Direct visualization of longitudinal effects of drug therapy on white matter in diffuse injured brain

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 DESCRIPTION (provided by applicant): This project will provide high-content data that will be used for both basic and preclinical research. BASIC RESEARCH ASPECT: We will use a novel method of high-resolution, subcortical, in vivo imaging to fill critical gaps in knowledge about th dynamics of diffuse traumatic brain injury at a cellular level in subcortical white matter in live mice over a 60-day period post-injury. This knowledge will give us new insights into understanding the progressive degeneration that happens after TBI and for optimizing therapeutic windows for future combination drug therapy. We will obtain these images in live mice using a permanently implanted microlens positioned over a subcortical white matter tract and periodically image through this lens using a multiphoton microscope. We will reveal previously unseen spatio-temporal dynamics of axon degeneration, microglia infiltration and activation, and microvascular changes with cellular resolution in this region. PRECLINICAL ASPECT: We will also use 3 key outcomes from our observations to evaluate the efficacy of a drug which is now in preclinical trials. This drug, minocycline, is an FDA-approved antibiotic that has reduced axonal loss and microglial activation when given in a single dose within a few hours of experimental traumatic brain injury in mice. We hypothesize that a dose given 3 days post-injury will have the same therapeutic benefits of significantly (1) reducing axonal loss and (2) reducing microglial activation. We further hypothesize that minocycline will result in significant improvement in microcirculation rates. Widening the therapeutic window for this promising drug will better position it for translation to the clinic.