DOCSLIB.ORG

Medullary Respiratory Circuit Is Reorganized by a Seasonally- Induced Program in Preparation for Hibernation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Medullary Respiratory Circuit Is Reorganized by a Seasonally- Induced Program in Preparation for Hibernation Research Collection Journal Article Medullary Respiratory Circuit Is Reorganized by a Seasonally- Induced Program in Preparation for Hibernation Author(s): Russell, Thomas L.; Zhang, Jichang; Okoniewski, Michal; Franke, Felix; Bichet, Sandrine; Hierlemann, Andreas Publication Date: 2019-04 Permanent Link: https://doi.org/10.3929/ethz-b-000342506 Originally published in: Frontiers in Neuroscience 13, http://doi.org/10.3389/fnins.2019.00376 Rights / License: Creative Commons Attribution 4.0 International This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library fnins-13-00376 April 24, 2019 Time: 17:29 # 1 ORIGINAL RESEARCH published: 26 April 2019 doi: 10.3389/fnins.2019.00376 Medullary Respiratory Circuit Is Reorganized by a Seasonally- Induced Program in Preparation for Hibernation Thomas L. Russell1*, Jichang Zhang1, Michal Okoniewski2, Felix Franke1, Sandrine Bichet3 and Andreas Hierlemann1 1 Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland, 2 Scientific IT Services, ETH Zurich, Zurich, Switzerland, 3 Friedrich Miescher Institute for Biomedical Research, Department of Histology, Basel, Switzerland Deep hibernators go through several cycles of profound drops in body temperature during the winter season, with core temperatures sometimes reaching near freezing. Yet unlike non-hibernating mammals, they can sustain breathing rhythms. The physiological processes that make this possible are still not understood. In this study, we focused on the medullary Ventral Respiratory Column of a facultative hibernator, the Syrian hamster. Using shortened day-lengths, we induced a “winter-adapted” physiological state, which is a prerequisite for hibernation. When recording electrophysiological signals Edited by: from acute slices in the winter-adapted pre-Bötzinger complex (preBötC), spike trains Hua Lou, Case Western Reserve University, showed higher spike rates, amplitudes, complexity, as well as higher temperature United States sensitivity, suggesting an increase in connectivity and/or synaptic strength during the Reviewed by: winter season. We further examined action potential waveforms and found that the Jiuyong Xie, University of Manitoba, Canada depolarization integral, as measured by the area under the curve, is selectively enhanced Sandy Martin, in winter-adapted animals. This suggests that a shift in the ion handling kinetics is also School of Medicine, University being induced by the winter-adaptation program. RNA sequencing of respiratory pre- of Colorado Denver, United States motor neurons, followed by gene set enrichment analysis, revealed differential regulation *Correspondence: Thomas L. Russell and splicing in structural, synaptic, and ion handling genes. Splice junction analysis [email protected] suggested that differential exon usage is occurring in a select subset of ion handling subunits (ATP1A3, KCNC3, SCN1B), and synaptic structure genes (SNCB, SNCG, Specialty section: This article was submitted to RAB3A). Our findings show that the hamster respiratory center undergoes a seasonally- Neurogenomics, cued alteration in electrophysiological properties, likely protecting against respiratory a section of the journal Frontiers in Neuroscience failure at low temperatures. Received: 29 November 2018 Keywords: microelectrode array, electrophysiology, hibernation, respiratory rhythms, ventral respiratory group, Accepted: 02 April 2019 medulla, Syrian hamster, pre-Bötzinger complex Published: 26 April 2019 Citation: Russell TL, Zhang J, INTRODUCTION Okoniewski M, Franke F, Bichet S and Hierlemann A (2019) Medullary Environments with large seasonal variances in temperatures often create regular conditions of Respiratory Circuit Is Reorganized by a Seasonally- Induced Program resource scarcity. Many animals adapted to living in such regions have evolved the ability to in Preparation for Hibernation. periodically engage bouts of torpor, whereby they lower their body temperatures, subsequently Front. Neurosci. 13:376. lowering metabolism and conserving energy. In deep hibernating rodents, these phases of profound doi: 10.3389/fnins.2019.00376 cooling can last days to weeks, whereupon the animal’s body temperature will fall to near freezing Frontiers in Neuroscience| www.frontiersin.org 1 April 2019| Volume 13| Article 376 fnins-13-00376 April 24, 2019 Time: 17:29 # 2 Russell et al. Respiratory Circuit Reorganization in Hibernation and then recover to full euthermic temperature. The torpor cycle MATERIALS AND METHODS is particularly interesting because it exposes the animal to the possibility of respiratory arrest, yet the animal manages to remain Animals in a state of respiratory fidelity. All procedures were approved by the Basel-City Cantonal Even though hibernators possess active metabolic controls Veterinary Authority. Male Syrian hamsters (Mesocricetus for avoiding hypoxia-ischemia during body temperature drops auratus) were received from the supplier (Janvier Labs, Le [as well as other mechanisms for lessening its effects such as Genest-Saint-Isle, France), who housed them under long day blood shunting (Frerichs et al., 1994) and elevated hemoglobin conditions (LD, 14 h:10 h). After receiving the animals, they O2 affinity (Maginniss and Milsom, 1994)], breathing rhythms were housed in the institutional animal facility under short must still be maintained, albeit at a slower rate. In adult rats, ◦ day conditions (SD, 8 h:16 h) for 1 week prior to beginning medullary temperatures below 16.6 C will induce respiratory the experiments (“autumn” control condition), or for 8 weeks arrest (Arokina et al., 2011). For homothermic mammals, the to induce physiological adaptations for hibernation (“winter” lack of temperature robustness in the breathing circuit itself poses condition), Figure 1A. Age of the animals ordered was controlled the risk of runaway hypoxia and death. Hibernators likely posses such that all animals were 11 weeks old at the time of sacrifice. unique neuronal circuitry characteristics that allow breathing After killing, testicles were dissected and weighed. Of all hamsters rhythm generation at low temperatures and protect against housed under short-day conditions, 74.6% showed a testicle respiratory arrest. weight reduction of at least 50% below the average testicle The presence of such a mechanism would not be unprece- weight of the control group (autumn) and were included in the dented, although investigations of seasonal changes in hibernation-adapted (winter) group (Figure 1B). mammalian brain electrophysiology are surprisingly scarce. Jinka et al.(2011) Illustrated an adenosine receptor-mediated seasonal “priming” of the central nervous system in ground Labeling of Respiratory Neurons squirrel. Similarly, Barrett et al.(2009) showed that exposing In order to label the respiratory region in the medulla for Siberian hamsters to a prolonged short photoperiod increases immunohistochemistry or RNA sequencing, some animals neuronal activity in the arcuate nucleus of the hypothalamus, received an injection of a fluorescent, trans-synapic, retrograde mediated by changes in expression of the histamine H3 receptor tracer. These animals were anesthetized with isoflurane and (Herwig et al., 2012). The hypothalamus incidentally is another bilaterally injected 10 ml of PBS containing 10 mg/ml Alexa488 brain region which remains active during hibernation likely conjugated Wheat Germ Agglutinin (WGA) (Thermo-Fisher, due to its role in timing of bouts (Heller and Ruby, 2004; Reinach, Switzerland) into the intrapleural cavity beneath the Bratincsák et al., 2009). fifth intercostal space of the rib cage (Figure 1C) as indicated in In this study, we explore the possibility that seasonal cues Buttry and Goshgarian(2014, 2015). Over the course of 48 h, the enact a genetic program to protect a deep hibernator against WGA was taken up by phrenic nerve efferents and retrogradely the threats posed by respiratory arrest. We used the Syrian transported to the phrenic nucleus in the spinal cord. Further hamster (Mesocricetus auratus), which can be cued by short day trans-synaptic retrograde transport took place and ultimately length to enter a physiological state that is a prerequisite for labeled cell bodies in the medulla, which presumably control hibernation to occur (Gaston and Menaker, 1967; Frehn and Liu, breathing rhythms. After 48 h, tissue was collected in the same 1970; Ueda and Ibuka, 1995). By comparing short day-length manner as animals used for electrophysiology, as follows. adapted “winter” hamsters with non-adapted “autumn” hamsters (Figure 1A), we were able to measure how this preparatory signal Tissue Preparation affected circuit functionality and cell viability in an area of the Animals were anesthetized with 30 mg/kg tiletamine- brain with critical functionality: the respiratory center. zolazepam/10 mg/kg xylazine and killed by decapitation. We reasoned that since the respiratory center is absolutely The brainstem was quickly removed after sacrifice and sliced critical for life, it must sustain breathing at low temperatures in 300-mm-thick sections on a Compresstome (Precisionary to prevent runaway hypoxia. This makes it plausible that our Instruments, Greenville, NC, United States) in 4◦C cutting experiments would uncover restructuring of respiratory circuits solution (93 mM NMDG, 2.5 mM KCl, 20 mM Hepes, 30 mM and synapses, representing an altogether novel means by which NaHCO3, 1.2
Load more

Recommended publications
  • Potassium Channels in Epilepsy
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potassium Channels in Epilepsy Ru¨diger Ko¨hling and Jakob Wolfart Oscar Langendorff Institute of Physiology, University of Rostock, Rostock 18057, Germany Correspondence: [email protected] This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dy- namic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With 80 potassium channel types, of which 10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. INTRODUCTION TO POTASSIUM evolutionary appearance of voltage-gated so- CHANNELS dium (Nav)andcalcium (Cav)channels, Kchan- nels are further diversified in relation to their otassium (K) channels are related to epilepsy newer function, namely, keeping neuronal exci- Psyndromes on many different levels, ranging tation within limits (Anderson and Greenberg from direct control of neuronal excitability and 2001; Hille 2001).
    [Show full text]
  • Rescue of Motor Coordination by Purkinje Cell-Targeted Restoration of Kv3.3 Channels in Kcnc3-Null Mice Requires Kcnc1
    The Journal of Neuroscience, December 16, 2009 • 29(50):15735–15744 • 15735 Cellular/Molecular Rescue of Motor Coordination by Purkinje Cell-Targeted Restoration of Kv3.3 Channels in Kcnc3-Null Mice Requires Kcnc1 Edward C. Hurlock, Mitali Bose, Ganon Pierce, and Rolf H. Joho Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111 The role of cerebellar Kv3.1 and Kv3.3 channels in motor coordination was examined with an emphasis on the deep cerebellar nuclei (DCN). Kv3 channel subunits encoded by Kcnc genes are distinguished by rapid activation and deactivation kinetics that support high-frequency, narrow action potential firing. Previously we reported that increased lateral deviation while ambulating and slips while traversing a narrow beam of ataxic Kcnc3-null mice were corrected by restoration of Kv3.3 channels specifically to Purkinje cells, whereas Kcnc3-mutant mice additionally lacking one Kcnc1 allele were partially rescued. Here, we report mice lacking all Kcnc1 and Kcnc3 alleles exhibit no such rescue. For Purkinje cell output to reach the rest of the brain it must be conveyed by neurons of the DCN or vestibular nuclei. As Kcnc1, but not Kcnc3, alleles are lost, mutant mice exhibit increasing gait ataxia accompanied by spike broadening and deceleration in DCN neurons, suggesting the facet of coordination rescued by Purkinje-cell-restricted Kv3.3 restoration in mice lacking just Kcnc3 is hypermetria, while gait ataxia emerges when additionally Kcnc1 alleles are lost. Thus, fast repolarization in Purkinje cells appears important for normal movement velocity, whereas DCN neurons are a prime candidate locus where fast repolarization is necessary for normal gait patterning.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • SUPPLEMENTARY APPENDIX Inflammation Regulates Long Non-Coding RNA-PTTG1-1:1 in Myeloid Leukemia
    SUPPLEMENTARY APPENDIX Inflammation regulates long non-coding RNA-PTTG1-1:1 in myeloid leukemia Sébastien Chateauvieux, 1,2 Anthoula Gaigneaux, 1° Déborah Gérard, 1 Marion Orsini, 1 Franck Morceau, 1 Barbora Orlikova-Boyer, 1,2 Thomas Farge, 3,4 Christian Récher, 3,4,5 Jean-Emmanuel Sarry, 3,4 Mario Dicato 1 and Marc Diederich 2 °Current address: University of Luxembourg, Faculty of Science, Technology and Communication, Life Science Research Unit, Belvaux, Luxemburg. 1Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg; 2College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea; 3Cancer Research Center of Toulouse, UMR 1037 INSERM/ Université Toulouse III-Paul Sabatier, Toulouse, France; 4Université Toulouse III Paul Sabatier, Toulouse, France and 5Service d’Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopôle, Toulouse, France Correspondence: MARC DIEDERICH - [email protected] doi:10.3324/haematol.2019.217281 Supplementary data Inflammation regulates long non-coding RNA-PTTG1-1:1 in myeloid leukemia Sébastien Chateauvieux1,2, Anthoula Gaigneaux1*, Déborah Gérard1, Marion Orsini1, Franck Morceau1, Barbora Orlikova-Boyer1,2, Thomas Farge3,4, Christian Récher3,4,5, Jean-Emmanuel Sarry3,4, Mario Dicato1 and Marc Diederich2 1 Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, 2540 Luxembourg, Luxemburg; 2 College of Pharmacy, Seoul National University, 1 Gwanak-ro,
    [Show full text]
  • Pflugers Final
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Serveur académique lausannois A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule. Sylvain Pradervand2, Annie Mercier Zuber1, Gabriel Centeno1, Olivier Bonny1,3,4 and Dmitri Firsov1,4 1 - Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland 2 - DNA Array Facility, University of Lausanne, 1015 Lausanne, Switzerland 3 - Service of Nephrology, Lausanne University Hospital, 1005 Lausanne, Switzerland 4 – these two authors have equally contributed to the study to whom correspondence should be addressed: Dmitri FIRSOV Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1005 Lausanne, Switzerland Phone: ++ 41-216925406 Fax: ++ 41-216925355 e-mail: [email protected] and Olivier BONNY Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1005 Lausanne, Switzerland Phone: ++ 41-216925417 Fax: ++ 41-216925355 e-mail: [email protected] 1 Abstract The distal parts of the renal tubule play a critical role in maintaining homeostasis of extracellular fluids. In this review, we present an in-depth analysis of microarray-based gene expression profiles available for microdissected mouse distal nephron segments, i.e., the distal convoluted tubule (DCT) and the connecting tubule (CNT), and for the cortical portion of the collecting duct (CCD) (Zuber et al., 2009). Classification of expressed transcripts in 14 major functional gene categories demonstrated that all principal proteins involved in maintaining of salt and water balance are represented by highly abundant transcripts. However, a significant number of transcripts belonging, for instance, to categories of G protein-coupled receptors (GPCR) or serine-threonine kinases exhibit high expression levels but remain unassigned to a specific renal function.
    [Show full text]
  • Anti-KCNC3 Antibody (ARG64170)
    Product datasheet [email protected] ARG64170 Package: 100 μg anti-KCNC3 antibody Store at: -20°C Summary Product Description Goat Polyclonal antibody recognizes KCNC3 Tested Reactivity Hu Tested Application WB Host Goat Clonality Polyclonal Isotype IgG Target Name KCNC3 Antigen Species Human Immunogen C-KPGPPSFLPDLNAN Conjugation Un-conjugated Alternate Names KSHIIID; KV3.3; SCA13; Voltage-gated potassium channel subunit Kv3.3; Potassium voltage-gated channel subfamily C member 3 Application Instructions Application table Application Dilution WB 0.3 - 1 µg/ml Application Note WB: Recommend incubate at RT for 1h. * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Calculated Mw 81 kDa Properties Form Liquid Purification Purified from goat serum by ammonium sulphate precipitation followed by antigen affinity chromatography using the immunizing peptide. Buffer Tris saline (pH 7.3), 0.02% Sodium azide and 0.5% BSA Preservative 0.02% Sodium azide Stabilizer 0.5% BSA Concentration 0.5 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. www.arigobio.com 1/2 Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Database links GeneID: 3748 Human Swiss-port # Q14003 Human Background The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies.
    [Show full text]
  • Neurology Genetics
    An Official Journal of the American Academy of Neurology Neurology.org/ng • Online ISSN: 2376-7839 Volume 3, Number 4, August 2017 Genetics Functionally pathogenic ExACtly zero or once: Clinical and experimental EARS2 variants in vitro A clinically helpful guide studies of a novel P525R may not manifest a to assessing genetic FUS mutation in amyotrophic phenotype in vivo variants in mild epilepsies lateral sclerosis Table of Contents Neurology.org/ng Online ISSN: 2376-7839 Volume 3, Number 4, August 2017 THE HELIX e171 Autopsy case of the C12orf65 mutation in a patient e175 What does phenotype have to do with it? with signs of mitochondrial dysfunction S.M. Pulst H. Nishihara, M. Omoto, M. Takao, Y. Higuchi, M. Koga, M. Kawai, H. Kawano, E. Ikeda, H. Takashima, and T. Kanda EDITORIAL e173 This variant alters protein function, but is it pathogenic? M. Pandolfo e174 Prevalence of spinocerebellar ataxia 36 in a US Companion article, e162 population J.M. Valera, T. Diaz, L.E. Petty, B. Quintáns, Z. Yáñez, ARTICLES E. Boerwinkle, D. Muzny, D. Akhmedov, R. Berdeaux, e162 Functionally pathogenic EARS2 variants in vitro may M.J. Sobrido, R. Gibbs, J.R. Lupski, D.H. Geschwind, not manifest a phenotype in vivo S. Perlman, J.E. Below, and B.L. Fogel N. McNeill, A. Nasca, A. Reyes, B. Lemoine, B. Cantarel, A. Vanderver, R. Schiffmann, and D. Ghezzi Editorial, e173 e170 Loss-of-function variants of SCN8A in intellectual disability without seizures e163 ExACtly zero or once: A clinically helpful guide to J.L. Wagnon, B.S. Barker, M.
    [Show full text]
  • Subcellular Localization of K+ Channels in Mammalian Brain Neurons: Remarkable Precision in the Midst of Extraordinary Complexity
    Neuron Review Subcellular Localization of K+ Channels in Mammalian Brain Neurons: Remarkable Precision in the Midst of Extraordinary Complexity James S. Trimmer1,2,* 1Department of Neurobiology, Physiology, and Behavior 2Department of Physiology and Membrane Biology University of California, Davis, Davis, CA 95616, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2014.12.042 Potassium channels (KChs) are the most diverse ion channels, in part due to extensive combinatorial assem- bly of a large number of principal and auxiliary subunits into an assortment of KCh complexes. Their structural and functional diversity allows KChs to play diverse roles in neuronal function. Localization of KChs within specialized neuronal compartments defines their physiological role and also fundamentally impacts their activity, due to localized exposure to diverse cellular determinants of channel function. Recent studies in mammalian brain reveal an exquisite refinement of KCh subcellular localization. This includes axonal KChs at the initial segment, and near/within nodes of Ranvier and presynaptic terminals, dendritic KChs found at sites reflecting specific synaptic input, and KChs defining novel neuronal compartments. Painting the remarkable diversity of KChs onto the complex architecture of mammalian neurons creates an elegant pic- ture of electrical signal processing underlying the sophisticated function of individual neuronal compart- ments, and ultimately neurotransmission and behavior. Introduction genes are expressed in distinct cellular expression patterns Mammalian brain neurons are distinguished from other cells by throughout the brain, such that particular neurons express spe- extreme molecular and structural complexity that is intimately cific combinations of KCh a and auxiliary subunits. However, the linked to the array of intra- and intercellular signaling events proteomic complexity of KChs is much greater, as KChs exist as that underlie brain function.
    [Show full text]
  • The Contribution of Calcium-Activated Potassium Channel Dysfunction to Altered Purkinje Neuron Membrane Excitability in Spinocerebellar Ataxia
    The Contribution of Calcium-Activated Potassium Channel Dysfunction to Altered Purkinje Neuron Membrane Excitability in Spinocerebellar Ataxia by David D. Bushart A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Integrative Physiology) in The University of Michigan 2018 Doctoral Committee: Professor Geoffrey G. Murphy, Co-Chair Associate Professor Vikram G. Shakkottai, Co-Chair Professor William T. Dauer Professor W. Michael King Professor Andrew P. Lieberman Professor Malcolm J. Low David D. Bushart [email protected] ORCiD: 0000-0002-3852-127X © David D. Bushart 2018 Acknowledgements I would like to acknowledge three groups which provided me with support and motivation to complete the studies in this dissertation, and for helping me keep my research efforts in perspective. First, I would like to acknowledge my friends and family. Their emotional support, and the time they have invested in supporting my growth as both a person and a scientist, cannot be overstated. I am eternally grateful to have a network of such caring people around me. Second, I would like to acknowledge cerebellar ataxia patients for their perseverance and positive outlook in the face of devastating circumstances. My ability to interact with patients at the National Ataxia Foundation meetings, along with the positive messages that my research efforts were met with, was my greatest motivating factor throughout the final years of my dissertation studies. I encourage other researchers to seek out similar interactions, as they will make for a more invested and focused scientist. Third, I would like to acknowledge the research animals used in the studies of this dissertation.
    [Show full text]
  • Graded Co-Expression of Ion Channel, Neurofilament, and Synaptic Genes in Fast- Spiking Vestibular Nucleus Neurons
    Research Articles: Cellular/Molecular Graded co-expression of ion channel, neurofilament, and synaptic genes in fast- spiking vestibular nucleus neurons https://doi.org/10.1523/JNEUROSCI.1500-19.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.1500-19.2019 Received: 26 June 2019 Revised: 11 October 2019 Accepted: 25 October 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 the authors 1 Graded co-expression of ion channel, neurofilament, and synaptic genes in fast-spiking 2 vestibular nucleus neurons 3 4 Abbreviated title: A fast-spiking gene module 5 6 Takashi Kodama1, 2, 3, Aryn Gittis, 3, 4, 5, Minyoung Shin2, Keith Kelleher2, 3, Kristine Kolkman3, 4, 7 Lauren McElvain3, 4, Minh Lam1, and Sascha du Lac1, 2, 3 8 9 1 Johns Hopkins University School of Medicine, Baltimore MD, 21205 10 2 Howard Hughes Medical Institute, La Jolla, CA, 92037 11 3 Salk Institute for Biological Studies, La Jolla, CA, 92037 12 4 Neurosciences Graduate Program, University of California San Diego, La Jolla, CA, 92037 13 5 Carnegie Mellon University, Pittsburgh, PA, 15213 14 15 Corresponding Authors: 16 Takashi Kodama ([email protected]) 17 Sascha du Lac ([email protected]) 18 Department of Otolaryngology-Head and Neck Surgery 19 The Johns Hopkins University School of Medicine 20 Ross Research Building 420, 720 Rutland Avenue, Baltimore, Maryland, 21205 21 22 23 Conflict of Interest 24 The authors declare no competing financial interests.
    [Show full text]
  • Genetic Testing Medical Policy – Genetics
    Genetic Testing Medical Policy – Genetics Please complete all appropriate questions fully. Suggested medical record documentation: • Current History & Physical • Progress Notes • Family Genetic History • Genetic Counseling Evaluation *Failure to include suggested medical record documentation may result in delay or possible denial of request. PATIENT INFORMATION Name: Member ID: Group ID: PROCEDURE INFORMATION Genetic Counseling performed: c Yes c No **Please check the requested analyte(s), identify number of units requested, and provide indication/rationale for testing. 81400 Molecular Pathology Level 1 Units _____ c ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (e.g., medium chain acyl dehydrogenase deficiency), K304E variant _____ c ACE (angiotensin converting enzyme) (e.g., hereditary blood pressure regulation), insertion/deletion variant _____ c AGTR1 (angiotensin II receptor, type 1) (e.g., essential hypertension), 1166A>C variant _____ c BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (e.g., maple syrup urine disease, type 1A), Y438N variant _____ c CCR5 (chemokine C-C motif receptor 5) (e.g., HIV resistance), 32-bp deletion mutation/794 825del32 deletion _____ c CLRN1 (clarin 1) (e.g., Usher syndrome, type 3), N48K variant _____ c DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), IVS14+1G>A variant _____ c F13B (coagulation factor XIII, B polypeptide) (e.g., hereditary hypercoagulability), V34L variant _____ c F2 (coagulation factor 2) (e.g.,
    [Show full text]
  • Robles JTO Supplemental Digital Content 1
    Supplementary Materials An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma based on mRNA, microRNA and DNA Methylation Biomarkers Ana I. Robles1, Eri Arai2, Ewy A. Mathé1, Hirokazu Okayama1, Aaron Schetter1, Derek Brown1, David Petersen3, Elise D. Bowman1, Rintaro Noro1, Judith A. Welsh1, Daniel C. Edelman3, Holly S. Stevenson3, Yonghong Wang3, Naoto Tsuchiya4, Takashi Kohno4, Vidar Skaug5, Steen Mollerup5, Aage Haugen5, Paul S. Meltzer3, Jun Yokota6, Yae Kanai2 and Curtis C. Harris1 Affiliations: 1Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 3Genetics Branch, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 4Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 5Department of Chemical and Biological Working Environment, National Institute of Occupational Health, NO-0033 Oslo, Norway. 6Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona (Barcelona), Spain. List of Supplementary Materials Supplementary Materials and Methods Fig. S1. Hierarchical clustering of based on CpG sites differentially-methylated in Stage I ADC compared to non-tumor adjacent tissues. Fig. S2. Confirmatory pyrosequencing analysis of DNA methylation at the HOXA9 locus in Stage I ADC from a subset of the NCI microarray cohort. 1 Fig. S3. Methylation Beta-values for HOXA9 probe cg26521404 in Stage I ADC samples from Japan. Fig. S4. Kaplan-Meier analysis of HOXA9 promoter methylation in a published cohort of Stage I lung ADC (J Clin Oncol 2013;31(32):4140-7). Fig. S5. Kaplan-Meier analysis of a combined prognostic biomarker in Stage I lung ADC.
    [Show full text]