The goal of this project is to study the 5-hydroxytryptamine 1F (5-HT1F) in stimulating mitochondrial biogenesis (MB) and recovery from spinal cord injury (SCI). SCI is a devastating disorder often resulting in loss of function below the injury site. While combat-related spinal trauma has been documented for centuries, in recent years, service members have been threatened by more advanced warfare, such as rocket-propelled grenades and improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. Further, and importantly, advancements in personal protection, vehicular protection and medical capabilities have allowed current military personnel to survive injuries that would have proven lethal in the past. The devastating and debilitating nature of these injuries, however, including SCI, has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. The development of pharmacological therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the military healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Neuronal loss of mitochondrial function ultimately leads to excitotoxicity and oxidative stress, emphasizing the critical nature of restoration of mitochondrial function following SCI. Evidence suggests that restoration of mitochondrial function after injury could protect against further injury progression and enhance recovery. Studies investigating mitochondria as a therapeutic target for SCI have only addressed individual aspects of mitochondrial function and have proven largely inefficacious. Therapeutics pursuing reestablishment of mitochondrial homeostasis through increased MB, however, following SCI could alleviate multiple facets of injury progression. Our preliminary data indicate that the 5-HT1F agonism induces MB in the spinal cord of both naïve mice and following SCI. Additionally, mice treated daily with the agonist LY344864 following SCI exhibited improved mitochondrial homeostasis, as well as decreased lesion volume, and increased vascular and locomotor activity by 7 days post-injury. Remarkably, LY344864 efficacy was similar when administration was initiated 1 or 8 h post-SCI. This effect was not observed in mice lacking the 5-HT1F receptor, indicating that the presence of this receptor is necessary for LY344864-induced MB. Lasmiditan is a potent and specific 5-HT1F receptor agonist that is undergoing phase III clinical trials for migraine headaches. Treatment with lasmiditan beginning 1 h post-SCI also induced MB and improved recovery. We hypothesize that treatment with LY344864/lasmiditan following SCI will increase MB, resulting in improved locomotor recovery a...