Age- and sex-dependent differences in white matter pathology in the chronic phase of diffuse traumatic brain injury in the mouse

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Traumatic brain injury (TBI) is commonly associated with white matter injury, leading to persistent symptoms and long-term disability. While advanced age is linked to worse outcome post-TBI, the influence of sex remains highly controversial. The present study aimed to identify age- and sex-dependent differences in white matter pathology during the chronic phase of TBI using the central (midline) fluid percussion injury (cFPI) model. Young (8-12 weeks) and aged (55-78 weeks) male and female mice were subjected to cFPI and end-point analyses were performed at 30 days post-injury (dpi). Histological and immunohistochemical assessments, combined with Western Blot analyses, were employed to evaluate white matter structure and changes in white matter related proteins, respectively. Furthermore, we conducted 5-ethynyl-2-deoxyuridine (EdU) labeling injections during the first week post-injury to assess whether post-injury oligodendrogenesis is related to white matter alterations at 30 dpi. Following TBI, male mice sustained higher ventricular expansion and external capsule atrophy compared to females. These changes were observed in the absence of TBI-induced cortical atrophy at 30 dpi. Regardless of age, male mice exhibited a more pronounced inflammatory response compared to females, characterized by a greater Ionized calcium-binding adaptor molecule 1 (Iba1) coverage and a higher number of Iba1+/EdU+ cells within their white matter tracts. A reduction in myelin basic protein (MBP) levels was evident in both male and female young mice but not in aged groups. When compared to young male mice, young female mice exhibited a distinct neurofilament heavy chain (NF-H) protein phosphorylation pattern, a difference absent in aged mice. Notably, while male mice showed a robust increase in newly generated mature oligodendrocytes within their white matter tracts, TBI did not induce comparable oligodendrogenesis in females. This study highlights sex- and age-related differences in white matter pathophysiology that may explain sex differences in outcomes following TBI.

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