Neurology Commons^™

Il-4 Signaling Drives A Unique Arginase+/Il-1Β+ Microglia Phenotype And Recruits Macrophages To The Inflammatory Cns: Consequences Of Age-Related Deficits In Il-4rα After Traumatic Spinal Cord Injury, Ashley M. Fenn, Jodie C.E. Hall, John C. Gensel, Phillip G. Popovich, Jonathan P. Godbout

Spinal Cord and Brain Injury Research Center Faculty Publications

Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα⁺ macrophages to …

Regional-Specific Effects Of Ovarian Hormone Loss On Synaptic Plasticity In Adult Human Apoe Targeted Replacement Mice, Rebecca C. Klein, Shyla Saini, Mary-Louise Risher, Shawn K. Acheson, Rebekah L. Fleming, Hannah G. Sexton, H. Scott Swartzwelder, Scott D. Moore

Biomedical Sciences

The human apolipoprotein ε4 allele (APOE4) has been implicated as one of the strongest genetic risk factors associated with Alzheimer’s disease (AD) and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR) mice were utilized to examine the effects of human APOE …

Inhibitory Effect Of Il-17 On Neural Stem Cell Proliferation And Neural Cell Differentiation., Zichen Li, Ke Li, Lin Zhu, Quancheng Kan, Yaping Yan, Priyanka Kumar, Hui Xu, Abdolmohamad Rostami, Guang-Xian Zhang

Department of Neurology Faculty Papers

BACKGROUND: IL-17, a Th17 cell-derived proinflammatory molecule, has been found to play an important role in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). While IL-17 receptor (IL-17R) is expressed in many immune-related cells, microglia, and astrocytes, it is not known whether IL-17 exerts a direct effect on neural stem cells (NSCs) and oligodendrocytes, thus inducing inflammatory demyelination in the central nervous system.

METHODS: We first detected IL-17 receptor expression in NSCs with immunostaining and real time PCR. We then cultured NSCs with IL-17 and determined NSC proliferation by neurosphere formation …

Global Profiling Of Alternative Splicing Events And Gene Expression Regulated By Hnrnph/F, Erming Wang, Vahid Aslanzadeh, Filomena Papa, Haiyan Zhu, Pierre De La Grange, Franca Cambi

Neurology Faculty Publications

In this study, we have investigated the global impact of heterogeneous nuclear Ribonuclear Protein (hnRNP) H/F-mediated regulation of splicing events and gene expression in oligodendrocytes. We have performed a genome-wide transcriptomic analysis at the gene and exon levels in Oli-neu cells treated with siRNA that targets hnRNPH/F compared to untreated cells using Affymetrix Exon Array. Gene expression levels and regulated exons were identified with the GenoSplice EASANA algorithm. Bioinformatics analyses were performed to determine the structural properties of G tracts that correlate with the function of hnRNPH/F as enhancers vs. repressors of exon inclusion. Different types of alternatively spliced events …

Nociceptive Neuropeptide Increases And Periorbital Allodynia In A Model Of Traumatic Brain Injury., Melanie B. Elliott, Michael L. Oshinsky, Peter S. Amenta, Olatilewa Awe, Jack I. Jallo

Department of Neurosurgery Faculty Papers

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury.

METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled …

Egr-1 Induces Darpp-32 Expression In Striatal Medium Spiny Neurons Via A Conserved Intragenic Element., Serene Keilani, Samira Chandwani, Georgia Dolios, Alexey Bogush, Heike Beck, Antonis K Hatzopoulos, Gadiparthi N Rao, Elizabeth A Thomas, Rong Wang, Michelle E Ehrlich

Farber Institute for Neuroscience Faculty Papers

DARPP-32 (dopamine and adenosine 3', 5'-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. …

Strain-Dependent Variation In The Early Transcriptional Response To Cns Injury Using A Cortical Explant System, David J. Graber, Brent T. Harris, William F. Hickey

Dartmouth Scholarship

While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains. Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

Molecular Cross Talk Between Misfolded Proteins In Animal Models Of Alzheimer's And Prion Diseases, Rodrigo Morales, Lisbell D Estrada, Rodrigo Diaz-Espinoza, Diego Morales-Scheihing, Maria C Jara, Joaquin Castilla, Claudio Soto

Faculty, Staff and Student Publications

The central event in protein misfolding disorders (PMDs) is the accumulation of a misfolded form of a naturally expressed protein. Despite the diversity of clinical symptoms associated with different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross talk at the molecular level. The main goal of this study was to analyze the interaction of the protein misfolding processes implicated in Alzheimer's and prion diseases. For this purpose, we inoculated prions in an Alzheimer's transgenic mouse model that develop typical amyloid plaques and followed the progression of pathological changes over time. Our findings show a dramatic acceleration …

Interaction Of The Mu-Opioid Receptor With Gpr177 (Wntless) Inhibits Wnt Secretion: Potential Implications For Opioid Dependence., Jay Jin, Saranya Kittanakom, Victoria Wong, Beverly A S Reyes, Elisabeth J Van Bockstaele, Igor Stagljar, Wade Berrettini, Robert Levenson

Department of Neurosurgery Faculty Papers

BACKGROUND: Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence. RESULTS: GPR177, the mammalian ortholog of Drosophila …

The Production Of Antibody By Invading B Cells Is Required For The Clearance Of Rabies Virus From The Central Nervous System., D Craig Hooper, Timothy W Phares, Marzena J Fabis, Anirban Roy

Department of Cancer Biology Faculty Papers

BACKGROUND: The pathogenesis of rabies is associated with the inability to deliver immune effectors across the blood-brain barrier and to clear virulent rabies virus from CNS tissues. However, the mechanisms that facilitate immune effector entry into CNS tissues are induced by infection with attenuated rabies virus.

METHODOLOGY/PRINCIPAL FINDINGS: Infection of normal mice with attenuated rabies virus but not immunization with killed virus can promote the clearance of pathogenic rabies virus from the CNS. T cell activity in B cell-deficient mice can control the replication of attenuated virus in the CNS, but viral mRNA persists. Low levels of passively administered rabies …

Mechanisms Of Primary Axonal Damage In A Viral Model Of Multiple Sclerosis., Jayasri Das Sarma, Lawrence C. Kenyon, Susan T. Hingley, Kenneth S. Shindler

Department of Neurology Faculty Papers

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. …

Intravenous Inoculation Of A Bat-Associated Rabies Virus Causes Lethal Encephalopathy In Mice Through Invasion Of The Brain Via Neurosecretory Hypothalamic Fibers., Mirjam A R Preuss, Marie-Luise Faber, Gene S Tan, Michael Bette, Bernhard Dietzschold, Eberhard Weihe, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown …

Prion Protein Glycosylation Is Not Required For Strain-Specific Neurotropism, Justin R. Piro, Brent T. Harris, Koren Nishina, Claudio Soto, Rodrigo Morales, Judy R. Rees, Surachai Supattapone

Dartmouth Scholarship

In this study, we tested the hypothesis that the glycosylation of the pathogenic isoform of the prion protein (PrP^Sc) might encode the selective neurotropism of prion strains. We prepared unglycosylated cellular prion protein (PrP^C) substrate molecules from normal mouse brain by treatment with PNGase F and used reconstituted serial protein cyclic misfolding amplification reactions to produce RML and 301C mouse prions containing unglycosylated PrP^Sc molecules. Both RML- and 301C-derived prions containing unglycosylated PrP^Sc molecules were infectious to wild-type mice, and neuropathological analysis showed that mice inoculated with these samples maintained strain-specific patterns of PrP …

Combined Effects Of Hyperglycemic Conditions And Hiv-1 Nef: A Potential Model For Induced Hiv Neuropathogenesis., Edward A Acheampong, Cassandra Roschel, Muhammad Mukhtar, Alagarsamy Srinivasan, Mohammad Rafi, Roger J Pomerantz, Zahida Parveen

Department of Neurology Faculty Papers

Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our in vitro study. The results show that in vitro hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and …

Functional Interleukin-17 Receptor A Is Expressed In Central Nervous System Glia And Upregulated In Experimental Autoimmune Encephalomyelitis., Jayasri Das Sarma, Bogoljub Ciric, Ryan Marek, Sanjoy Sadhukhan, Michael L. Caruso, Jasmine Shafagh, Denise C. Fitzgerald, Kenneth S. Shindler, Am Rostami

Department of Neurology Faculty Papers

BACKGROUND: Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood.

METHODS: EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ …

Experimental Optic Neuritis Induced By A Demyelinating Strain Of Mouse Hepatitis Virus., Kenneth S. Shindler, Lawrence C. Kenyon, Mahasweta Dutt, Susan T. Hingley, Jayasri Das Sarma

Department of Neurology Faculty Papers

Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS). Pathological mechanisms and potential treatments for ON have been studied via experimental autoimmune MS models. However, evidence suggests that virus-induced inflammation is a likely etiology triggering MS and ON; experimental virus-induced ON models are therefore required. We demonstrate that MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting mixed inflammatory cell infiltration. In contrast, MHV-2, a nondemyelinating MHV strain, does not induce ON. Results reveal a reproducible virus-induced ON model important for the evaluation of …

Elucidating A Normal Function Of Huntingtin By Functional And Microarray Analysis Of Huntingtin-Null Mouse Embryonic Fibroblasts., Hua Zhang, Sudipto Das, Quan-Zhen Li, Ioannis Dragatsis, Joyce Repa, Scott Zeitlin, György Hajnóczky, Ilya Bezprozvanny

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: The polyglutamine expansion in huntingtin (Htt) protein is a cause of Huntington's disease (HD). Htt is an essential gene as deletion of the mouse Htt gene homolog (Hdh) is embryonic lethal in mice. Therefore, in addition to elucidating the mechanisms responsible for polyQ-mediated pathology, it is also important to understand the normal function of Htt protein for both basic biology and for HD. RESULTS: To systematically search for a mouse Htt function, we took advantage of the Hdh +/- and Hdh-floxed mice and generated four mouse embryonic fibroblast (MEF) cells lines which contain a single copy of the Hdh …

The Cns Role Of Toll-Like Receptor 4 In Innate Neuroimmunity And Painful Neuropathy, Flobert Y. Tanga, Nancy Nutile-Mcmenemy, Joyce A. Deleo

Dartmouth Scholarship

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and …