triplication of human chromosome 21, which contains approximately 550 genes. DS is the most common autosomal aneuploidy occurring with an incidence of 1 in 793 live births. Hallmarks of DS include abnormal central nervous system (CNS) development and function resulting in intellectual disability (ID), motor dysfunction, and early onset Alzheimer’s neuropathology. Studies have elucidated widespread neurohistological abnormalities in brains of fetuses with DS as early as 20 weeks of gestation, suggesting that early dysfunction in neural development may set the stage for exacerbated CNS abnormalities throughout life. Additionally, the complex constellation of symptoms associated with DS changes over the lifespan, particularly in adolescence and in middle to old age. Thus, these periods may represent opportune windows for age-specific therapeutic interventions. Due to ethical and practical constraints, use of human samples is alone insufficient to characterize the etiological underpinnings of DS phenotypes across the lifespan. Furthermore, while human data are instructive for drug development, preclinical trials are necessary for target validation, to establish dosage, and to prove safety and efficacy of any proposed therapeutic. With the advent of mouse models of DS, informative studies on the neurobiology of DS as well as preclinical testing of proposed therapies are possible. Here, we use a multi-pronged approach to assess molecular, neuroanatomical, and behavioral phenotypes indicative of brain and SC function in three distinct mouse models of DS: Ts1Cje, Ts65Dn, and Dp16. We identify neurodevelopment phenotypes, cytoarchitectural aberrations, bioenergetic abnormalities, myelination deficits, and motor/cognitive dysfunction at multiple ages spanning the period between embryonic day 12.5 and 6-7 months in trisomic mice. Additionally, we show that while Ts65Dn mice recapitulate all known phases of histological, functional, and behavioral phenotypes typical of DS starting from prenatal development and into middle age, this is not true for the Ts1Cje or Dp16 models. Lastly, we present promising outcomes of two possible therapies for cognitive and motor dysfunction in Ts65Dn mice. Altogether our findings provide insights into the underlying neurobiology of ID and motor dysfunction in DS and elucidate molecular changes that can be targeted for future therapeutic intervention. / 2018-07-09T00:00:00Z

The full text will be available at the end of the embargo period: 5th March 2027

No description available.

No description available.

The development of the nervous system is a multi-level, time-sensitive process that relies heavily on cell differentiation. However, the molecular mechanisms that control brain development remain poorly understood. We generated a knockout (KO) mouse for the cilia associated gene Spag17. These animals develop hydrocephalus and enlarged ventricles consistent with the role of Spag17 in the motility of ependymal cilia. However, other phenotypes that cannot be explained by this role were also present. Recently, a mutation in Spag17 has been associated with brain malformations and severe intellectual disability in humans. Therefore, we hypothesized that Spag17 plays a crucial role in nervous system development. To investigate this possibility, we first characterized the spatiotemporal expression of Spag17 in the developing brain by using Beta-galactosidase staining and immunohistochemistry. Results showed Spag17 expression in the spinal cord in embryonic E11. By E11.5-12.5 the expression extends to the rhombic lip from the developing hindbrain, as well as to the forebrain and midbrain regions. E14.5-15.5 embryos exhibit an intense expression in the developing ventricles as well as the cerebellum. From E17.5 to birth (P0), the gene is more broadly expressed. We then used a global Spag17 KO mouse model to characterize the function of Spag17 during brain development. Immunohistochemical studies performed in brain sections from E15.5 and P0 time points showed increased expression of the neural progenitor marker Nestin, and reduced expression of mature neuron marker NeuN, increasing positive trend with the young neuron marker Tuj1. Altogether, these findings reveal that Spag17 has a unique spatiotemporal distribution and may be critical for the maturation of neural progenitor cells.

Functional and temporal-spatial studies of Netrin and its receptors have been reported in several species including, M. musculus, D. melanogaster and C. elegans. These studies indicate that Netrins are a family of evolutionarily conserved, secreted proteins that function to elicit the extension and turning responses of axons. Here, I describe the sequences for netrin and its receptors, unc5 and neogenin, in Strongylocentrotus purpuratus and show that the larval nervous system is patterned predictably with respect to cell body and axon location, early in its development. These findings led to a tentative hypothesis that Sp-Netrin functions to guide axonal growth in the larval nervous system. Quantitative PCR indicates that Sp-netrin and Sp-unc5 are expressed prior to neurogenesis, whereas Sp-neogenin is expressed close to the stage at which neurons differentiate. A polyclonal antibody to Sp-Netrin and in situ hybridizations reveal that Sp-Netrin is initially expressed in the vegetal plate, the archenteron and the protein is present on the basal surface of the oral ectoderm in early prism stage embryos. Suppression of Netrin expression, with a morpholino antisense oligonucleotide, results in loss of neurons, loss of ciliary band cells and loss of the oralectoderm markers, Chordin and Goosecoid. These findings suggest that Netrin is responsible for maintaining or differentiating oral and ciliary band ectoderm, which is necessary for neural specification or differentiation. Further study of this model is necessary to determine if Sp-Netrin retains a role in axon guidance.