Sharp wave ripple stimulation as a potential strategy to enhance memory after TBI

Abstract One of the key complaints of persons who sustain a traumatic brain injury (TBI) is persistent memory dysfunction. While a large body of evidence indicates that preventing neuronal loss in the acute stage of TBI can improve outcome, strategies aimed at improving the function of the surviving neurons are scarce. The hippocampus, which is essential for learning and memory, is a key region of the brain whose function is often compromised in experimental models of TBI as well as in human patients. The ensuing learning and memory impairments can interfere with every day activities and compromise quality of life. These deficits, which can occur in the absence of neuronal loss, are likely due to perturbations of hippocampal function. As an animal learns new information, hippocampal neurons fire and change their properties (e.g. undergo plasticity) in order to store the new information. In periods of awake restfulness and sleep, the hippocampus spontaneously and rapidly “replays” the learned information in a pattern called a sharp wave-ripple (SPW-R). It is thought that SPW-Rs play a critical role in reinforcing the learning experience, with disruption of SPW-Rs being demonstrated to cause hippocampal- dependent memory impairments. Although TBI is known to cause learning and memory impairments, it is not known if these deficits result, in part, from reduced SPW-Rs, or if memory can be restored by augmenting ripples. In order to bridge this knowledge gap, we propose to record SPW-R activity in behaving animals using probes implanted into the dorsal hippocampus of sham and TBI rats. We will then test if optogenetic or pharmacological stimulation of hippocampal ripples can be used to improve the memory of TBI animals. The research proposed in this R21 application aims to obtain maximum payoff, and thus has risk that goes along with it.