Project

Back to overview

Causes and consequences of circuit remodelling by synaptic plasticity on the dynamics of cortical neuronal networks in chronic pain

English title Causes and consequences of circuit remodelling by synaptic plasticity on the dynamics of cortical neuronal networks in chronic pain
Applicant Nevian Thomas
Number 159872
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Neurophysiology and Brain Research
Start/End 01.05.2015 - 30.09.2018
Approved amount 600'000.00
Show all

Keywords (7)

cortex; synaptic plasticity; chronic pain; disinhibiton; neuronal network; neuropathic pain; anterior cingulate cortex

Lay Summary (German)

Lead
Chronische Schmerzen sind ein weit verbreitetes Krankheitsbild, an dem allein in der Schweiz über eine Millionen Menschen leiden. Leider, fehlen bei vielen Patienten bisher wirksame Therapieansätze. Anhaltende Schmerzen führen zu einer massiven Beeinträchtigung der Lebensqualität der betroffenen Personen und stellen eine ausserordentliche emotionale Belastung dar. Daher ist die Erforschung der Entstehung chronischer Schmerzen eine wichtige Aufgabe der neurobiologischen Forschung.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Chronische Schmerzen entstehen durch langanhaltende und irreversible Modifikationen der Nervenzellen und deren Netzwerke, die an der Schmerzwahrnehmung beteiligt sind. Ein wichtiges Hirnareal, in dem die emotionale und affektive Komponente dieser Schmerzen bewusst wird ist der Gyrus Cinguli. Wir untersuchen die neuroplastischen Veränderungen in dieser Region und haben eine massive Restrukturierung der neuronalen Netzwerke beobachten können. Inhibitorische Interneurone, die die elektrische Aktivität des Gyrus Cinguli kontrolieren, verlieren bei chronischen Schmerzen ihren Einfluss. Dieses bedeutet, dass es zu einer verstärkten Erregung der Schmerznetzwerke kommt und so eine erhöhte Schmerzwahrnehmung resultiert. Die zellulären Mechanismen, die zu diesem Verlust der Inhibition führen sind bisher unbekannt. In einem Teilprojekt werden wir die Ursachen und Mechanismen der Modifikation der inhibitorischen Synapsen untersuchen. Diese Ergebnisse werden wir benutzen, um in einem zweiten Schritt pharmakologische Substanzen zu untersuchen, die die Inhibition verstärken und somit einen schmerzlindernden Einfluss ausüben sollten. Weiterhin wird untersucht werden, ob diese Therapieansätze auch positive Auswirkungen auf die häufig mitauftretenden emotionalen Beeinträchtigungen, wie Angstzustände und Depression haben.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit Grundlagenforschung, die das Wissen über die grundlegenden Abläufe bei der Entstehung von chronischen Schmerzen erweitern soll. Aus diesen Erkenntnissen könnten potentielle neue Strategien für die Schmerztherapie entwickelt werden. Dieses könnte in der Zukunft zu einer besseren Behandlung von chronischen Schmerzen beitragen.

Direct link to Lay Summary Last update: 28.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
The cingulate cortex: divided in pain
Nevian Thomas (2017), The cingulate cortex: divided in pain, in Nature Neuroscience, 20(11), 1515-1517.
The brain-penetrant 5-HT 7 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-HT 7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain, in Neurobiology of Disease, 106, 214-221.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Walter Senn / University of Bern 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
Pain Meeting Talk given at a conference Network dynamics in chronic pain 06.08.2018 Taormina, Italy Nevian Thomas;
Neuromodulation Talk given at a conference Neuromodulation in chronic pain 18.09.2017 Lausanne, Switzerland Nevian Thomas;
Pain and Emotions Talk given at a conference Plasticity of cortical circuits in neuropathic pain 17.08.2017 Toronto, Canada Nevian Thomas;
Pain Meeting Poster Network dynamics in chronic pain 01.03.2017 Cambridge, Great Britain and Northern Ireland Nevian Thomas;
Seminar des Sonderforschungsbereichs Schmerz Individual talk Plasticity of cortical circuits in chronic pain 26.10.2016 Heidelberg, Germany Nevian Thomas;
Winter Conference on Neuronal Plasticity Talk given at a conference Mechanisms of long term depression 31.01.2016 Maui, United States of America Nevian Thomas;
Seminar Institut für Neuroinformatik Individual talk Neuronal plasticity in chronic pain 20.11.2015 Zürich, Switzerland Nevian Thomas;
7th Cannabinoid Workshop Talk given at a conference Retrograde signalling in spike-timing dependent depression 17.09.2015 Sestri Levante, Italy Nevian Thomas;
Minisymposium Learnin and Memory Talk given at a conference Mechanisms of spike-timing dependent plasticity 08.09.2015 Paris, France Nevian Thomas;


Self-organised

Title Date Place
Swiss Memory Workshop, Session Synaptic Plasticity Mechanisms 24.08.2015 Spiez, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Die Schönheit des Gehirns, Museumsnacht Bern German-speaking Switzerland 2018
Talks/events/exhibitions Nacht der Forschung, Neurophysiologie German-speaking Switzerland 2017
Talks/events/exhibitions Institutsführung für Schüler German-speaking Switzerland 2016
Talks/events/exhibitions Kinderuniversität Bern, Wie kommt der Schmerz in den Kopf German-speaking Switzerland 2016

Awards

Title Year
Pfizer Research Prize 2016

Associated projects

Number Title Start Funding scheme
128415 Dendritic excitability and synaptic plasticity of cortical neurons under physiological and pathological conditions of neuropathic pain 01.07.2010 SNSF Professorships
182571 Function and plasticity of afferent inputs to the anterior cingulate cortex in chronic pain 01.09.2019 Project funding (Div. I-III)
173486 Cortico-striatal neuronal plasticity and processing of pain affect during the transition to chronic pain 01.04.2018 Bilateral programmes

Abstract

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Chronic neuropathic pain is characterized by unexplainable widespread pain, burning sensation, pain caused by light touch or acute pain in the absence of a noxious stimulus that can last for months. In addition to modifications in the periphery and in the spinal cord, changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits and what functional relevance they have. We studied the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. The ACC is also a key brain region contributing to the development of chronic pain. We are investigating the neuronal plasticity mechanisms of cortical neurons that contribute to chronic pain. In particular we are interested in the changes that occur at synapses, dendrites, neurons and neuronal networks under conditions of neuropathic pain. We found that sciatic nerve damage resulted in a striking remodelling of the neuronal circuitry in layer 5 of the ACC. We observed a loss of connections between excitatory and inhibitory neurons in both directions suggesting that neuropathic pain causes a disinhibtion of cortical neuronal networks. Network modelling suggested that this disinhibtion results in increased excitability of the ACC and thus contributes to increased pain sensation.We would like to understand this remodelling of the neuronal networks in ACC after nerve injury in greater detail. Particularly, we would like to elucidate some of the cellular mechanisms that lead to the loss of neuronal connections and measure the resulting network dynamics in vivo. Furthermore, we would like to study the consequences of these plastic changes on the behaviour of the animal and test if targeted pharmacological interventions can reverse the pain-induced behaviour. Understanding the cellular mechanisms of chronic pain is of high clinical importance because so far there are no satisfactory treatment strategies for most chronic pain syndromes. The proposed experiments will give fundamental insights into the consequences of neuropathic pain in cortical neuronal networks. Furthermore, we will gain novel insight into cortical plasticity mechanisms and this might lead to the identification of novel treatment strategies for chronic pain.
-