Molecular and Cellular Neuroscience Commons^™

Reactive Oxygen Species-Mediated Neurodegeneration Is Independent Of The Ryanodine Receptor In Caenorhabditis Elegans, Lyndsay E.A. Young, Daniel C. Williams

Journal of the South Carolina Academy of Science

Despite the significant impacts on human health caused by neurodegeneration, our understanding of the degeneration process is incomplete. The nematode Caenorhabditis elegans is emerging as a genetic model organism well suited for identification of conserved cellular mechanisms and molecular pathways of neurodegeneration. Studies in the worm have identified factors that contribute to neurodegeneration, including excitotoxicity and stress due to reactive oxygen species (ROS). Disruption of the gene unc-68, which encodes the ryanodine receptor, abolishes excitotoxic cell death, indicating a role for calcium (Ca²⁺) signaling in neurodegeneration. We tested the requirement for unc-68 in ROS-mediated neurodegeneration using the …

Characterizing The Rogfp2-Orp1 Fluorescent Biosensor For Detecting Oxidative Stress In Mammalian Cells, Sara A. Doan, Stevie Norcross, Mathew Tantama

The Summer Undergraduate Research Fellowship (SURF) Symposium

Parkinson’s disease is a neurodegenerative disease involving the death of neurons in the substantia nigra and loss of the neurotransmitter, dopamine. The disease leads to progressive loss of motor control. Exact causes and mechanisms by which Parkinson’s disease proceeds are unknown, however, previous experiments determine oxidative stress in mitochondria as a factor that results in cell death. Strategies have been implemented to generate fluorescent biosensors to monitor reactive oxygen species (ROS) concentrations while simultaneously measuring the spatiotemporal distribution and correlation between the ROS, cellular function and organelle. Orp1, an enzyme found in yeast, is a sensitive oxidizing species and when …

Characteristics Of Exocytosis And Endocytosis In Photoreceptors, Karlene M. Cork

Theses & Dissertations

Photoreceptors signal changes in light intensity to downstream retinal neurons through the exocytosis of glutamate-containing synaptic vesicles. The maintenance of the vesicle exocytosis and endocytosis process is essential for ongoing synaptic signaling. This study investigated the properties of exocytosis and endocytosis in photoreceptors and their role in ongoing neurotransmission.

I used electrophysiology and imaging techniques to study the properties of vesicle exocytosis and endocytosis in photoreceptors. First, we examined baseline release in photoreceptors that occurs in the absence of depolarizing stimulation. We measured mEPSCs in whole cell patch clamp recordings from horizontal cells. After inhibiting Ca²⁺ influx and efflux …

A Screen To Identify Saga-Activated Genes That Are Required For Proper Photoreceptor Axon Targeting In Drosophila Melanogaster, Kaelan J. Brennan, Vikki M. Weake, Jingqun Q. Ma

The Summer Undergraduate Research Fellowship (SURF) Symposium

The inherited human genetic disease spinocerebellar ataxia type 7 (SCA7) is characterized by progressive neurodegeneration and visual impairment that ultimately leads to blindness. SCA7 results from a mutation in the human ATXN7 gene that causes an expansion of polyglutamine tracts in this gene’s corresponding protein. Human ATXN7 protein serves as a component of the deubiquitylase (DUB) module of the large, multi-subunit complex Spt-Ada-Gcn acetyltransferase, or SAGA. SAGA is a transcriptional coactivator and histone modifier that functions to deubiquitylate histone H2B and allow for transcription of SAGA-mediated genes to occur. In Drosophila, mutations in SAGA DUB’s Nonstop and sgf11 components …

Analysis Of Mitochondrial Turnover In Neuromuscular Junctions Of Parkin Mutants, Kenny Nguyen, Hyun Sung, Peter J. Hollenbeck

The Summer Undergraduate Research Fellowship (SURF) Symposium

The accumulation of dysfunctional or damaged mitochondria in neurons has been linked to the pathogenesis of many neurodegenerative diseases, such as Parkinson’s disease. It has been proposed that proteins PINK1 and Parkin regulate mitochondrial quality control by selectively targeting depolarized mitochondria for autophagic degradation, a process known as mitophagy. Though previously analyzed in the cell bodies and axons of neurons, the role of the PINK1/Parkin pathway in the synapse is unclear, and it is not known whether mitochondrial turnover occurs in the neuromuscular junctions (NMJs). To study this, intact Drosophila nervous systems were analyzed in vivo by performing gentle dissections …

Hippocalcin Response To Calcium: Do Conserved Tryptophans – W30 Or W103 – Matter?, Sunkesula K. Sagar

Graduate School of Biomedical Sciences Theses and Dissertations

Changes in intracellular calcium levels play a very important role in cell signaling, in turn, affecting neuronal functions such as memory, learning and cell death. A class of proteins called Neuronal Calcium Sensor (NCS) proteins serves to modulate the functioning of the neuronal cells in response to changes in calcium levels, and prevent neuronal apoptosis. Structurally, all NCS proteins have 4 calcium-binding EF hand motifs, although EF1 does not bind to calcium in many members. All NCS proteins have an acyl modification at the N- terminus – where a myristoyl group is added post-translationally. Hippocalcin (HPCA) is an NCS protein, …

Canonical Bmp Signaling Is Required For Allodynia In Drosophila Melanogaster, Taylor L. Follansbee

All Theses And Dissertations

In the United States alone over 100 million people suffer from chronic pain and unfortunately, even still, there is a lack in scientific understanding for the mechanisms of abnormal pain sensitivity. The present study utilized a candidate gene approach to identify novel components required for modulation of the tissue damage induced pain sensitization pathway in Drosophila melanogaster. We have shown that RNAi silencing of decapentaplegic (dpp), a member of the Bone Morphogenetic Protein (BMP) signaling pathway, specifically in the class IV multidendritic nociceptor neurons significantly attenuated UV-induced nociceptive sensitization. Furthermore, overexpression of dpp in nociceptor neurons was sufficient to …

Structure And Composition Of Postsynaptic Densities, Madeline Farley

Dissertations and Theses (Open Access)

Communication between neurons within the brain occurs at chemical synapses and is fundamental for all brain functions. Modulation of the strength of communication is controlled by both presynaptic and postsynaptic mechanisms and is termed synaptic plasticity. One postsynaptic structure postulated to regulate synaptic strength is the postsynaptic density (PSD), a large electron dense protein complex located just below the synaptic membrane. The PSD, which is composed of signaling, scaffold and cytoskeletal proteins, supports and organizes neurotransmitter receptors within the synaptic membrane in addition to bridging signaling with the actin cytoskeletal network. The protein composition and structure of PSDs is known …

Inverse Changes In Ghrelin And A2a Receptor Gene Expression Levels In The Hippocampus Of Heart Failure Canines Following Spinal Cord Stimulation, Benjamin E. Jewett

Undergraduate Honors Theses

Myocardial infarction (MI), often referred to as a heart attack, is a serious health issue in the United States. There is a well-documented link between MI and major depressive disorder (MDD), with a high incidence of MDD occurring after an MI. Overlapping pathologies have been observed within the hippocampus of the brain in animal models of MI and depression. These observations suggest that pathobiological cross-talk between the heart and brain could have a role in the etiology of MDD that occurs after an MI. Spinal cord stimulation (SCS) has previously been shown to have both cardioprotective and neuroprotective effects post-MI, …

Exercise-Induced Adult Neruogenesis And The Seizure Threshold: The Role Of Cox-2, Gina Kim

Renée Crown University Honors Thesis Projects - All

Neurogenesis, the generation of new neurons, is most prevalent when the brain is being formed during pre-natal development. However, this process continues in select areas in the brain during adult life as well. One such area in the brain is the dentate gyrus (DG) of the hippocampus, an area known to be associated with learning and memory. In this region, neurogenesis is believed to contribute to neuroplasticity as well as improving its functions in learning and memory. Interestingly, this synthesis of neurons is increased by physical activity—predominantly running—and by seizures originating in the limbic system. The increased excitatory neuronal activity …

Pathological Effects Of Repeated Concussive Tbi In Mouse Models: Periventricular Damage And Ventriculomegaly, Richard H. Wolferz Jr.

Honors Scholar Theses

Repeated concussive traumatic brain injury (rcTBI) is the most prominent form of head injury affecting the brain, with an estimated 1.7 million Americans affected each year (Kuhn 2012). Neurologists have been concerned about the danger of repeated head impacts since the 1920’s, but researchers have only begun to understand the long-term effects of rcTBI (McKee 2009). Although symptoms can be as mild as dizziness, current research suggests that multiple concussions can lead to a progressive degenerative brain disease known as chronic traumatic encephalopathy (CTE) (Luo 2008, McKee 2009, Kane 2013). Research on the brain is just beginning to scratch the …

Death Associated Protein Kinase (Dapk) -Mediated Neurodegenerative Mechanisms In Nematode Excitotoxicity, John S. Del Rosario, Katherine Genevieve Feldmann, Towfiq Ahmed, Uzair Amjad, Bakkeung Ko, Junhyung An, Tauhid Mahmud, Maha Salama, Shirley Mei, Daniel Asemota, Itzhak Mano

Publications and Research

Background: Excitotoxicity (the toxic overstimulation of neurons by the excitatory transmitter Glutamate) is a central process in widespread neurodegenerative conditions such as brain ischemia and chronic neurological diseases. Many mechanisms have been suggested to mediate excitotoxicity, but their significance across diverse excitotoxic scenarios remains unclear. Death Associated Protein Kinase (DAPK), a critical molecular switch that controls a range of key signaling and cell death pathways, has been suggested to have an important role in excitotoxicity. However, the molecular mechanism by which DAPK exerts its effect is controversial. A few distinct mechanisms have been suggested by single (sometimes contradicting) studies, and …

Neuroinflammation And J2 Prostaglandins: Linking Impairment Of The Ubiquitin-Proteasome Pathway And Mitochondria To Neurodegeneration, Maria E. Figueiredo-Pereira, Patricia Rockwell, Thomas Schmidt-Glenewinkel, Peter Serrano

Publications and Research

The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly …

Pcdh19 Expression In Normal And Regenerating Adult Zebrafish Retinas, Kristin N. Forkapa Ms.

Williams Honors College, Honors Research Projects

My Honors Research Project will test the function of the N-cadherin molecule on the zebrafish optic nerve regeneration. N-cadherin is a member of the cadherin superfamily. Cadherins are cell adhesion molecules important for animal development and maintenance of adult structures. Unlike mammals, fish and amphibians have the ability to regenerate their optic nerve after damages. Molecular mechanisms underlying the optic nerve regeneration are still under intense investigation. Studies in Dr. Liu’s laboratory showed that expression of several cadherins, including N-cadherin, was greatly increased during adult zebrafish optic nerve regeneration, suggesting that cadherins may be involved in the optic nerve regeneration …

Targeting Methylglyoxal And Ppar Gamma To Alleviate Neuropathic Pain Associated With Type 2 Diabetes, Ryan B. Griggs

Theses and Dissertations--Physiology

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance …

Signals From The 4th Dimension: Role Of Extracellular Matrix Signaling In Synaptic Plasticity Mediating Addiction, Alexander C. W. Smith

MUSC Theses and Dissertations

Chronic cocaine abuse causes maladaptive neuroadaptations that underlie vulnerability to relapse, even after protracted abstinence. A great deal of work has examined mechanisms of neuroplasticity by which these occur. However, the majority of experimentation has focused on intracellular signaling cascades, while the extracellular compartment has been largely ignored. In the past decade, work has emerged in the learning and memory literature that indicates that extracellular matrix remodeling and signaling is required for adaptive forms of neuroplasticity (e.g. learning and memory), although it has not been thoroughly examined in models of maladaptive neuroplasticity. Throughout this dissertation a drug self-administration, extinction and …

Elucidating The Role Of Endogenous Electric Fields In Regulating The Astrocytic Response To Injury In The Mammalian Central Nervous System, Matthew L. Baer

Theses and Dissertations

Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the …

Gliopathy Of Demyelinating And Non-Demyelinating Strains Of Mouse Hepatitis Virus, Lawrence Charles Kenyon, Kaushiki Biswas, Kenneth Shindler, Manasi Nabar, Marjorie Stout, Susan T. Hingley, Judith B. Grinspan, Jayasri Das Sarma

PCOM Scholarly Works

Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white …

Clique Topology Reveals Intrinsic Geometric Structure In Neural Correlations, Chad Giusti, Eva Pastalkova, Carina Curto, Vladimir Itskov

Department of Mathematics: Faculty Publications

Detecting meaningful structure in neural activity and connectivity data is challenging in the presence of hidden nonlinearities, where traditional eigenvalue-based methods may be misleading. We introduce a novel approach to matrix analysis, called clique topology, that extracts features of the data invariant under nonlinear monotone transformations. These features can be used to detect both random and geometric structure, and depend only on the relative ordering of matrix entries. We then analyzed the activity of pyramidal neurons in rat hippocampus, recorded while the animal was exploring a 2D environment, and confirmed that our method is able to detect geometric organization using …

An Epigenetic Hypothesis For The Genomic Memory Of Pain, Sebastian Alvarado, Maral Tajerian, Matthew Suderman, Ziv Machnes, Stephanie Pierfelice, Magali Millecamps, Laura S. Stone, Moshe Szyf

Publications and Research

Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA,serve as a “genomic” memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC). We have previously reported …

Enhanced Cgmp-Dependent Signaling In Astrocytes: Novel Therapeutic Target In Alzheimer's Disease, Nyema M. Woart

PCOM Biomedical Studies Student Scholarship

Over five million Americans suffer from Alzheimer’s Disease (AD), with an expected 34% increase in the incidence in this disease over the next decade. Unfortunately, there is no cure for AD. Recent studies have indicated that drugs which increase the levels of cyclic guanosine-3’5’-monophosphate (cGMP) may help preserve learning and memory in AD and enhance cognition in the aging brain; however, the mechanism(s) of how cGMP exerts this beneficial effect is unknown. The present findings now suggest that elevation of cGMP in astrocytes depresses inhibitory potassium currents in these cells to stimulate their protective influence on neuronal activity. Cellular currents …

Glutamatergic Neurotransmission In The Prefrontal Cortex Mediates The Suppressive Effect Of Intra-Pfc Infusion Of Bdnf On Cocaine-Seeking, Bok Soon Go

MUSC Theses and Dissertations

Infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) immediately after the last session of cocaine self-administration prevents cocaine-mediated malfunction of synaptic modulation in the dmPFC that mediates relapse to cocaine-seeking through both GluN2A subunit-containing NMDA receptors and GluN2B subunit-containing NMDA receptors (NMDARS). Intra-dmPFC BDNF is known to suppress cocaine-seeking by normalization of cocaine self-administration- induced disturbance of glutamatergic transmission in the nucleus accumbens (NAc) and by prevention of the cocaine self-administration-induced decrease in extracellular signal-regulated kinase (ERK) activity in the dmPFC through activation of tyrosine receptor kinase B (TrkB). Neuronal activity is required for BDNF-induced ERK activation and the …

Gene Expression And Alzheimer's Disease: Evaluation Of Gene Expression Patterns In Brain And Blood For An Alzheimer's Disease Mouse Model, Amanda Hazy

Senior Honors Theses

Previous studies have established a causative role for altered gene expression in development of Alzheimer’s disease (AD). These changes can be affected by methylation and miRNA regulation. In this study, expression of miRNA known to change methylation status in AD was assessed by qPCR. Genome-wide expression changes were determined by RNA-sequencing of mRNA from hippocampus and blood of control and AD mice. The qPCR data showed significantly increased expression of Mir 17 in AD, and sequencing data revealed 230 genes in hippocampus, 58 genes in blood, and 8 overlapping genes showing significant differential expression (p value ≤ 0.05). Expression data …

Characterization Of The Trans-Plasma Membrane Electron Transport System In The Myelin Membrane, Afshan Sohail

Theses and Dissertations (Comprehensive)

Myelination is the key feature of evolution in the nervous system of vertebrates. Myelin is the protrusion of glial cells. More specifically, "oligodendrocytes" in the central nervous system (CNS), and "Schwann" cells in the peripheral nervous system (PNS) form myelin membranes. Myelin remarkably, enhances the propagation of nerve impulses. However, myelin restricts the access of extracellular metabolites to the axons. A pathology called "demyelination" is associated with myelin. The myelin sheath is not only an insulator, but it is itself metabolically active. In this study it is hypothesized that the ratio of NAD(P)⁺/NAD(P)H and the glycolytic pathway of …