Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
PLoS One. 2022 May 27;17(5):e0268901. doi: 10.1371/journal.pone.0268901. eCollection 2022.
A mild traumatic brain injury is a neurological dysfunction caused by biomechanical forces transmitted to the brain in physical impacts. The current understanding of the neuropathological cascade resulting in the manifested clinical signs and symptoms is limited due to the absence of sensitive brain imaging methods. Zebrafish are established models for the reproduction and study of neurobiological pathologies. However, all available models mostly recreate moderate-to-severe focal injuries in adult zebrafish. The present work has induced a mild brain trauma in larval zebrafish through a non-invasive biomechanical approach. A custom-made apparatus with a commercially available motor was employed to expose larvae to rapidly decelerating linear movements. The neurophysiological changes following concussion were assessed through behavioural quantifications of startle reflex locomotor distance and habituation metrics. Here we show that the injury was followed, within five minutes, by a transient anxiety state and CNS dysfunction manifested by increased startle responsivity with impaired startle habituation, putatively mirroring the human clinical sign of hypersensitivity to noise. Within a day after the injury, chronic effects arose, as evidenced by an overall reduced responsivity to sensory stimulation (lower amplitude and distance travelled along successive stimuli), reflecting the human post-concussive symptomatology. This study represents a step forward towards the establishment of a parsimonious (simple, less ethically concerning, yet sensitive) animal model of mild TBI. Our behavioural findings mimic aspects of acute and chronic effects of human concussion, which warrant further study at molecular, cellular and circuit levels. While our model opens wide avenues for studying the underlying cellular and molecular pathomechanisms, it also enables high-throughput testing of therapeutic interventions to accelerate post-concussive recovery.
轻度创伤性脑损伤是一种由物理冲击传递到大脑的生物力学力引起的神经功能障碍。由于缺乏敏感的脑成像方法，目前对导致明显临床体征和症状的神经病理级联反应的理解有限。斑马鱼是重现和研究神经生物学病理学的成熟模型。然而，所有现有的模型大多在成年斑马鱼中重现中度至重度局灶性损伤。本工作通过非侵入性生物力学方法在幼鱼中诱导轻度脑外伤。使用带有市售电机的定制设备使幼虫暴露于快速减速的线性运动中。通过对惊跳反射运动距离和习惯化度量的行为量化来评估脑震荡后的神经生理变化。在这里，我们表明，在五分钟内，损伤后会出现短暂的焦虑状态和中枢神经系统功能障碍，表现为惊跳反应性增加，惊跳习惯化受损，推测模拟了人类对噪声过敏的临床症状。在受伤后一天内，出现了慢性影响，表现为对感觉刺激的整体反应性降低（后续刺激的幅度和行进距离降低），反映了人类脑震荡后的症状。这项研究代表着在建立一种简单（简单、伦理问题较少、但敏感）的轻度创伤性脑损伤动物模型方面迈出了一步。我们的行为发现模拟了人类脑震荡的急性和慢性影响的某些方面，这需要在分子、细胞和电路水平上进一步研究。虽然我们的模型为研究潜在的细胞和分子病理机制开辟了广阔的途径，但它也能够高通量测试治疗干预措施，以加速脑震荡后的恢复。
