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Circadian control of microglial activation in chronic pain states

Principal Investigator:
  • Nader Ghasemlou, Queen's University

Project Overview

Circadian, or 24-hour, rhythms control almost all biological systems in our bodies with sleep-wake cycles and body temperature control the best known examples. Interestingly, pain is also governed by these 24-hour rhythms. People suffering from chronic neuropathic pain have been found to rate their pain as being worse during the night than in the morning. Work from others has shown a critical role for microglia, an immune-like cell in the nervous system that functions to maintain homeostasis and clear pathogens/debris from the brain and spinal cord. When microglia are activated, they can take on a pro-inflammatory phenotype which has been shown to be responsible for potentiating pain outcomes in mice. We now show that the activation profile of microglia and chronic pain outcomes are under circadian control in mice. We have found that mice are more sensitive to mechanical stimulation during the light phase (corresponding to their night-time, or resting phase) than during the dark phase; interestingly, microglia isolated from the spinal cord show a pro-inflammatory phenotype only during the light phase and take on an anti-inflammatory phenotype during the dark phase. Our group now seeks to identify the mechanisms controlling this response by generating a new transgenic mouse that lacks circadian rhythms only in microglia. We will first assess the impact of circadian rhythms on microglial activation in wildtype and transgenic mice. The contribution of microglial circadian rhythms to pain outcomes will then be identified, and changes at the gene level in microglial determined in cells lacking circadian rhythms. There are few treatment options for chronic neuropathic pain. Understanding how circadian rhythms control this response may help identify novel therapeutic targets. Our work may also help uncover new mechanisms underlying microglial activation, and can extend to various disorders, including Alzheimer’s disease, traumatic CNS injury, and autism.