Microglial reactivity and functional deficits following traumatic brain injury in the neonate rat

Abstract

Traumatic brain injury (TBI) is a leading cause of disability in young children as survivors face life-long physical and cognitive impairments. Inflammation, specifically microglia/macrophage activation, has been identified as a target for acute therapeutic intervention for the traumatically-injured adult brain, but it is unclear whether this strategy will be effective in the immature injured brain. Closed head injury in the 11-day-old rat induced robust microglia/macrophage reactivity in multiple brain regions and was associated with neurodegeneration and axonal injury. Additionally, brain-injured animals demonstrated cognitive deficits and motor function impairments at 4 weeks post-injury, mirroring the sustained functional deficits observed in humans. Immediately after injury, intracerebral depletion of microglia/macrophages with clodronate or inhibition of active microglia/macrophages systemically with minocycline decreased the number of total and activated microglia/macrophages in the injured brain. This effect was accompanied by an increase in neurodegeneration at 3 days post-injury, suggestive of a lack of clearance of degenerating cells. Both of these acute manipulations, however, were associated with an increase in microglia/macrophage reactivity and neurodegeneration at 4 weeks post-injury that coincided with hyperactivity (clodronate) or hypoactivity (minocycline) within the injury site. In addition, systemic minocycline administration reversed alterations in cortical activity, deficits in working memory, and impairment of forelimb function that were not associated with neurodegeneration or microglia/macrophage activation. These results are not only suggestive of off-target effects of minocycline, but also emphasize the importance of acute post-injury microglia/macrophage reactivity and the need for a more target-specific anti-inflammatory therapeutic strategy in the developing brain.%%%%Ph.D., Neuroscience – Drexel University, 2017