Fundamental astrocyte-neuronal coupling mechanisms in neuroplasticity of nociceptive circuits.

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Neuroplasticity underlies all types of experience-driven, long-term changes brain function. It is a fundamental process that promotes lasting changes in behaviour, such as nociceptive hypersensitivity. Although most research on brain plasticity has focused on neurons, several other cell types also appear to be involved. Astrocytes, a type of glial cell, are the most abundant cells in the central nervous system, and although classically considered supportive cells, recent evidence indicates that they are dynamic players in neuroplasticity. Exciting new findings indicate that nociceptive hypersensitivity increases astrocytic activity within the central nervous system. I have recently shown that, in the rat hippocampus, astrocyte-neuronal lactate shuttling during associative learning provides neurons with energy substrates that are necessary for neuronal changes involved in memory formation, including translation of several proteins that are critical for long-term memory. Multiple lines of research indicate that nociceptive hypersensitivity and long-term memory correspond with many similar molecular mechanisms and changes in neuronal activity. However, whether nociception-induced neuroplasticity engages astrocyte-neuronal lactate shuttling, and whether it is necessary for the development of nociceptive hypersensitivity has not been tested. My research program will employ nociceptive hypersensitivity as a model of experience-induced plasticity. The long-term objective of this research is to characterize astrocyte-neuronal interactions in neuroplastic changes within brain networks involved in nociception. We will first test the hypothesis that astrocyte-neuronal lactate shuttling is critically involved in nociception and nociceptive hypersensitivity. The specific objectives of my research program over the next five years are, 1) to demonstrate temporal effects of nociceptive hypersensitivity development on astrocyte-neuronal lactate shuttling; 2) to demonstrate whether astrocyte-neuronal lactate shuttling in the mPFC during noxious stimulation is necessary for behavioural responses and nociception-induced activity in the nociceptive brain circuit; and 3) to demonstrate the necessity of astrocyte-neuronal metabolic coupling in nociceptive hypersensitivity. Using nociceptive hypersensitivity as a model of neuroplasticity, our laboratory will identify the critical contributions of astrocyte-neuronal coupling in long term changes in neuronal function. This research program will establish our lab as a leader in the study of basic mechanisms of brain plasticity.