Xu, Yajing; (2020) The role of microglia in shaping dorsal horn sensory circuitry during normal development and after early postnatal injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In recent years, infant pain research has revealed strong evidence that pain history impacts sensory processing in adulthood. It has become clear that (1) somatosensory processing in the neonatal CNS differs substantially from that in adults both in terms of structure and function and (2) that the neonatal period constitutes a critical time window during which noxious stimuli, e.g. injury, can cause persistent changes in somatosensory processing. While neuro-glia interactions are known to play a role in shaping neural circuits, the role of spinal cord microglia in the developmental and injury induced plasticity of somatosensory circuits is not known. Over postnatal development, dorsal horn circuits undergo considerable refinement both in terms of afferent input and local connections. I hypothesised that microglia cells, the innate immune cells of the CNS, are involved in this process. Further, I hypothesised that neonatal injury alters microglial refinement of synapses in the dorsal horn and that this process underlies the persistent changes in dorsal horn processing. In Chapter 2, I describe postnatal changes in microglial density and phagocytosis, and show that microglia do indeed refine A-fibre afferents in the dorsal horn through phagocytosis. In Chapter 3, I show the necessity of normal microglial function for dorsal horn maturation. Inhibiting microglial function postnatally with the drug minocycline or genetically with \textit{Tmem16f} cKO both altered dorsal horn sensory processing in adulthood. In Chapter 4, I investigate the acute effect of neonatal incision on microglial engulfment of synapses and show that the microglial removal of A-fibres and inhibitory synapses, but not excitatory synapses, was increased following incision. In Chapter 5, I investigated whether neonatal pain history alters microglial phagocytosis of synapses following a second injury in adulthood. Phagocytosis of synapses was increased following adult injury, but was not affected by pain history. In conclusion, microglia emerge as central players in the postnatal refinement of the dorsal horn, and disturbance of their normal function pharmacologically, genetically, or through injury can have profound effects on sensory processing in adulthood.

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