Injury during adolescence leads to sex-specific executive function deficits in adulthood in a pre-clinical model of mild traumatic brain injury

Adolescents are more likely than adults to develop chronic symptoms, such as impulsivity and difficulty concentrating, following a mild traumatic brain injury (mTBI) which may relate to disruption of pre-frontal cortex (PFC development). During adolescence the PFC is undergoing extensive remodelling, driving maturation of executive functions incorporating attention, motivation and impulse control. In part maturation of the PFC is driven by outgrowth of dopaminergic neurons to the PFC under the guidance of specific axonal targeting cues, including netrin-1. How a mTBI in adolescence may alter the expression of these axonal targeting cues, and the influence on PFC development is not yet known. As such the effects of mTBI in mid-adolescence on executive functioning in adulthood (12 weeks) were examined via the 5-choice serial reaction task in both male and female Sprague Dawley rats. Animals at p35 (n = 12-16 per group) were injured via weight drop (100 g from 0.75 m) and injury confirmed by a significant increase in righting reflex. Interestingly, while a mid-adolescence mTBI in females led to significantly higher omissions and decreased accuracy when task difficulty was high (stimulus duration 1 s), males had significantly increased premature response rate when the intertrial interval was varied. Examination of levels of TH, as a reflection of dopaminergic innervation, found no difference in either gender post-TBI in the PFC, but a significant increase in the limbic system (nucleus accumbens) in males, but not females, chronically post-TBI, suggesting an imbalance between the regions. The increase in TH was accompanied by a chronic reduction in netrin-1 within the nucleus accumbens in males only. Taken together, these results indicate that mTBI in adolescence leads to sex specific effects in different domains of PFC function in adulthood, which may relate to subtle alterations in the developmental trajectory of the mesocortical limbic pathway in males only.