Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults. Despite initial cognitive deficits, many individuals experience significant recovery. This proposal investigates how the ability to learn and recall information recovers. The limbic system plays a prominent role in memory formation, consolidation, and recall. Using the clinically relevant mouse lateral fluid percussion injury (FPI) model of TBI, preliminary data show time-dependent recovery in an anterograde cognitive task. Permanent negative alterations in neuronal number and circuitry occur in the ipsilateral hippocampus. The central hypothesis of this proposal contends that the time-dependent functional improvement following FPI is due to the reorganization of anatomic and physiologic circuits within the contralateral hippocampus. Experiments will test three hypotheses: 1) mouse lateral FPI transiently alters neuronal function, but not the anatomy of the contralateral hippocampus, 2) multiple sub-cellular events occur in the contralateral hippocampus enabling functional improvement and 3) the contralateral hippocampus plays the major role in cognitive recovery. A systems approach is used, incorporating design-based stereology to quantify neuronal and synapse number by light and electron microscopy, determination of dendritic re-modeling using dil label and confocal microscopy, field and single cell electrophysiology in hippocampal slices to analyze circuitry, and performance in the conditioned-fear paradigm to test cognitive function after manipulations of the contralateral hippocampus. The compensatory mechanisms demonstrated in the contralateral hippocampus may help us better understand cognitive recovery in human TBI and lead to novel strategies for improving speed and extent of recovery. ? ?
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