Epigenetic control of structural and functional plasticity in spinal circuits

A08 2Neurons have a highly specialized morphology, key to their functioning, which can undergo remodelling. Structural changes take place in response to physiological as well as to pathological stimulation. One of the pathological states in which maladaptive morphological rearrangements can be observed is chronic pain. The molecular players and genes regulating the structural changes underlying the critical transition between acute pain and chronic pathological pain have not been thoroughly investigated. Recently, it has been demonstrated that the shift from normal nociception towards hypersensitivity and hyperalgesia typical of chronic pain requires changes in gene expression in neurons of the dorsal horn of the spinal cord. Nuclear calcium is one of the most prominent regulators of gene transcription in hippocampal and spinal cord neurons. It modulates gene expression by directly acting on transcription factors or by regulating epigenetic processes. Interestingly, genes regulated by nuclear calcium signalling are emerging as key regulators of neuronal morphology. However, if and how epigenetic gene regulatory events control structural remodelling of spinal cord circuits and central sensitization remains to be investigated.

We hypothesize that, in the dorsal horn of the spinal cord, epigenetic processes modulate nociception-induced gene transcription and contribute to circuitry remodelling and central sensitization.

Our study includes in vivo experiments in which neurons of the spinal cord dorsal horn of adult mice are being manipulated using genetic tools and analysed functionally and morphologically. Additional experiments will be done with dissociated cultured mouse spinal cord neurons.

A08 1Key Questions:

  1. 1. Does nociceptive activity in different pain states mediate transcription by influencing epigenetic processes?
  2. 2. What is the role of epigenetic mechanisms in chronic pain states and spinal circuitry remodelling? Does modulation of DNA methylation and/or histone acetylation influence maladaptive responses in pain models? Do these phenomena alter structural features of spinal circuits (i.e., synapse number, dendrites)?
  3. 3. Which genes are controlled by epigenetic modulators in spinal cord neurons in models of chronic inflammatory or neuropathic pain?  

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