Thyroid hormone (TH) is essential for normal brain development and promotes recovery and neuronal regeneration after brain injury. TH acts in the brain predominantly through the nuclear receptor, TH receptor alpha (THRA). Additional factors that impact TH action in the brain including metabolism, activation of thyroxine (T4) to triiodothyronine (T3) by the enzyme 5′-deiodinase Type 2(Dio2), inactivation by the enzyme 5- deiodinase Type 3 (Dio3) to reverse T3 (rT3), which occurs in glial cells, and uptake across the cell membrane by the Mct8 transporter in neurons. Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and neuronal death. In clinical studies, serum levels of T4 and T3, as well as TH levels in the brain, are reduced. We have utilized rodent models of TBI to demonstrate that treatment with T4, 1 hour after injury (selected to model a practical time of administration after injury), is protective, reduces edema, and promotes neuronal recovery. We have identified a similar protective effect of TH in an in vitro model of neuronal injury from hypoxia as well as neuronal inflammation. We will study the mechanism of TH protection from neuronal injury, utilizing in vivo mouse models of TBI. We have preliminary data identifying genes whose expression is impacted by hypoxic neuronal injury and those that are normalized by TH treatment. We will characterize these genes in the brains of mice after injury to identify specific pathways and locations influenced by TH treatment with a whole genome approach. Hypoxic injury increases histone methylation in neurons and this is reduced by T3 treatment. We believe that this is an important mechanism for T3 protection after injury. We will also identify T3- stimulated pathways that activate neural regeneration. We have also shown that injury impairs glial cell proliferation and migration, partially restored by T4 treatment. We will utilize in vivo rodent models of TBI and in vitro models to identify the actions of TH on glial cells and the resulting balance of pro- and anti- inflammatory pathways. The response to TH therapy will include assessment of the brain lesions by imaging and brain region-specific patterns of gene expression. TH reduction in brain edema and cell death, and promotion of neuronal regeneration, should provide a beneficial effect after brain injury. These studies should provide guidance for clinical strategies to use TH, likely with other agents that are anti-inflammatory, to reduce the impact of brain injury and promote recovery.