UC Irvine

Traumatic brain injury produces lasting cognitive impairments that can persist long after the initial insult. Although the primary injury may be spatially restricted, its effects on neural circuits can be widespread, beyond the site of tissue damage and evolve over time. In this dissertation, I investigated the effects of brain injury across multiple levels of neural circuit organization, from early patterns of neuronal activation to the functional integrity of hippocampal spatial representations. First, I examined the spatial extent of neuronal activation during the initial response to focal injury using a targeted recombination in active populations (TRAP) reporter mouse model. I found widespread activation of neurons that extended well beyond the glial response to injury. Second, using rabies virus whole-brain tracing, I found that brain injury reorganized inhibitory circuits in the hippocampus, converting interneurons into hyperconnected hubs while reducing their long-range inputs. Interestingly, this same pattern of reorganization was seen in a distant brain region, the prefrontal cortex, that is not directly damaged by the injury. Finally, I examined the functional consequences of chronic circuit disruption within the hippocampus, a structure critical for learning and spatial memory. Using longitudinal in vivo calcium imaging of CA1 neurons in freely behaving mice, I evaluated how brain injury alters the activity and spatial coding of individual neurons. Despite relatively preserved overall neuronal activity and the continued presence of place cells, brain injury degraded the precision of spatial representations in the hippocampus. Place cells exhibited broader tuning and the population of cells capable of participating in spatial representations was diminished after injury. These alterations were accompanied by impaired spatial novelty discrimination, linking disrupted spatial coding and cognitive impairment. Together, these findings support a model in which chronic dysfunction after injury emerges not only from neuronal loss but from widespread and lasting changes in the organization and function of surviving circuits.