Grant: Project Grant

In the nervous system, neurons and glial cells are embedded within a network of molecules called the extracellular matrix (ECM). The ECM components provide structural support, regulate synapse formation and function, and modulate neuronal excitability. In the brain, the ECM restricts neuroplasticity; thus, enzymatic digestion of the ECM enhances acquisition of memories and promotes cognitive flexibility and extinction. In the pain pathway, matrix metalloproteinases (MMPs), the major ECM-digesting enzymes, are activated in neuropathic pain conditions to promote mechanical hypersensitivity. However, it remains unknown whether this remodelling of the spinal cord ECM contributes to pathological changes in dorsal horn nociceptive circuits and pain hypersensitivity. We hypothesize that, similar to cognitive functions, the ECM restrains spinal plasticity and its remodelling facilitates the sensitization of nociceptive circuits. One of the major forms of the ECM found in the nervous system is perineuronal nets (PNNs). PNNs are densely packed network of the ECM located around cell bodies and proximal dendrites, predominantly enwrapping a subset of inhibitory interneurons. Inhibitory neurons have been shown to suppress nociceptive circuits' activation in the dorsal horn. Interestingly, digestion of PNNs around inhibitory neurons decreases their inhibitory activity. This raises the hypothesis that the digestion of PNNs in neuropathic pain sensitizes spinal cord central circuits by decreasing the activity of the inhibitory neurons. We will study the remodeling of spinal PNNs in neuropathic and inflammatory pain, and examine whether the degradation of PNNs surrounding inhibitory neurons in the spinal cord contributes to hyperexcitability. In summary, we will test the intriguing hypothesis that the ECM in the spinal cord restricts neuroplasticity, and that the remodeling of the ECM in neuropathic pain conditions contributes to the hypersensitivity.