Project

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Cortical mechanisms controlling migraine pain

Applicant Santello Mirko
Number 161504
Funding scheme Ambizione
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 01.01.2016 - 31.12.2018
Approved amount 579'371.00
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Keywords (5)

glutamate; pain; astrocyte; migraine; cortex

Lay Summary (Italian)

Lead
L'emicrania è una patologia cronica molto frequente, caratterizzata da mal di testa ricorrenti. L'Organizzazione Mondiale della Sanità annovera l'emicrania tra le venti patologie più invalidanti. C’è una scarsa comprensione delle cause che scatenano l'emicrania. Questo progetto ha come scopo quello di far luce su alcuni dei meccanismi resposabili degli attacchi emicranici studiando l’attività di un’area del cervello deputata alla percezione del mal di testa.
Lay summary

L’emicrania affligge più del 10% della popolazione e costituisce pertanto un problema sociale molto rilavante. Molti aspetti della fisiopatologia dell’emicrania sono ancora ignoti. È anche per questo motivo che i trattamenti farmacologici attualmente disponibili non sono in grado di prevenire completamente l’insorgere degli attacchi di emicrania o di alleviarne efficacemente tutti i sintomi. Nonostante l'emicrania sia considerata un problema di sanità pubblica urgente, sorprendentemente la ricerca preclinica su questa patologia è molto limitata. Questo progetto mira a scoprire alcuni aspetti chiave di questa patologia: il ruolo delle alterazioni delle aree cerebrali deputate alla percezione del dolore nello sviluppo della malattia. Useremo come modello sperimentale topi portatori delle stesse mutazioni trovate nei pazienti affetti da una forma ereditabile di emicrania. Lo studio dell’attività neuronale in questo modello ci permetterà di scoprire alcuni dei meccanismi che sono alla base dell’insorgere della malattia. In particolare, testeremo l’ipotesi che un malfunzionamento della corteccia cingolata anteriore alteri la percezione del dolore, aumentando così il rischio di attacchi emicranici e la cronicizzazione dell’emicrania stessa. Verranno utilizzati farmaci in grado di influenzare l'attività neuronale in questa regione del cervello e verrà testato il loro potere analgesico e/o di prevenzione dell’attacco. Questa ricerca potrà aiutare a migliorare l'azione di alcuni farmaci attualmente disponibili per il trattamento l'emicrania e/o a contribuire a definire nuove strategie farmacologiche.

Direct link to Lay Summary Last update: 25.08.2015

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Efficient low-pass dendro-somatic coupling in the apical dendrite of layer 5 pyramidal neurons in the anterior cingulate cortex
Marti Mengual Ulisses, Wybo Willem A.M., Spierenburg Lotte J.E., Santello Mirko, Senn Walter, Nevian Thomas (2020), Efficient low-pass dendro-somatic coupling in the apical dendrite of layer 5 pyramidal neurons in the anterior cingulate cortex, in The Journal of Neuroscience, JN-RM-3028-JN-RM-3028.
Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine
Romanos Jennifer, Benke Dietmar, Pietrobon Daniela, Zeilhofer Hanns Ulrich, Santello Mirko (2020), Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine, in Science Advances, 6(23), eaaz1584-eaaz1584.
Diving into new depths of astrocyte signaling
Romanos Jennifer, Thieren Laetitia, Santello Mirko (2019), Diving into new depths of astrocyte signaling, in Nature Neuroscience, 22(11), 1749-1750.
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.
Astrocyte function from information processing to cognition and cognitive impairment
Santello Mirko, Toni Nicolas, Volterra Andrea (2019), Astrocyte function from information processing to cognition and cognitive impairment, in Nature Neuroscience, 22(2), 154-166.
Differences in glutamate uptake between cortical regions impact neuronal NMDA receptor activation
Romanos Jennifer, Benke Dietmar, Saab Aiman, Zeilhofer Hanns Ulrich, Santello Mirko (2019), Differences in glutamate uptake between cortical regions impact neuronal NMDA receptor activation, in Communications Biology, 2.
The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain
Santello Mirko, Bisco Alberto, Nevian Natalie Elisabeth, Lacivita Enza, Leopoldo Marcello, Nevian Thomas (2017), The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain, in Neurobiology of Disease, 106, 214-221.
Defective glutamate and K + clearance by cortical astrocytes in familial hemiplegic migraine type 2
Capuani Clizia, Melone Marcello, Tottene Angelita, Bragina Luca, Crivellaro Giovanna, Santello Mirko, Casari Giorgio, Conti Fiorenzo, Pietrobon Daniela (2016), Defective glutamate and K + clearance by cortical astrocytes in familial hemiplegic migraine type 2, in EMBO Molecular Medicine, 8(8), 967-986.
Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells
Fruh S., Romanos J., Panzanelli P., Burgisser D., Tyagarajan S. K., Campbell K. P., Santello M., Fritschy J.-M. (2016), Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells, in Journal of Neuroscience, 36(40), 10296-10313.

Collaboration

Group / person Country
Types of collaboration
Jean-Marc Fritschy Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Andrea Volterra, University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Daniela Pietrobon, University of Padua Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Wen-Biao Gan United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ETH post-doc day Poster Migraine Associated Cellular Dysfunctions In The Anterior Cingulate Cortex 14.09.2018 Zurich, Switzerland Romanos Jennifer;
Center for Neuroscience symposium 2018 Poster Migraine Associated Cellular Dysfunctions In The Anterior Cingulate Cortex 13.09.2018 Zurich, Switzerland Romanos Jennifer;
16th World congress on pain Poster Glial and neuronal dysfunctions in the Anterior Cingulate Cortex of a mouse model of migraine 11.09.2018 Boston, United States of America Santello Mirko;
Glia in Health & Disease, Cold Spring Harbor meeting Poster Differences in astrocytic glutamate uptake between cortical regions impact neuronal NMDA receptor activation 19.07.2018 Cold Spring Harbor, NY, United States of America Santello Mirko;
Glia in Health & Disease, Cold Spring Harbor meeting Poster Migraine-related cellular dysfunctions in the anterior cingulate cortex 19.07.2018 Cold Spring Harbor (NY), United States of America Romanos Jennifer;
11th FENS Forum of Neuroscience Poster Differential glutamate buffering between cortical regions impacts synaptic functions 11.07.2018 Berlin, Germany Santello Mirko;
Federation of of European Neuroscience forum 2018 (FENS) Poster Migraine-related cellular dysfunctions in the anterior cingulate cortex 07.07.2018 Berlin, Germany Romanos Jennifer;
Giessbach Meeting – Cellular and Molecular Neurobiology of Mental Disease Talk given at a conference Migraine-associated cellular dysfunctions in the anterior cingulate cortex 24.05.2018 Giessbach, Switzerland Romanos Jennifer;
Giessbach Meeting – Cellular and Molecular Neurobiology of Mental Disease Talk given at a conference Differences in glutamate uptake between cortical regions impact synaptic functions 24.05.2018 Giessbach (BE),, Switzerland Romanos Jennifer; Santello Mirko;
Swiss Society of Neuroscience meeting 2018 Poster Dierences in astrocytic glutamate uptake between cortical regions impact neuronal NMDA receptor activation 09.02.2018 Zurich, Switzerland Romanos Jennifer;
ZNZ Symposium 2017 Poster Differential glutamate buffering between cortical regions impacts synaptic functions 14.09.2017 Zurich, Switzerland Romanos Jennifer; Santello Mirko;
The XIII European Meeting on Glial Cells in Health and Disease Poster Differential glutamate buffering between cortical regions impacts synaptic functions 08.07.2017 Edinburg, Great Britain and Northern Ireland Santello Mirko;
The XIII European Meeting on Glial Cells in Health and Disease Poster Glial and neuronal dysfunctions in the anterior cingulate cortex of a mouse model of migraine 08.07.2017 Edinburg, Great Britain and Northern Ireland Romanos Jennifer;
Dendrites: Molecules, Structure & Function" Gordon Research Conference Poster Migraine-associated dendritic dysfunctions 26.03.2017 Barga, Italy Santello Mirko;
ZNZ Symposium Poster Astrocytic glutamate and K+ uptake in the anterior cingulate cortex in familial hemiplegic migraine type 2 mouse model 15.09.2016 Zurich, Switzerland Romanos Jennifer;
ZNZ Symposium Talk given at a conference Cortical dysfunctions in pathological pain 15.09.2016 Zurich, Switzerland Santello Mirko;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Visit at Montessori School and presenation my research in Zurich Performances, exhibitions (e.g. for education institutions) 06.12.2018 chatel st denis (FR), Switzerland Santello Mirko;
LS2 Annual Meeting 2017 Workshop 02.02.2017 Zurich, Switzerland Santello Mirko;


Self-organised

Title Date Place
Neuroscience Careers in Academia and in Industry, gender Issues 24.04.2018 Zurich, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Moderator at - Neuroscience Careers in Academia and in Industry (ognized by ZNZ Zurich) German-speaking Switzerland 2018
Talks/events/exhibitions Academic Careers in the Life Sciences (young academia). German-speaking Switzerland 2017
Talks/events/exhibitions Migraine & pain- BrainFair, University of Zurich open day. German-speaking Switzerland 2017
Media relations: print media, online media Santello_Lab Twitter Twitter International 2017

Awards

Title Year
Pfizer Forschungspreis: Neurowissenschaften und Erkrankungen des Nervensystems 2016
Winner (+150 candidates) of a Group Leader position in Neuroscience at VIB-Leuven (Belgium) 2016

Abstract

Background: Migraine is a severely debilitating disorder affecting a large fraction of the population and it has been classified as one of the 20 most disabling diseases. It is characterized by long-lasting pulsating unilateral headache often accompanied by a number of other neurological symptoms (aura). There is only limited knowledge on the mechanism underlying the occurrence of migraine attacks. The current hypothesis points for increased cortical excitability as the cause for migraine. Thus, in migraine patients sudden raise in brain activity triggers the so-called cortical spreading depression (CSD), a depolarizing wave that slowly travels through the cortex, which underlies aura and leads to transient activation of meningeal nociceptors. Yet, enhanced excitability of cortical areas responsible for pain perception may play a role in the establishment of the pathological condition. I could recently demonstrate that plasticity of specific dendritic channels in one of these areas (the anterior cingulate cortex, ACC) is at least partially responsible for neuropathic pain occurrence. Since migraine and chronic pain share many important features (spontaneous pain episodes, allodynia, hyperalgesia, etc.) and both pathologies are associated with recurrent activation of the cortical pain matrix my hypothesis is that they may be caused by similar mechanisms. Working hypothesis: I hypothesize that, in a mouse model of migraine caused by a mutation of a gene expressed by glial cells, neurons of the ACC display intrinsic hyperexcitability. Since glial cells can strongly influence activity of neurons, this mutation may engender secondary neuronal malfunction leading to ACC hyperexcitability. Altered activity of this brain area could be responsible for increased likelihood of episodic activation and sensitization of the trigeminovascular pain and implicated in migraine chronification.Aims and experimental design: Neuronal properties in the migraine mouse model will be assessed by double somatic and dendritic patch-clamp recordings in a brain slice preparation containing the ACC. Plasticity of glial cell function will be assessed by recording K+ and glutamate uptake currents in parallel with Na+ and glutamate imaging in situ. The inhibitory effect of agonists and antagonists of receptors for neuromodulators will be tested on ACC neurons by somatic and dendritic recordings in the slice and in vivo microinjections.Expected results and impact: If the ACC, a cortical region implicated in pain perception, displays altered neuronal activity, this will be the first report showing that abnormal cortical activity is not only responsible for spreading depression occurrence but it may additionally favor pain establishment and central sensitization. Characterization of these neuronal alterations and candidate receptors able to modulate neuron’s activity in the ACC will help to devise new and/or more targeted treatment strategies for migraine therapy.
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