PROJECT SUMMARY (ABSTRACT) An athletic career filled with head impacts (HI) predisposes athletes to memory impairments and is a risk factor for dementias including Alzheimer’s disease. While proteinopathy is clearly linked to brain dysfunction in the late stages of these disease, memory problems are also a common symptom in reported cases with early-stage disease – and even those cases with no neurodegenerative disease pathology. To understand the nature of the chronic memory impairments caused by HI, we are focused on the physiological changes that occur in the brain after exposure to a high frequency of non-damaging HI (HFHI), and comparing our results to a single severe single TBI. Our preliminary data shows that exposing mice to HFHI causes an adaptive response in excitatory synapses. These adaptations occur at the cost of normal brain function, with widespread and prolonged impairments in learning and memory. This synaptic dampening is permanent, and does not spontaneously reverse. In this proposal we aim to determine if we can reverse chronic synaptic dysfunction in the injured brain, and recall a forgotten memory. In this proposal we will test the hypothesis that HFHI disrupts synaptic transmission within the memory circuits of the hippocampus, and that activation of engram neurons can override these cognitive deficits and reanimate a forgotten memory. These data will allow us to test if it will be possible to treat cognitive impairments by targeting the synapse in different types of TBI. This will have profound implications for the millions of people living with cognitive and behavioral dysfunction after head impact, and could be harnessed to reduce the number of TBI patients that progress to develop Alzheimer’s disease each year.