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Dorsal Horn Neuronal Circuits Processing Itch

English title Dorsal Horn Neuronal Circuits Processing Itch
Applicant Zeilhofer Hanns Ulrich
Number 176398
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2017 - 31.05.2021
Approved amount 855'546.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Pharmacology, Pharmacy

Keywords (4)

GABA; spinal cord; glycine; itch

Lay Summary (German)

Lead
Chronischer Juckreiz ist eine häufige, sehr beeinträchtigende und nur schwer behandelbare Erkrankung. In den letzten Jahren wurden Entdeckungen gemacht, die es jetzt ermöglichen die neurophysiologischen Grundlagen des Juckreizes besser zu verstehen. Ähnlich wie Schmerzsignale werden auch Juckreizsignale bevor sie in Gehirn gelangen von einem Netzwerk von Nervenzellen im Rückenmark verarbeitet. Unser Projekt zielt darauf, die an dieser Verarbeitung beteiligten Nervenzellen, Ihre Verschaltung, Kommunikation und die Regulation ihrer Aktivität besser verstehen zu können, um dieses Wissen später zur Therapie von Patienten ausnutzen zu können.
Lay summary

Wir verwenden molekularbiologische Methoden und Gewebefärbungen, um die an der Juckreizverarbeitung beteiligten Neuronen zu identifizieren. In Gewebeschnitten und in narkotisierten Mäusen führen wir bildgebende und elektrische Messungen durch, um zu untersuchen, durch welche Botenstoffe und Rezeptoren die Aktivität dieser Zellen reguliert wird. Der mögliche therapeutische Nutzen dieser Ergebnisse wird dann in pharmakogenetischen und pharmakologischen Experimenten überprüft. Wir erhoffen uns von diesem Projekt nicht nur ein besseres Verständnis der neurophysiologischen Grundlagen der Juckreizverarbeitung, sondern hoffen auch die Grundlagen für neue therapeutische Ansätze zu legen.

Direct link to Lay Summary Last update: 06.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
In-Depth Characterization of Layer 5 Output Neurons of the Primary Somatosensory Cortex Innervating the Mouse Dorsal Spinal Cord
Frezel N, Platonova E, Voigt F F, Mateos J M, Kastli R, Ziegler U, Karayannis T, Helmchen F, Wildner H, Zeilhofer H U (2020), In-Depth Characterization of Layer 5 Output Neurons of the Primary Somatosensory Cortex Innervating the Mouse Dorsal Spinal Cord, in Cerebral Cortex Communications, 1(1), 1-16.
Dorsal horn pain mechanisms
ZeilhoferHanns Ulrich, GanleyRobert (2020), Dorsal horn pain mechanisms, in Wood John N., Wood John N. (ed.), Oxford University Press, Oxford, 1-29.
The mesoSPIM initiative: open-source light-sheet microscopes for imaging cleared tissue
Voigt Fabian F., Kirschenbaum Daniel, Platonova Evgenia, Pagès Stéphane, Campbell Robert A. A., Kastli Rahel, Schaettin Martina, Egolf Ladan, van der Bourg Alexander, Bethge Philipp, Haenraets Karen, Frézel Noémie, Topilko Thomas, Perin Paola, Hillier Daniel, Hildebrand Sven, Schueth Anna, Roebroeck Alard, Roska Botond, Stoeckli Esther T., Pizzala Roberto, Renier Nicolas, Zeilhofer Hanns Ulrich, Karayannis Theofanis, Ziegler Urs, Batti L, Holtmaat Anthony, Luscher Christian, Aguzzi Adriano, Helmchen Fritjof (2019), The mesoSPIM initiative: open-source light-sheet microscopes for imaging cleared tissue, in Nature Methods, 16(11), 1105-1108.
Flexible and Lightweight Devices for Wireless Multi-Color Optogenetic Experiments Controllable via Commercial Cell Phones
Mayer Philipp, Sivakumar Nandhini, Pritz Michael, Varga Matjia, Mehmann Andreas, Lee Seunghyun, Salvatore Alfredo, Magno Michele, Pharr Matt, Johannssen Helge C., Troester Gerhard, Zeilhofer Hanns Ulrich, Salvatore Giovanni Antonio (2019), Flexible and Lightweight Devices for Wireless Multi-Color Optogenetic Experiments Controllable via Commercial Cell Phones, in Frontiers in Neuroscience, 13, 1-14.
How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch
Pagani Martina, Albisetti Gioele W., Sivakumar Nandhini, Wildner Hendrik, Santello Mirko, Johannssen Helge C., Zeilhofer Hanns Ulrich (2019), How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch, in Neuron, 103(1), 102-117.e5.
Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals
Albisetti Gioele W., Pagani Martina, Platonova Evgenia, Hösli Ladina, Johannssen Helge C., Fritschy Jean-Marc, Wildner Hendrik, Zeilhofer Hanns Ulrich (2019), Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals, in The Journal of Neuroscience, 39(12), 2238-2250.
Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors
Ralvenius William T., Neumann Elena, Pagani Martina, Acuña Mario A., Wildner Hendrik, Benke Dietmar, Fischer Nina, Rostaher Ana, Schwager Simon, Detmar Michael, Frauenknecht Katrin, Aguzzi Adriano, Hubbs Jed Lee, Rudolph Uwe, Favrot Claude, Zeilhofer Hanns Ulrich (2018), Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors, in Nature Communications, 9(1), 3230-3230.
Circuit dissection of the role of somatostatin in itch and pain
Huang Jing, Polgár Erika, Solinski Hans Jürgen, Mishra Santosh K., Tseng Pang-Yen, Iwagaki Noboru, Boyle Kieran A., Dickie Allen C., Kriegbaum Mette C., Wildner Hendrik, Zeilhofer Hanns Ulrich, Watanabe Masahiko, Riddell John S., Todd Andrew J., Hoon Mark A. (2018), Circuit dissection of the role of somatostatin in itch and pain, in Nature Neuroscience, 21(5), 707-716.
Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus
Albisetti Gioele W., Ghanem Alexander, Foster Edmund, Conzelmann Karl-Klaus, Zeilhofer Hanns Ulrich, Wildner Hendrik (2017), Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus, in The Journal of Neuroscience, 37(43), 10358-10371.
Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters
Haenraets Karen, Foster Edmund, Johannssen Helge, Kandra Vinnie, Frezel Noémie, Steffen Timothy, Jaramillo Valeria, Paterna Jean-Charles, Zeilhofer Hanns Ulrich, Wildner Hendrik (2017), Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters, in Journal of Neurochemistry, 142(5), 721-733.

Datasets

Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals

Author Pagani, Martina
Publication date 10.01.2019
Persistent Identifier (PID) unknown
Repository g-node


Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors

Author Ralvenius, William
Publication date 12.07.2018
Persistent Identifier (PID) unknown
Repository g-node


Collaboration

Group / person Country
Types of collaboration
Klaus Conzelmann Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
AMGEN United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Engrail Therapeutics United States of America (North America)
- Industry/business/other use-inspired collaboration
Andrew Todt; University of Glasgow Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Fritjof Helmchen, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Gerhard Troester, ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Eliem Therapeutics Great Britain and Northern Ireland (Europe)
- Industry/business/other use-inspired collaboration
Adriano Aguzzi, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Neurocycle Therapeutics United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Claude Favrot, VetSuisse Faculty, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
FENS 2020 Virtual Forum Talk given at a conference Gating of spinal itch circuits by gastrin-releasing-peptide 15.07.2020 N/A, Switzerland Zeilhofer Hanns Ulrich;
10th World Congress on Itch Individual talk Postsynaptic gating mechanisms of chemical itch in the dorsal horn 17.11.2019 Sydney, Australia Zeilhofer Hanns Ulrich;
98th meeting of the German Physiological Society Talk given at a conference Probing spinal cord circuits with optogenetics and chemogenetics 30.09.2019 Ulm, Germany Zeilhofer Hanns Ulrich;
Montreal Conference on Pain Circuits Talk given at a conference How gastrin-releasing peptide opens the spinal gate for itch 03.08.2019 Montreal, Canada Zeilhofer Hanns Ulrich;
Seminar at Centro de Biología Molecular “Severo Ochoa” Individual talk Neurons and circuits for descending pain control 10.05.2019 Madrid, Spain Zeilhofer Hanns Ulrich;
Seminar at the Department of Fundamental Neurosciences. Université de Lausanne Individual talk Neurons and circuits for stress-induced analgesia 11.11.2018 Lausanne, Switzerland Zeilhofer Hanns Ulrich;
Meeting of the Study group “Molecular Neurobiology” of the Gesellschaft für Biochemie und Molekularbiologie (GBM) Talk given at a conference Investigating spinal sensory circuits through intersectional gene manipulation 22.09.2018 Marburg, Germany Zeilhofer Hanns Ulrich;
17th World Congress in Pain Talk given at a conference GABA and glycine in segmental and descending pain control 12.09.2018 Boston, United States of America Zeilhofer Hanns Ulrich;
17th World Congress in Pain Talk given at a conference Synaptic communication between GRP and GRPR neurons 12.09.2018 Boston, United States of America Zeilhofer Hanns Ulrich;
17th World Congress in Pain Talk given at a conference Basic mechanisms and neurobiology of acute and chronic pain – spinal cord 12.09.2018 Boston, United States of America Zeilhofer Hanns Ulrich;
Pain Mechanisms and Therapeutics Conference Talk given at a conference GABAergic interneurons and GABAA receptors controlling the spinal relay of itch 08.06.2018 Taormina, Italy Zeilhofer Hanns Ulrich;
Cellular and Molecular Neurobiology of Mental Disease Talk given at a conference GRP and GRP neurons in itch processing circuits of the spinal cord 26.05.2018 Giessbach, Switzerland Zeilhofer Hanns Ulrich;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Jahreskongress der Schweizerischen Gesellschaft für Rheumatologie Talk 06.09.2019 Interlaken, Switzerland Zeilhofer Hanns Ulrich;
21. Basler Symposium für Kinderorthopädie Talk 06.09.2018 Basel, Switzerland Zeilhofer Hanns Ulrich;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions BrainFair German-speaking Switzerland 2018

Associated projects

Number Title Start Funding scheme
197888 Neurons and Circuits for Stress-Induced Analgesia 01.06.2021 Project funding
170804 The airy scan detector for improved sensitivity and resolution analysis of functional neuroanatomy, neuronal regulation, and pericyte biology 01.04.2017 R'EQUIP
156393 Dorsal Horn Neuronal Circuits Processing Itch 01.12.2014 Project funding
156393 Dorsal Horn Neuronal Circuits Processing Itch 01.12.2014 Project funding

Abstract

The present proposal addresses dorsal horn neuronal circuits involved in itch processing and their control by inhibitory interneurons, inhibitory neurotransmitters and itch-related neuropeptides. For the up-coming funding period, we propose to focus on the following three aims: (1) Cellular mechanisms underlying the role of b-type natriuretic peptide (BNP) in spinal itch transmission. BNP is a potential peptide messenger contributing to transmission between pruritoceptive sensory neurons (primary pruritoceptors) and second order itch neurons in the spinal dorsal horn. It is mainly expressed in the neurotensin (NTS) positive population of primary pruritoceptors. Using optogenetic stimulation of NTS positive axon terminals and targeted recordings from second order itch (GPR positive) neurons in mouse spinal cord slices we will investigate the role of BNP at the first synapse of the itch pathway. (2) Identification of subpopulations of glycinergic neurons controlling spinal itch circuits. Using retrograde monosynaptic tracing, we found that second order itch neurons receive synaptic input from local inhibitory and excitatory interneurons. Consistent with this inhibitory innervation, ablation and silencing of inhibitory glycinergic (GlyT2-positive) deep dorsal horn neurons induced aversive behaviour reminiscent of chronic itch. Using cre/dre intersectional gene targeting, we will further dissect the glycinergic population of dorsal horn neurons to narrow down on more restricted inhibitory neuron populations that control itch. (3) Subtypes of GABA-A receptors controlling itch responses - beyond diversity of the alpha subunit. While the great majority of benzodiazepine-sensitive GABA-A receptors contain a gamma2 subunit, we found that the spinal antipruritic actions of several benzodiazepine site agonists are maintained in the absence of gamma2 subunits. Preliminary gene expression analyses suggest that primary sensory neurons and central neurons of the spinal dorsal horn express significant amounts gamma1 subunits in addition to gamma2. We have meanwhile generated gamma1 (Gabrg1)-deficient mice and will perform comprehensive comparisons of these mice with wild-type mice and mice lacking gamma2 subunits from the spinal cord. From these experiments, we expect to gain novel insights into the spinal control of the still poorly understood itch sense.
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