Following traumatic brain injury (TBI), patients often develop significant disability in cognition, communication, and behavioral or emotional stability. Problems with memory commonly occur following TBI and underlie some of the morbidity accompanying each of these affected areas. In addition, there is some spontaneous recovery after brain injury that occurs largely by unknown remodeling processes. It has been known for some time that TBI elicits increased generation of new neurons in the hippocampus; the significance of this, however, has not been clear. We have recently demonstrated that injury-induced neurogenesis underlies at least some of the spontaneous recovery associated with TBI. ApoE is a gene that commonly occurs in 3 different isoforms in humans and the particular isoform expressed is predictive of recovery following TBI. We have recently identified ApoE as an important regulator of hippocampal neurogenesis. The overall goals of this project are to determine how ApoE directs injury-induced neurogenesis following TBI and to investigate mechanisms that regulate this process.
In Specific Aim 1, we will establish how ApoE and two commonly occurring human isoforms, APOE3 and APOE4 regulate injury-induced neurogenesis.
For Specific Aim 2, we will use our recently generated floxed ApoE mouse to conditionally ablate ApoE specifically from progenitors and astrocytes to determine its in vivo function on neurogenesis during development and following injury. Finally, in Specific Aim 3, we will analyze injury-induced neurons in a variety of ApoE states and analyze how these states affect activation during learning and overall integration into the hippocampus. This project will therefore serve as the basis for translational studies aimed at using the presence of specific APOE isoforms in humans to direct reparative therapy following serious brain injuries such as TBI.
Following traumatic brain injury (TBI), patients often develop persistent disabilities, and specific problems with memory underlie much of the long-term adverse outcomes associated with serious brain injury. We have recently demonstrated that the some of the spontaneous recovery that occurs after TBI is due to generation of new neurons within the hippocampus, the part of the brain that mediates memory formation. We have also demonstrated that ApoE, a gene long associated with outcome following TBI, directs hippocampal development and the purpose of this project is to determine how ApoE regulates injury-induced neurogenesis.
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