INJURY-INDUCED SPATIAL MEMORY IMPAIRMENTS ARE LINKED TO UNCOORDINATED HIPPOCAMPAL NEURONAL FIRING

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PROJECT SUMMARY Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults1. TBI afflicts more than two million people annually in the United States, with an estimated 5.3 million TBI survivors living with lasting neurological impairments2,3. Mild TBI (mTBI) or concussion, accounts for nearly 90% of TBIs, with symptoms including deficits in learning and memory that profoundly affect the daily life and overall health of TBI survivors. Although TBI survivors suffer a range of cognitive impairments, deficits in learning and memory are most common4–6. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by TBI. Little is known about the precise mechanisms by which hippocampal damage produces memory deficits. Our preliminary data indicate that spatial memory (a type of episodic memory required for the discrimination of a spatially moved object), requires coordinated hippocampal theta and gamma rhythms in the local field potential and neuronal firing time-locked to those rhythms (Figures 7-9 and Innovation section below). Both of these required components are critically dependent on the activity of inhibitory neurons, and specific inhibitory neurons in hippocampal area CA1 and the dentate gyrus (DG) are significantly altered after TBI7,8. Based on these results we hypothesize that altered synaptic transmission in specific hippocampal inhibitory neuron populations alters the balance between excitation and inhibition (E/I balance), leading to local circuit dysfunction and significant weakening of the coordinated hippocampal oscillations and neuronal firing required for normal spatial memory. To test this hypothesis, in vivo and in vitro recordings together with chemogenetic manipulation of specific subpopulations of inhibitory neurons in area CA1 and DG will be used to determine whether restoring normal inhibitory neuron function will reinstate normal rhythms, time-locked action potential firing, and normal spatial memory.