Uncovering the cortical cellular basis of specificity and chronicity of pain

Descrizione del progetto

I meccanismi neurali coinvolti nel dolore cronico

Il dolore cronico è una delle maggiori sfide della medicina perché i circuiti neurali che lo sostengono si sovrappongono a quelli che regolano la sensazione, il pensiero e l’emozione, confondendo il confine tra lesione fisica ed esperienza vissuta. Il progetto PAIN ENSEMBLES, finanziato dal CER, esplorerà come gruppi di neuroni co-attivi nella neocorteccia influenzino la percezione del dolore e si adattino ai ricordi del dolore e della paura passati. Utilizzando tecniche avanzate in modelli murini, il progetto identificherà questi ensemble neuronali legati al dolore, valuterà la loro connettività e attività e comprenderà il loro ruolo nella transizione dal dolore acuto a quello cronico. Esaminerà inoltre l’impatto della rete di salienza sulla percezione del dolore e studierà metodi non invasivi per alleviare il dolore invertendo la plasticità neuronale.

Obiettivo

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.