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Function and plasticity of afferent inputs to the anterior cingulate cortex in chronic pain

English title Function and plasticity of afferent inputs to the anterior cingulate cortex in chronic pain
Applicant Nevian Thomas
Number 182571
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 01.09.2019 - 31.08.2023
Approved amount 1'008'000.00
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Keywords (5)

two-photon imaging; neuronal network; synaptic plasticity; nociception; chronic pain

Lay Summary (German)

Lead
Chronische Schmerzen sind ein weit verbreitetes Krankheitsbild, an dem allein in der Schweiz über eine Millionen Menschen leiden.Aus den anhaltenden Schmerzen, die zu einer massiven Beeinträchtigung der Lebensqualität führen, entwickeln sich emotionale Begleiterscheinungen, wie Antriebsschwäche, Schlaflosigkeit, Angstzustände und Depressionen. Dieses Projekt untersucht die Mechanismen der Entstehung dieser Begleitsymptome bei chronischen Schmerzen.
Lay summary

Chronische Schmerzen entstehen durch langanhaltende 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. Insgesamt, werden die Nervenzellen aktiver und dadurch wird die Schmerzwahrnehmung verstärkt. Diese Veränderungen haben auch Einfluss auf die emotionale Schmerzverarbeitung. Bisher ist wenig darüber bekannt, wie die Informationen, die der Gyrus Cinguli aus anderen schmerz-assoziierten Hirnarealen erhält verarbeitet werden und ob  diese Eingangskanäle schon veränderte Aktivitätsmuster bei chronischen Schmerzen zeigen. Wir werden daher untersuchen, wie verschiedene Hirnareale mit dem Gyrus Cinguli kommunizieren und wie dieser die Informationen verarbeitet.

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 und die emotionalen Begleiterscheinungen dämpfen.
Direct link to Lay Summary Last update: 07.08.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
159872 Causes and consequences of circuit remodelling by synaptic plasticity on the dynamics of cortical neuronal networks in chronic pain 01.05.2015 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. It is characterized by unexplainable widespread pain, burning sensations, pain caused by light touch or spontaneous pain in the absence of a noxious stimulus that can last for months. Furthermore, comorbid symptoms of chronic pain include increased anxiety, lack of motivation and depression. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. 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 cause the modifications in the cortical circuits and what functional relevance they have. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. The ACC is a hub for pain processing that is well connected to most brain regions of the pain matrix. We found that sciatic nerve damage resulted in a remodelling of the neuronal circuitry in layer 5 of the ACC with a loss of connections between excitatory and inhibitory neurons in both directions suggesting that neuropathic pain causes a disinhibtion of cortical neuronal networks. Furthermore, pyramidal neurons show increased excitability and synaptic plasticity mechanisms are impaired. The plasticity mechanisms that lead to the increased excitability in the ACC are still elusive. We hypothesise that increased afferent drive to the ACC induced by peripheral and spinal modifications as well as inputs from other brain areas of the pain matrix is instrumental to the observed changes. We would like to elucidate the properties, function and modification of the afferent inputs to the ACC in neuropathic pain. After a general mapping of inputs, we will focus some important afferents to the ACC in particular. Afferent input mapping to the ACC. The anatomical connectivity of the ACC was recently published. We will now map the functional connectivity of these afferents of the pain matrix to the ACC in a layer and cell type specific manner and investigate plastic modifications of these inputs in neuropathic pain. In this way, we will be able to derive the consequences of modifications of altered afferent drive to the ACC network. This will be important to understand the local network dynamics and to disentangle ACC intrinsic modifications from altered afferent inputs. We will use channelrhodopsin-2 (ChR2) assisted input mapping by viral vectors injected into the brain regions that project to the ACC. Cell type and layer specific patch-clamp recordings together with optogenetic stimulation will allow to investigate the afferent inputs in control and neuropathic pain conditions. Transgenic mouse lines with markers in the different interneuron subtypes (PV, SOM, 5-HT3) will be used to map the inputs onto these interneurons differentially.Understanding the cellular mechanisms of chronic pain is of high clinical relevance because so far there are no satisfactory treatment strategies for most chronic pain syndromes. The proposed experiments will give fundamental insights into the role of the afferent inputs to the chronification of pain in a cortical brain area that is engaged in the emotional and affective processing of pain. Furthermore, we will gain novel knowledge about the cortical plasticity mechanisms leading to persistent pain and this might lead to the identification of novel treatment strategies for this pathological condition.
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