Abstract. Half of all traumatic brain injuries cause changes in white matter integrity. Whereas progress is being made in understanding the mechanisms that lead to acute axonal injury, there is an unmet need for therapeutics to prevent delayed neuronal injury and restore neurological function. We recently demonstrated that the acute intranasal (IN) administration of the cytokine Leukemia Inhibitory factor (LIF) reduced gliosis, preserved corpus callosal myelination, preserved neocortical volumes and improved sensorimotor behavior in a neonatal hypoxic-ischemic brain injury. Here, in a mouse closed head injury (CHI) TBI model, we show that delayed IN LIF Rx prevents sensorimotor functional decline and reduces anxiety when IN LIF Rx is initiated at 6 wks of recovery. Therefore, our overall hypothesis is that intranasal LIF Rx can decrease neurological deficits after TBI by preventing delayed white matter injury and nurturing axonal regeneration by inhibiting SARM1 activation. Unequivocally demonstrating that an intervention is slowing a degenerative process and nurturing regeneration requires monitoring over time to show that it prevents the evolution of tissue damage and stimulates regeneration. Therefore, we propose to utilize high resolution multiple modality live animal magnetic resonance imaging to determine the structural and functional changes in response to IN LIF Rx. We will complement the in vivo imaging with ex-vivo diffusion tensor imaging studies and will correlate the findings with histological and neurological functional analyses. These studies will pave the way for future clinical trials where similar radiological markers can be assessed to prevent delayed white matter injury. 1

The proposed research is important to public health and is relevant to the part of NIH’s mission because it will determine traumatic brain injury (TBI)-related changes in white matter and its impact on regional brain function and neurological outcomes. The studies will determine the protective impact of a novel cytokine (Leukemia Inhibitory Factor) treatment in a delayed manner after TBI in mice. With the current expansion of imaging applications to clinical populations, brain injury-related impact on the neuronal, neurovascular and neurometabolic domains using clinically relevant imaging markers and how they respond to preclinical treatments in animal model studies are crucial for translation to humans. Proposed study outcomes will benefit the rapidly growing brain concussion individuals in the US.