Katherine Burton

Introduction. Traumatic Brain Injury (TBI) is characterized as any external force to the head followed by altered brain function.¹ TBI may occur from many different causes and can vary according to gender, age, race, and geographic location.¹ Long-term effects of repetitive TBI have been linked to later development of neurodegenerative diseases, including Alzheimer’s Disease (AD), Chronic Traumatic Encephalopathy (CTE), as well as cognitive and mood dysfunction.¹ Recently, it has been discovered that much like the macrophage, microglia polarize into two different subsets with different functions after TBI. M1-like microglia are considered “pro-inflammatory” and release cytokines that promote inflammation, such as IL-6.² They are involved in the necessary process of clearing debris and dead cells from the injury site.² M2-like microglia are “anti-inflammatory” and release cytokines that promote healing.² New research suggests M1-like microglia can become dysregulated and cause chronic neurodegeneration potentially for years after an initial brain injury.^2,3  Methods. A custom-designed Controlled Cortical Impact (CCI) injury device was utilized on adult male C57B1/6 mice. Sham animals underwent the same procedure as injured mice except for the impact. In study 1, moderate-level CCI TBI mice were used in longitudinal T2-weighted MRI analysis 3, 6 and 12 months post-injury. Cortical tissue was harvested for biochemical analysis at 12 months post-injury. In study 2, moderate-level CCI TBI mice were used for histological analysis at 1, 5, 12, or 52 weeks after injury. Sham-injured mice were used as non-injured controls at 1 week and 52 weeks post-injury. Results.  MRI study demonstrated that lesion volumes expanded significantly from 17.81  1.99 mm³ at 6 months post-injury to 24.09  1.58 mm³ at 12 months post-injury (p = 0.0314, paired Student t-test).³ Stereological analysis of microglial number and activation status showed significant increase in numbers of activated microglia in the 1-week, 5-week, and 12-week TBI groups (p < 0.001 for each) versus the sham-injured group.³ There was a significant increase in the number of activated microglia in the 52-week TBI group versus the 1-week or 52-week sham-injured groups (p < 0.01 for each).³ Microglia remained chronically activated through 1 year post-injury and did not return to sham-injured levels.³ Conclusion. Ongoing neuroinflammatory processes persist for up to 1 year after a single moderate-TBI in adult male mice. This study suggests a link between TBI-induced neuroinflammation and progressive neurodegeneration, which indicates a therapeutic window for treatment of TBI to be longer than initially expected.

1. Gardner AJ, Zafonte R. Neuroepidemiology of traumatic brain injury. Handbook of Clinical Neurology. 2016;138(207-223). doi:10.1016/B978-0-12-802973-2.00012-4.
2. Loane DJ, Kumar A. Microglia in the TBI Brain: The Good, The Bad, And The Dysregulated. Experimental neurology. 2016;275(0 3):316-327. doi:10.1016/j.expneurol.2015.08.018.
3. Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive Neurodegeneration after Experimental Brain Trauma: Association with Chronic Microglial Activation. Journal of neuropathology and experimental neurology. 2014;73(1):14-29. doi:10.1097/NEN.0000000000000021.