Kaukas Lola, Holmes Joshua L, Rahimi Freshta, Collins-Praino Lyndsey, Corrigan Frances
Adelaide Medical School, University of Adelaide, Australia.
Adelaide Medical School, University of Adelaide, Australia.
Behav Brain Res. 2021 Mar 26;402:113067. doi: 10.1016/j.bbr.2020.113067. Epub 2020 Dec 14.
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.
与成年人相比，青少年在轻度创伤性脑损伤（mTBI）后更易出现慢性症状，如冲动和注意力不集中，这可能与前额叶皮质（PFC）发育中断有关。在青春期，PFC正在经历广泛重塑，推动包括注意力、动机和冲动控制在内的执行功能成熟。PFC的部分成熟是由多巴胺能神经元在特定轴突靶向线索（包括netrin-1）的引导下向PFC生长所驱动的。青春期的mTBI如何改变这些轴突靶向线索的表达以及对PFC发育的影响尚不清楚。因此，通过对雄性和雌性Sprague Dawley大鼠进行5选连续反应任务，研究了青春期中期mTBI对成年期（12周）执行功能的影响。35日龄的动物（每组n = 12 - 16）通过重物坠落（从0.75米高度坠落100克重物）致伤，并通过翻正反射显著增加来确认损伤。有趣的是，虽然青春期中期雌性mTBI在任务难度较高（刺激持续时间1秒）时导致遗漏显著增加且准确性降低，但当试验间隔变化时，雄性的过早反应率显著增加。作为多巴胺能神经支配的反映，对TH水平的检测发现，TBI后PFC中两性均无差异，但TBI后长期来看，雄性边缘系统（伏隔核）中有显著增加，而雌性没有，这表明区域之间存在不平衡。TH的增加仅伴随着雄性伏隔核内netrin-1的慢性减少。综上所述，这些结果表明，青春期的mTBI会对成年期PFC功能的不同领域产生性别特异性影响，这可能仅与雄性中脑皮质边缘通路发育轨迹的细微改变有关。
