Traumatic brain injury (TBI) is a serious condition, with an incidence of approximately 22 out of 100,000 people per year in the United States. Of those, over 90% fall into the mild TBI (mTBI) category. In the military, TBI accounts for approximately 22% of all reported injuries resulting from the most recent military conflicts in Afghanistan and Iraq. As with many injuries to neural tissue, the immediacy of a treatment for TBI may play an important role in minimizing the detrimental effects of the injury. An immediately available treatment, in the form of a small, portable kit that can be carried by troops and easily self-administered or given by another Soldier or medic, could be an invaluable benefit and drastically reduce the time until return to duty after a mTBI or improve patient stability and reduce post-hospital impairments in moderate or severe TBI. The scope of this work is to determine the optimal treatment conditions of intranasal insulin (INI) as an acute, on-field treatment for TBI. This proposal will test the hypothesis that INI will be effective in improving functional recovery in male and female rodent models and in the gyrencephalic ferret model of TBI. To test this hypothesis, we will evaluate INI in rat and mouse models of TBI in two different laboratories using two different TBI models, as well as in both the male and female sexes. In addition, we will test INI in a clinically relevant blast and rotational acceleration model of TBI in the gyrencephalic ferret model, to more closely mimic the clinical condition. Our previous studies have shown that INI improves memory function and reduces brain inflammation after TBI; we will continue this work to evaluate memory, learning, anxiety-like behavior, and pathological outcomes after injury and INI treatment. This proposal will establish the ideal therapeutic INI approach to guide future translation to a phase 1 clinical trial and will move us closer to a clinically viable treatment for TBI.