Traumatic brain injury initiates a sequence which includes both beneficial and detrimental events. Injury to the cerebral cortex results in rapid degeneration of thalamic neurons which are not available for reconnection to undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 (MCP-1) is a chemokine expressed following injury which attracts microglia and other cells of the monocyte lineage. Preliminary experiments have identified rapid expression of MCP-1 in the thalamus following cortical lesions. The hypothesis is that MCP-1 is the critical molecule in modulation brain repair responses. In this proposal, induced mutants/genetic models of brain-targeted MCP-1 over-expression, knockout of MCP-1, and knockout of the high affinity MCP-1 receptor (CCR2), will provide in vivo modulation of MCP-1. The proposed experiments will examine the extend and temporal pattern of axotomized neuron death and of microglial migration, activation and proliferation in the thalamus. The following specific aims are proposed 1) To determine the effect of brain-targeted over- expression of MCP-1 on degeneration of thalamic neurons following cortical injury, 3) to determine the effect of ablation of MCP-1 and of its high affinity receptor, CCR-2, on degeneration of thalamic neurons following cortical injury, 4) to determine the effect of genetic manipulation of MCP-1 and its receptor n monocyte trafficking and microglial migration following cortical lesions. Understanding the role of MCP-1 in attracting of monocytes and microglial to sites of damage, and in activation of these cells, may lead to determination of targets for therapies for treatment for brain injury.
