Persistent ultrastructural changes to callosal axons three months after repetitive brain injury across age groups

Repetitive mild traumatic brain injury (r-mTBI) is strongly associated with the increased risk of developing neurodegenerative diseases. Previously, we have revealed the histopathological, biochemical, and transcriptional changes following exposure to chronic r-mTBI in wild-type (WT) mice. Herein, we performed a complementary electron microscopy analysis in a young adult (3-month-old) WT cohort to reveal the ultrastructural changes observed 3 months following chronic r-mTBI. Additionally, because age at injury has been associated with an increased risk for poorer outcomes after TBI, an older WT cohort (12-month-old, middle-aged) was included to determine this relationship. While the cortical grey-matter exhibited minimal ultrastructural abnormalities after r-mTBI, we observed prominent TBI-related changes in the corpus callosum, including increased axonal g-ratios and higher density of degenerating axons in both cohorts. However, no age-dependent injury differences were observed across measured parameters, except for a notable TBI-dependent increase in phagolysosome-bearing perivascular cells within the corpus callosum of injured aged mice compared to younger TBI counterparts. Collectively, these findings suggest that chronic r-mTBI in young adulthood and middle age produces similar white matter ultrastructural changes 3 months after r-mTBI. Future studies are warranted to determine whether ultrastructural differences emerge with injuries administered earlier in life or at advanced age.