Role of dentate gyrus gating and neurogenesis in the pathophysiology of mild TBI

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Summary/ Abstract CHANGE OF GRANTEE ORGANIZATION REQUEST Traumatic brain injury (TBI) affects approximately 1.7 million people in the United States every year and it is estimated that up to 75% of these injuries are classified as mild TBI. However, the word “mild” is an inadequate description as mild TBI (mTBI) is typically accompanied acutely by significant deficits in cognition that often manifest as long-term alterations in learning and memory, attention, and emotional control. Despite the high incidence and often lasting impact of mild TBI, the factors that induce long-term cognitive deficits remain unknown. Consequently, the goal of this project is to identify alterations in neuronal function that may underlie long-term deficits caused by mTBI. Based on our preliminary data, we hypothesize that mTBI causes structural and functional alterations in the dentate gyrus that contribute to lasting cognitive deficits. A principal function of the dentate gyrus is to restrict the flow of neural activity through the hippocampus. This “gating” function is essential for propagating sparse representation of cortical sensory signals to downstream pyramidal cells and is achieved by strong local inhibitory circuitry. Furthermore, the dentate gyrus is one of two brain regions where neural progenitor cells continuously generate newborn neurons. Our preliminary data indicate that a single episode of mTBI acutely disrupts the balance of inhibition and excitation and is followed by a robust enhancement in neurogenesis that persists for months. We propose that the transient breakdown of the dentate gate leads to activity-induced enhanced neurogenesis and predict that mTBI-induced neurogenesis has long-term detrimental effects on dentate function that contribute to lasing cognitive impairments. Using a clinically-relevant mouse model of mTBI, we will evaluate our hypothesis using three specific aims. First, we will determine how mTBI alters the gating function of the dentate gyrus using electrophysiological techniques in hippocampal slices and corroborate these findings in vivo after mTBI. In the second aim, we will use transgenic reporter mice to determine how mTBI alters the structural and functional properties of mTBI-induced new neurons. We will evaluate how newly generated cells integrate into the circuitry of the dentate gyrus and affect the gating function. In the third aim, we will test the hypothesis that dentate alterations contribute to cognitive impairments. At time points when dentate abnormalities are present, mice that received mTBI will be evaluated in a variety of well-established behavioral paradigms to test learning, memory, attention and emotional control. We will also test whether manipulating gating and neurogenesis are sufficient to recapitulate and block the behavioral impairments caused by mTBI. The successful completion of this project will elucidate a potential mechanism for cognitive deficits after mTBI as well as identify novel targets for treating the most common form of brain injury.