Determine the Role of Microglia in Adult Circuit Remodeling in a Mouse Model of Whisker Denervation

About This Grant

Project Summary Denervation injuries lead to altered neural activity in sensory processing regions of the brain. Recovery from these injuries is achieved by learning new motor skills to perform tasks of daily living; this requires successful cortical remapping. This remapping is thought to be mediated in part by changes in thalamocortical (TC) connections from the thalamus to cortex. However, the reasons that some patients recover well while others do not is poorly understood. Microglia shape circuits during development by pruning synapses in an activity dependent manner. Neurons and other cells express “eat me” and “don’t eat me” signals that act through microglial receptors to guide removal of underused synaptic connections such as those arising from the denervated body part. Large scale activity changes in sensory circuits after denervation injury lead to altered signaling through these microglial receptors, altering the activity and function of synapse-associated microglia. However, it is poorly understood how microglia coordinate with neurons to direct adult cortical circuit reorganization after peripheral injury. The goals of this project are to determine the necessity of microglia for post-injury adult circuit reorganization, determine the impact of aberrant signaling from unpruned connections, and identify the molecular mechanisms microglia and neurons utilize to coordinate their activity with other cells in the brain. To understand how microglia mediate post-denervation circuit remodeling, we will use a mouse model of unilateral infraorbital nerve transection (IONX). IONX mimics many aspects of circuit remodeling that occurs after unilateral denervation injury. We hypothesize that IONX causes microglia-mediated TC remodeling in the deprived somatosensory cortex of adult mice. This remodeling is expected to cause behavioral adaptations, particularly related to orofacial sensory/motor function. We will address this hypothesis by 1) determining the necessity of microglia for TC synapse density changes after IONX. Using tissue collected from acute, subacute and chronic timepoints, we will quantify changes in thalamocortical input density within the deprived somatosensory cortex, and microglial association with and removal of TC synapses. We will then deplete microglia to establish if microglia are required for the changes in the deprived somatosensory cortex. We will assess orofacial function in sham and IONX mice to demonstrate the impact of microglial TC circuit reorganization on behavioral adaptations. We will also modulate the activity of TC connections in the deprived somatosensory cortex to establish that preserved, erroneous activity after IONX leads to orofacial dysfunction. 2) We will use gene expression to identify the mechanisms by which microglia and neurons influence adult circuit remodeling after injury, such as identification of inactive synapses and increased phagocytosis. The findings of this proposal will improve our mechanistic understanding of how cells in the adult brain adapt to peripheral denervation injury, and can be used to gain insight into healthy adult plasticity.