**3. Discussion**

Different visual problems, such as blurred vision, visual acuity loss, and visual field defects, have been reported in patients with previous history of moderate to severe TBI [38], but much less is known about these impairments and pathological changes in the visual system following mild and especially repetitive mTBI [39]. Studies exploring neuropathological changes in the visual system in animal models of repeated head traumas are scant [27,40–43]. The aims of this study were focused on the chronic effects of repetitive mTBI on some parts of the visual system in wild-type and TDP-43G348C mice. As in our previous study [27], we used the abovementioned mice with overexpression of human familial ALS-linked mutant TDP-43 protein and a predisposition to the pathological accumulation of its aggregates, cytotoxic cleavage fragments, axonopathy, and neuroinflammation in the brain and the spinal cord [28]. The mentioned pathological and biochemical changes are age-related [28]. Thus, the TDP-43 G348C mice did not develop TDP-43-positive aggregates at an early age of 9–11 weeks, as they were at the beginning of the study. The TDP-43-positive aggregates can be detected in these mice starting at 10 months of age [28]. The rationale behind using the young TDP-43 transgenic mice was to explore whether a subtle (2.3–3-fold) overexpression of TDP-43 represents an additional risk factor in the context of mild repetitive TBI, as well as to observe whether it would predispose and/or trigger more intense neurodegeneration, as observed in the model of stroke [44]. Furthermore, there is growing evidence that exposure to repetitive mTBI is associated with an increased risk for ALS/FTLD, especially in a subset of vulnerable individuals with

genetic predisposition [12,45–48]. Furthermore, since the results of our previous study suggested that genetically acquired TDP-43 dysregulation might predispose the OT to more intense acute and subacute damage following repetitive mTBI [27], we wanted to further explore whether TDP-43 proteinopathy is associated with marked long-term posttraumatic changes in the mentioned brain structure, as well as in the investigated nuclei of the visual pathway. We used a clinically relevant model of repetitive TBI that includes the elements of acceleration/deceleration and rotational injuries of the freely moving mouse head and body resulting in diffuse brain damage. This method produced mild injuries with no skull fractures, intracranial bleeding, respiratory arrest, or seizures, and the mice quickly recovered and demonstrated normal behavior following head impacts.
