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Depressive-like impairment evident as early as 1 month post traumatic brain injury.Cognitive flexibility impaired at 3 months post injury on Barnes Maze.Changes in prefrontal cortex synaptic and axonal integrity evident at 1 month post injury.TBI is a significant risk factor for the development of dementia, with the interaction between structural damage from TBI and neuroinflammation potentially driving this relationship. This study investigated the early chronic post-TBI neuroinflammatory response and its relationship to both neurodegenerative pathology and functional impairment up to 3 months post-injury. Sprague-Dawley rats underwent either sham surgery or the Marmarou model of diffuse moderate-severe TBI. At 1-month and 3-months post-injury, a functional battery encompassing motor function, depressive-like behaviour, anxiety and cognition was performed. Western blot and immunohistochemical analysis assessed a range of inflammatory, neurodegenerative and oxidative stress markers. At both 1 and 3-months post injury, depressive-like behaviour was significantly increased in TBI animals, with TBI animals also exhibiting impaired cognitive flexibility at 3 months, although learning and memory remained intact. This was accompanied by a significant decrease in markers of synaptic integrity and astrocytic and microglia number within the pre-frontal cortex at 1-month post-injury, although this resolved by 3-months post-injury. In contrast, minimal pathology was evident within the hippocampus at 1 month, with only a decrease in neurofilament-light seen at 3 months post-injury. Thus, following a moderate-severe diffuse injury, the pre-frontal cortex is most vulnerable to early neuro-structural changes. While these changes are resolved at 3 months post-injury, future studies should investigate whether they re-emerge or progress to other areas, such as the hippocampus, at later time points, which could predispose individuals to the development of dementia.