Project Summary 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 previously 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 kind of isoform expressed is predictive of recovery following TBI. We have 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 define the ApoE-dependent memory trace after injury to get a comprehensive picture of how altered hippocampal circuitry affects the entire brain. For Specific Aim 2, we will use our recently generated ApoE4 mouse to conditionally replace ApoE with human ApoE4 and prove our underlying hypothesis that ApoE4 functions as a dominant negative. Finally, in Specific Aim 3, we will elucidate the mechanism underlying ApoE’s role in injury-induced neurogenesis by exploring how microglial TREM2 regulates this process via binding of astrocytic ApoE. 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.