Molecular and Cellular Neuroscience Commons^™

Differential Expression Of Genes Related To Innate Immune Responses In Ex Vivo Spinal Cord And Cerebellar Slice Cultures Infected With West Nile Virus, Amber M. Paul, Parminder J.S. Vig, Deyin Lu, Ram Kuwar, Maria Lopez, Dobrivoje S. Stokic, A. Arturo Leis, Michael R. Garrett, Fengwei Bai

Publications

West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While neurons are a main target of WNV, other cell types, especially astrocytes, play an important role in promoting WNV-mediated central nervous system (CNS) damage. Conversely, it has been shown that cultured primary astrocytes secrete high levels of interferons (IFNs) immediately after WNV exposure to protect neighboring astrocytes, as well as neurons. However, how intrinsic responses to WNV …

Stress-Induced Heat Shock Protein 40 And Immune Function In Altered Gravity, Amber M. Paul, Brooke D. Shepard, Sharmila Bhattacharya

Publications

In space, astronauts are more susceptible to pathogens, viral reactivation and immunosuppression, which poses limits to their health and the mission. Interestingly, during space flight, stress-inducible heat shock proteins (HSP) are robustly induced, and the overexpression of HSPs have been implicated in immune dysregulation, therefore HSPs may be critically involved in regulating immune homeostasis. HSP40/DNAJ1 plays a major role in proper protein translation and folding. Its loss of function has been implicated in susceptibility to microbial infection, while its overexpression has been implicated in autoimmunity, collectively suggesting its complicated, but necessary, role in maintaining immunological function. To determine the role …

Spinal Cord Trauma: An Overview Of Normal Structure And Function, Primary And Secondary Mechanisms Of Injury, And Emerging Treatment Modalities, Daniel Morin

Senior Honors Theses

The structures of the spinal cord and vertebral column are designed to provide flexibility, while still providing ample protection for the spinal cord deep within. While it does offer remarkable protection against most routine trauma, the spinal cord is still vulnerable to high-force etiologies of trauma and may become damaged as a result. These events are referred to as primary injury. Following the initial injury, the body’s own physiological responses cause a cascade of deleterious effects, known as secondary injury. Secondary injury is a major therapeutic target in mitigating the effects of spinal cord injury (SCI), and much research is …

Calnexin Is Necessary For T Cell Transmigration Into The Central Nervous System, Amber M. Paul, Joanna Jung, Paul Eggleton, Alison Robinson, Jessica Wang, Nick Gutowski

Publications

In multiple sclerosis (MS), a demyelinating inflammatory disease of the CNS, and its animal model (experimental autoimmune encephalomyelitis; EAE), circulating immune cells gain access to the CNS across the blood-brain barrier to cause inflammation, myelin destruction, and neuronal damage. Here, we discovered that calnexin, an ER chaperone, is highly abundant in human brain endothelial cells of MS patients. Conversely, mice lacking calnexin exhibited resistance to EAE induction, no evidence of immune cell infiltration into the CNS, and no induction of inflammation markers within the CNS. Furthermore, calnexin deficiency in mice did not alter the development or function of the immune …

Methylglyoxal Requires Ac1 And Trpa1 To Produce Pain And Spinal Neuron Activation, Ryan B. Griggs, Don E. Laird, Renee R. Donahue, Weisi Fu, Bradley K. Taylor

Physiology Faculty Publications

Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated …

A Customized Quantitative Pcr Microrna Panel Provides A Technically Robust Context For Studying Neurodegenerative Disease Biomarkers And Indicates A High Correlation Between Cerebrospinal Fluid And Choroid Plexus Microrna Expression, Wang-Xia Wang, David W. Fardo, Gregory A. Jicha, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNA (miRNA) expression varies in association with different tissue types and in diseases. Having been found in body fluids including blood and cerebrospinal fluid (CSF), miRNAs constitute potential biomarkers. CSF miRNAs have been proposed as biomarkers for neurodegenerative diseases; however, there is a lack of consensus about the best candidate miRNA biomarkers and there has been variability in results from different research centers, perhaps due to technical factors. Here, we sought to optimize technical parameters for CSF miRNA studies. We examined different RNA isolation methods and performed miRNA expression profiling with TaqMan® miRNA Arrays. More specifically, we developed a customized …

P2x2 Dominant Deafness Mutations Have No Negative Effect On Wild-Type Isoform: Implications For Functional Rescue And In Deafness Mechanism, Yan Zhu, Juline Beudez, Ning Yu, Thomas Grutter, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

The P2X2 receptor is an ATP-gated ion channel, assembled by three subunits. Recently, it has been found that heterozygous mutations of P2X2 V60L and G353R can cause autosomal dominant nonsyndromic hearing loss. However, the underlying mechanism remains unclear. The fact that heterozygous mutations cause deafness suggests that the mutations may have dominant-negative effect (DNE) on wild-type (WT) P2X2 isoforms and/or other partners leading to hearing loss. In this study, the effect of these dominant deafness P2X2 mutations on WT P2X2 was investigated. We found that sole transfection of both V60L and G353R deafness mutants could efficiently target to the plasma …

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers, Fei Tang, Anika M. S. Hartz, Björn Bauer

Pharmaceutical Sciences Faculty Publications

Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against …

Hypothesis Of K+-Recycling Defect Is Not A Primary Deafness Mechanism For Cx26 (Gjb2) Deficiency, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

K⁺-recycling defect is a long-standing hypothesis for deafness mechanism of Connexin26 (Cx26, GJB2) mutations, which cause the most common hereditary deafness and are responsible for >50% of nonsyndromic hearing loss. The hypothesis states that Cx26 deficiency may disrupt inner ear gap junctions and compromise sinking and recycling of expelled K⁺ ions after hair cell excitation, causing accumulation of K⁺-ions in the extracellular space around hair cells producing K⁺-toxicity, which eventually induces hair cell degeneration and hearing loss. However, this hypothesis has never been directly evidenced, even though it has been widely referred …

Encoding Of Saltatory Tactile Velocity In The Adult Orofacial Somatosensory System, Rebecca Custead

College of Education and Human Sciences: Dissertations, Theses, and Student Research

Processing dynamic tactile inputs is a key function of somatosensory systems. Spatial velocity encoding mechanisms by the nervous system are important for skilled movement production and may play a role in recovery of motor function following neurological insult. Little is known about tactile velocity encoding in trigeminal networks associated with mechanosensory inputs to the face, or the consequences of movement.

High resolution functional magnetic resonance imaging (fMRI) was used to investigate the neural substrates of velocity encoding in the human orofacial somatosensory system during unilateral saltatory pneumotactile inputs to perioral hairy skin in 20 healthy adults. A custom multichannel, scalable …

Interaction Of Tau With The Rna-Binding Protein Tia1 Regulates Tau Pathophysiology And Toxicity, Tara Vanderweyde, Daniel J. Apicco, Katherine Youmans-Kidder, Peter E. A. Ash, Casey Cook, Edroaldo Lummertz Da Rocha, Karen Jansen-West, Alissa A. Frame, Allison Citro, John D. Leszyk, Pavel Ivanov, Jose F. Abisambra, Martin Steffen, Hu Li, Leonard Petrucelli, Benjamin Wolozin

Sanders-Brown Center on Aging Faculty Publications

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown …

Utilization Of The Clinical Laboratory For The Implementation Of Concussion Biomarkers In Collegiate Football And The Necessity Of Personalized And Predictive Athlete Specific Reference Intervals, Stefanie Podlog (Nee Schulte), Natalie N. Rasmussen, Joseph W. Mcbeth, Patrick Q. Richards, Eric Yochem, David J. Petron, Frederick G. Strathmann

Athletic Training Collection

Background: A continued interest in concussion biomarkers makes the eventual implementation of identified biomarkers into routine concussion assessment an eventual reality. We sought to develop and test an interdisciplinary approach that could be used to integrate blood-based biomarkers into the established concussion management program for a collegiate football team.

Methods: We used a CLIA-certified laboratory for all testing and chose biomarkers where clinically validated testing was available as would be required for results used in clinical decision making. We summarized the existing methods and results for concussion assessment across an entire season to identify and demonstrate the challenges with the …

Role Of The Calcium Plateau In The Neuronal Injury And Behavioral Morbidities Following Organophosphate Intoxication, Laxmikant S. Deshpande, Robert E. Blair, Kristin F. Phillips, Robert J. Delorenzo

Neurology Publications

Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular …

Cannabinoid Receptor Interacting Protein Suppresses Agonist-Driven Cb1 Receptor Internalization And Regulates Receptor Replenishment In An Agonist-Biased Manner, Lawrence C. Blumes, Sandra Leone-Kabler, Deborah J. Luessen, Glenn S. Marrs, Erica Lyons, Caroline E. Bass, Rong Chen, Dana E. Selley, Allyn C. Howlett

Neurology Publications

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that modulates CB1R signaling via G proteins, and CB1R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB(1)Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown …

Vitamin D Clinical Relevance In The Recovery From Traumatic Brain Injury Among The Military Population, Yuisa M. Colón

Honors Undergraduate Theses

Background: Traumatic brain injury (TBI) still remains a difficult disorder to treat. TBI has been associated to chronic neuroinflammation and a high risk for neurodegenerative disorders. Since 2001 between ten to twenty percent of all deployed military members have suffered a combat-related TBI. Nearly twenty to thirty percent of those will experience chronic cognitive, behavioral and somatic symptoms after suffering a TBI.
Methods: The objective of this review is to evaluate current literature examining vitamin D as a neurosteroid with protective properties and its clinical relevance after traumatic brain injury. Vitamin D is known to participate in neurobiological …

Analysis Of Differential Mrna And Mirna Expression In An Alzheimer’S Disease Mouse Model, Amanda Hazy, Matthew Dalton

Other Undergraduate Scholarship

Research has shown that changes in gene expression play a critical role in the development of Alzheimer’s Disease (AD). Our project will evaluate genome-wide RNA expression patterns from brain and blood in an AD mouse model. This analysis will provide insight regarding the mechanisms of AD pathology as well as determine a possible diagnostic tool utilizing RNA expression patterns found in the blood as biomarkers for AD.

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Doxorubicin-Induced, Tnf-Α-Mediated Brain Oxidative Stress, Neurochemical Alterations, And Cognitive Decline: Insights Into Mechanisms Of Chemotherapy Induced Cognitive Impairment And Its Prevention, Jeriel T. Keeney

Theses and Dissertations--Chemistry

The works presented in this dissertation provide insights into the mechanisms of chemotherapy-induced cognitive impairment (CICI or “ChemoBrain”) and take steps toward outlining a preventive strategy. CICI is now widely recognized as a complication of cancer chemotherapy experienced by a large percentage of cancer survivors. Approximately fifty percent of existing FDA-approved anti-cancer drugs generate reactive oxygen species (ROS). Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, produces the reactive superoxide radical anion (O₂^-•) in vivo. Dox treatment results in oxidation of plasma proteins, including ApoA-I, leading to TNF-α-mediated oxidative stress in plasma and brain. TNF-α elevation in brain …

Parkinson’S Disease: Molecular Mechanisms And Treatments, Delia Vahey

Senior Honors Theses

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. …

Impairments In Attention In Occasionally Snoring Children: An Event-Related Potential Study., Maria E. Barnes, Elizabeth A. Huss, Krista N. Garrod, Eric Van Ray, Ehab Dayyat, David Gozal, Dennis L. Molfese

Faculty and Staff Scholarship

Objective: To determine whether minimal snoring is benign in children. Procedure: 22 rarely snoring children (mean age = 6.9 years, 11 females) and age- and sex-matched controls participated in an auditory oddball task wearing 128-electrode nets. Parents completed the Conners Parent Rating Scales–Revised Long (CPRS–R:L). Results: Snorers scored significantly higher on four CPRS-R:L subscales. Stepwise regression indicated that two ERP variables from a region of the ERP that peaked at 844 msec post-stimulus onset predicted CPRS-R:L Attention Deficit Hyperactivity Disorder (ADHD) Index scores. Conclusions: Occasional snorers, according to parental report, do exhibit ADHD-like behaviors. Basic sensory processing is longer than …