Molecular and Cellular Neuroscience Commons^™

Roles Of Autism Gene Arid1b In Murine Brain Development And Behavior, Amanda L. Smith

Theses & Dissertations

Autism spectrum disorder (ASD) and intellectual disability (ID) are highly prevalent neurodevelopmental disorders characterized by social and communication deficits, stereotyped behaviors, cognitive dysfunction, and deficits in adaptive behaviors. The pathogenesis underlying these disorders remains unknown, and thus no pharmacologic or genetic therapies are currently available. Recent progress in the field has shown that haploinsufficiency of the AT-rich interactive domain-containing 1B (ARID1B) gene is a genetic cause of ASD and ID. Our lab recently developed an Arid1b knockout mouse model to better study its role in the pathogenesis of these disorders. One theory regarding the cause of neurodevelopmental disorders …

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

A Novel Switch-Like Function Of Delta-Catenin In Dendrite Development, Ryan Baumert

Dissertations & Theses (Open Access)

The formation of neuronal networks in the brain is tightly regulated, and dependent on the morphology of dendrites, the branch-like signal-receiving structures extending from neurons. Disruptions in dendrite development, or dendritogenesis, can lead to the atypical neuronal connectivity associated with multiple neurodevelopmental diseases. My research addresses molecular processes that underlie dendritogenesis via analysis of a pair of novel interactions involving the protein delta-catenin.

In neurons, delta-catenin localizes to dendrites and synapses, where it functions in their development and maintenance. Structurally, delta-catenin possesses a central Armadillo domain and a C-terminal PDZ-binding motif. This motif associates with PDZ domain-containing proteins, and is …

Investigating The Effects Of Excitotoxic Stimuli On The Suprachiasmatic Nucleus, Rachel A. Brandes

Chancellor’s Honors Program Projects

No abstract provided.

Micrornas Are Necessary For Bmp-7-Induced Dendritic Growth In Cultured Rat Sympathetic Neurons, Vidya Chandrasekaran

Vidya Chandrasekaran

Hyaluronan At The Brain-Environment Interface, Donald M. Thevalingam

Dissertations, Theses, and Capstone Projects

Hyaluronan (HA; Hyaluronic Acid), a primary scaffolding component of the brain extracellular matrix, serves as an integral structural component to the brain extracellular space (ECS). The fossorial African naked mole-rat (Heterocephalus glaber; NM-R), a mammal which lives in a low-oxygen environment and is capable of tolerating hypoxia and hypercapnia, has been shown to synthesize and sustain a unique high-molecular-mass variant of hyaluronan macromolecule (HMM-HA). This body of work highlights HA’s role in mediating the interplay between brain ECM composition, ECS structure, and cell viability.

Here we employ the NM-R as a unique animal model to observe the role of the …

The Functional Conservation Of Frazzled In Insects, Benjamin Wadsworth

Graduate Theses and Dissertations

Axons in the developing embryo receive and react to signals that direct their growth to reach target tissues at specified locations. The signal pathways that direct midline crossing of axons during embryonic development have been comprehensively examined in the past years using the Drosophila ventral nerve cord or the spinal cord as a model system. A number of these signaling mechanisms are conserved, however disparities have been found between species in general strategy or the molecular signals controlling the response of axons to guidance cues.

The Netrin-Frazzled pathway has been shown to aid in midline crossing of axons in the …

The Functional And Structural Analysis Of Drosophila Robo2 In Axon Guidance, Lafreda Janae Howard

Graduate Theses and Dissertations

In animals with complex nervous systems such as mammals and insects, signaling pathways are responsible for guiding axons to their appropriate synaptic targets. Importantly, when this process is not successful during the development of an organism, outcomes include catastrophes such as human neurological diseases and disorders. It is vital to determine the underlying causes of such diseases by understanding the development of the nervous system. There are many pathways that have been identified to play a role in this, however, we lack an understanding of how these pathways can promote such diverse outcomes in different populations of neurons. These pathways …

Comparison Of Nickel And Cobalt Induced Hypoxic Cell Models Using Cell Proliferation Assay, Melissa Delcasale

Seton Hall University Dissertations and Theses (ETDs)

Hypoxia is an imbalance in oxygen delivery and oxygen consumption, ultimately affecting cell survival. Low levels of oxygen diminish adenosine triphosphate synthesis resulting from a decline in oxidative phosphorylation in the mitochondria, therefore inducing apoptosis and cell death. To create a hypoxia mimicked environment, we used hypoxia mimetic compounds cobalt and nickel to treat human neuroblastoma (NMB) cells. Using hypoxic mimic human neuronal cell models, we examined and compared the effects of compound-induced hypoxia on NMB cell proliferation. The cells were treated with 100mM and 300mM concentrations of each compound at 24- and 48-hour intervals. To investigate cell proliferation, the …

Evolutionary Expansions And Neofunctionalization Of Ionotropic Glutamate Receptors In Cnidaria, Ellen G. Dow

FIU Electronic Theses and Dissertations

Reef ecosystems are composed of a variety of organisms, transient species of fish and invertebrates, microscopic bacteria and viruses, and structural organisms that build the living foundation, coral. Sessile cnidarians, corals and anemones, interpret dynamic environments of organisms and abiotic factors through a molecular interface. Recognition of foreign molecules occurs through innate immunity via receptors identifying conserved molecular patterns. Similarly, chemosensory receptors monitor the environment through specific ligands. Chemosensory receptors include ionotropic glutamate receptors (iGluRs), transmembrane ion channels involved in chemical sensing and neural signal transduction. Recently, an iGluR homolog was implicated in cnidarian immunological resistance to recurrent infections of …

Novel Characterization Of The Role Of Orthologous Xap5 In Caenorhabditis Elegans, Nabor Vazquez

Lawrence University Honors Projects

Cilia are one of the oldest and most well conserved cellular organelles. Cilia provide an essential role in cellular locomotion, fluid regulation, and are a site for signal transduction pathways involved in sensation. A new study suggests that XAP5 is a transcription factor in a unicellular organism, Chlamydomonas reinhardtii, which regulates gene expression needed for proper cilium assembly. Our study investigates the conservation of the role of XAP5 in a multicellular system, Caenorhabditis elegans. Alignments between protein, coding region, and promoter sequences for XAP5 orthologs from related species show a good conservation in DNA and protein sequences. As part of …

Targeted Genome-Scale Gene Activation And Gene Editing In Human Cells To Understand Disease Models, Michael De La Cruz

KGI Theses and Dissertations

Since the discovery of sequence directed DNA editing reagents such as CRISPR-Cas9 RNA-guided and TALEN DNA endonucleases, there has been a snowball of advances in the life sciences due to the ability to efficiently edit and control genomes within living cells. CRISPR-Cas9 based genomic tools, which facilitate the high-throughput precise manipulation of genes, allow for unbiased functional genomic screens. We used a human CRISPR-Cas9 Synergistic Activation Mediator pooled library which utilizes an engineered protein complex for transcriptional activation of 23,430 endogenous genes to investigate the development of novel resistance mechanisms to lung cancer targeted therapy, Erlotinib. We set out to …

Towards A Better Understanding Of Temporomandibular Disorder, Jessica R. Cox

MSU Graduate Theses

Results from the OPPERA study provided evidence that risk factors such as neck muscle tension, prolonged jaw opening, and female gender increase the likelihood of developing temporomandibular joint disorders (TMJD), which are prevalent, debilitating orofacial pain conditions. Peripheral and central sensitization, which mediate a lowering of the stimulus required for pain signaling, are implicated in the underlying pathology of chronic TMJD. The goal of my study was to investigate cellular changes in the expression of proteins associated with the development of central sensitization. Female Sprague-Dawley rats were injected with complete Freund’s adjuvant in the upper trapezius muscles to promote trigeminal …

Notch Inhibitors And The Bet Inhibitor Jq-1 Decrease The Growth Of Primary Tumor Cells Derived From A Novel Mouse Model Of C11orf95-Rela Induced Brain Tumor, Ericka Randazzo, Jesse Dunnack, Justin Fang, Joseph Loturco Phd

University Scholar Projects

Brain tumors are the most common childhood solid malignancy, and because of remarkable advances in treating many cancers outside of the brain, they have become the leading cause of cancer mortality in children. Ependymomas are a class of brain tumors which can be further subdivided into three groups based upon their location and genetic features. Of the three classes, supratentorial ependymomas are the only subgroup known to be marked by an oncogenic driver gene, which consists of a fusion mutation between the C11orf95 and RELA genes. C11orf95-RELA positive tumors are the most aggressive and lethal of …

The 5-Ht1a-R Knockout Mouse As A Model Of Later Life Anxiety Disorders: Implications For Sex Differences, Tatyana Budylin

Dissertations, Theses, and Capstone Projects

Anxiety affects nearly twice as many women as it affects men across all cultures and economic groups. Importantly, girls have a higher chance of inheriting anxiety disorders than boys, and many anxiety disorders appear at a very young age. However, little is known about sex differences in brain and behavioral development and how they relate to anxiety in adulthood. Serotonin 1A receptor (5-HT_1A-R) mediated signaling has been implicated in depression and anxiety, however most studies that focus on the involvement of the 5-HT_1A-R have been conducted in adults. Little is known about how the 5-HT_{1A …}

A Novel Kinesin Adapter Directly Mediates Dendritic Mrna Localization During Synapse Development, Hao Wu

Dissertations, Theses, and Capstone Projects

Cytoskeleton based active transport with motor proteins is essential for mRNA localization and local protein translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased screen for interaction between mRNA binding proteins (RBP) and motor proteins, we identified protein interacting with APP tail 1 (PAT1) as a potential direct adapter between the β-actin mRNA Zipcode-binding protein 1 (ZBP1) and Kinesin-1 motor complex.

Mouse PAT1 is similar to the Kinesin Light Chain (KLC) in amino acid sequence and binds directly to KLC. High-resolution images from structured illumination microscopy (SIM) indicates that synaptic stimulation …

The Role Of Ash1l During Human Neurodevelopment, Anna Bagnell

Senior Theses

Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. A significant proportion of ASD cases are of complex genetic etiology; complexity which might reflect the impact of gene-environment interactions. However, there is a gap in our understanding of the mechanisms that underlie the gene-environment interaction in autism complex etiology. Genome wide association studies in large ASD cohorts identified high risk variants associated with autism in genes that regulate histone modifications and remodel chromatin. These findings highlight the relevance of chromatin regulatory mechanisms in the pathology of ASD. Changes in Histone H3 methylation have been …

The Drosophila Neuroblasts: A Model System For Human Ribosomopathies, Sonu Shrestha Baral

LSU Doctoral Dissertations

This dissertation describes the use of Drosophila neuroblasts (NBs) to model human ribosomopathies; the overall goal is to understand why specific stem cell and progenitor cell populations are the primary targets in nucleolar stress as seen in the ribosomopathies. Chapter 1 provides an overview of relevant literature. Chapter 2 describes nucleolar stress in Drosophila neuroblasts as a model for human ribosomopathies. For this, we induce nucleolar stress by using the UAS-GAL4 system to express RNAi that depletes Nopp140 transcripts, and we also employ homozygous, CRISPR-Cas9-generated Nopp140 gene disruptions with a systemic null phenotype (Nopp140-/-). Embryonic lethality was observed …

The Integration Of Multiple Sources Of Sonic Hedgehog In The Spinal Cord Contribute To The Production Of First-Born Oligodendrocyte Precursor Cells Which Become Critical For Synapse Remodeling In Response To Adult Motor Neuron Injury, Lev Starikov

Dissertations, Theses, and Capstone Projects

Oligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here I show that interrupting Sonic hedgehog (Shh) signaling originating from nascent ventricular zone derivatives (VZD), motor neurons and the lateral floor plate, almost completely blocks ventral but not dorsal oligodendrogenesis without noticeably affecting early tissue patterning and embryonic development. In the absence of ventral OPCs, dorsal OPCs increase proliferation and populate the entire spinal cord with increased density. In these mutant mice, dOPCs take …

Molecular Analysis Of Cone Photoreceptor Genesis From A Specific Retinal Progenitor Population, Diego F. Buenaventura

Dissertations, Theses, and Capstone Projects

There are two types of photosensitive cells of the retina that contribute to image formation: Cone photoreceptors that mediate color discrimination and rods that provide photosensitivity in low-light conditions. Given the importance of cones in high acuity and color vision, deficiencies in this cell type that result from ailments such as retinitis pigmentosa and macular degeneration can lead to a debilitating loss of vision. Currently, one of the most pressing goals in the field of retinal development is the elucidation of the gene regulatory networks (GRN) involved in inducing an undifferentiated cell into becoming a functional cone photoreceptor.

Recently, an …

The Effects Of A Ketone Body On Synaptic Transmission, Alexandra Elizabeth Stanback

Theses and Dissertations--Biology

The ketogenic diet is commonly used to control epilepsy, especially in cases when medications cannot. The diet typically consists of high fat, low carb, and adequate protein and produces a metabolite called acetoacetate. Seizure activity is characterized by glutamate excitotoxicity and therefore glutamate regulation is a point of research for control of these disorders. Acetoacetate is heavily implicated as the primary molecule responsible for decreasing glutamate in the synapse; it is believed that acetoacetate interferes with the transport of glutamate into the synaptic vesicles. The effects on synaptic transmission at glutamatergic synapses was studied in relation to the ketogenic diet …

Mutations Of Fus Cause Aggregation Of Rna Binding Proteins, Disruptions In Protein Synthesis, And Dysregulation Of Nonsense Mediated Decay, Marisa Elizabeth Kamelgarn

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death and subsequent muscle atrophy. Approximately 15% of ALS cases are inheritable, and mutations in the Fused in Sarcoma (FUS) gene contribute to approximately 5% of these cases, as well as about 2% of sporadic cases. FUS performs a diverse set of cellular functions, including being a major regulator of RNA metabolism. FUS undergoes liquid- liquid phase transition in vitro, allowing for its participation in stress granules and RNA transport granules. Phase transition also contributes to the formation of cytoplasmic inclusions found in the …

Spag17 Deficiency Impairs Neuronal Cell Differentiation In Developing Brain, Olivia J. Choi

Theses and Dissertations

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 …