Role of hippocampal adult-born granule cells in TBI-induced dentate gyrus circuit pathology and pattern separation deficit

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Project Summary Traumatic brain injury (TBI) is a highly prevalent health issue that results in cognitive and psychological deficits such as memory dysfunction, depression, anxiety, and epilepsy. Following TBI in rodent models, there is a robust and transient increase in hippocampal adult neurogenesis. Adult-born granule cells (abGCs) born in response to cortical impact injury exhibit altered morphology and migration patterns, suggesting these neurons may make aberrant connections within the dentate gyrus network. Normally, abGCs mature to form functional excitatory synapses onto parvalbumin expressing interneurons by 8 weeks post-mitosis and act to suppress the dentate gyrus excitability through activation of inhibitory circuits. If abGCs born in response to injury fail to integrate into their respective inhibitory networks, then they may contribute to dysfunctional inhibition, hyperexcitability, and altered memory processing in the dentate gyrus following TBI. Specifically, pattern separation, a dentate-dependent memory function necessary to distinguish overlapping spatial and physical information, relies on neurogenesis and sparse dentate activity levels. Normal pattern separation function is largely mediated by abGC coupling to feedback inhibition in the dentate gyrus and is drastically hindered following TBI. I hypothesize that TBI-induced abGCs are dysfunctional in their coupling to feedback inhibition and contribute to pattern separation deficits after brain injury. The proposed study will use the Fluid Percussion Injury (FPI) model of TBI which induces greater hippocampal neuropathology than cortical impact, and examine morphology, migration, and electrophysiological properties of TBI-induced abGCs at the 8 week post-injury time point. In-vivo and ex-vivo optogenetic manipulation of TBI-induced abGCs will be performed to analyze their contribution to network excitability and functional synapses onto target neurons respectively. TBI-induced abGC contribution to pattern separation deficit will be examined through optogenetic suppression during a hippocampal dentate-specific spontaneous location recognition task. The results of this study will resolve controversies about the role of injury-induced dysfunctional abGCs in dentate excitability and pattern separation deficits in response to injury.