Uncovering the cortical cellular basis of specificity and chronicity of pain

Description du projet

Les mécanismes neuronaux impliqués dans la douleur chronique

La douleur chronique constitue l’un des plus grands défis de la médecine, car les circuits neuronaux qui la sous-tendent se recoupent avec ceux qui régissent les sensations, la pensée et les émotions, brouillant ainsi la frontière entre la lésion physique et l’expérience vécue. Le projet PAIN ENSEMBLES, financé par le CER, étudiera comment les groupes de neurones coactifs du néocortex influencent la perception de la douleur et s’adaptent aux souvenirs de douleur et de peur passés. À l’aide de techniques de pointe sur des modèles murins, ce projet permettra d’identifier ces ensembles neuronaux liés à la douleur, d’évaluer leur connectivité et leur activité, et de comprendre leur rôle dans la transition de la douleur aiguë à la douleur chronique. L’équipe examinera également l’impact du réseau de la saillance sur la perception de la douleur et étudiera des méthodes non invasives de soulagement de la douleur par le biais d’une inversion de la plasticité neuronale.

Objectif

Chronic pain remains a fundamental unsolved puzzle in biology and an unmet global challenge in clinical practice. Progress is limited by major gaps in knowledge on neural substrates, owing to overwhelming redundancy of implicated regions and pathways with several pain-unrelated sensory, cognitive and emotional functions as well as lack of understanding on the origins of plasticity and cellular substrates for diverse psychosocial and environmental influences on pain. Here we propose that neocortical neuronal ensembles, i.e. discrete cohorts of co-active neurons intermingled within seemingly redundant pathways, represent a mechanistic correlate for imparting specificity to pain perception, while also providing adaptive flexibility to context and introspective bodily states, and serve as convergent substrates for divergent influences, such as past experience of pain, fear memory and expectation. Using cutting-edge in vivo methods, such as multiphoton imaging of activity and structure, electrophysiological parallel recordings of hundreds of neurons, fine-grained behavioral analyses, activity-based cell tagging approaches, opto-chemogenetic manipulations and single cell transcriptomics in mouse models of acute and chronic pain, we aim to (i) identify neocortical pain ensembles that delineate pain from other sensory percepts, valence states and cognitive functions, and determine their composition, connectivity, coordinated activity in local and across distant networks and functional relevance to pain, (ii) study their dynamic plasticity over the transition from acute to chronic pain and delineate bottom-up (peripheral-spinal) and top-down (brain intrinsic) influences, with a focus on studying the role of the salience network in channeling context, expectation and fear memory and its dysfunction in chronic pain and (iii) study the potential of reversing plasticity of neuronal ensembles by non-invasive neurostimulation and behavioral approaches for achieving pain relief.