Traumatic brain injury is a devastating public health problem, the eighth leading cause of death across the world. To improve our understanding of how injury at the cellular scale affects neural circuit function, we developed a protocol to precisely injure individual neurons within an in vitro neural network. We used high speed calcium imaging to estimate alterations in neural activity and connectivity that occur followed targeted microtrauma. Our studies show that mechanically injured neurons inactivate following microtrauma and eventually re-integrate into the network. Single neuron re-integration is dependent on its activity prior to injury and initial connections in the network: more active and integrated neurons are more resistant to microtrauma and more likely to re-integrate into the network. Micromechanical injury leads to neuronal death 6 hours post-injury in a subset of both injured and uninjured neurons. Interestingly, neural activity and network participation after injury were associated with survival in linear discriminate analysis (77.3% correct prediction, Wilks’ Lambda = 0.838). Based on this observation, we modulated neuronal activity to rescue neurons after microtrauma. Inhibition of neuronal activity provided much greater survivability than did activation of neurons (ANOVA, p<.01 with post-hoc Tukey HSD, p<.01). Rescue of neurons by blocking activity in the post-acute period is partially mediated by mitochondrial energetics, as we observed silencing neurons after micromechanical injury led to a significant reduction in mitochondrial calcium accumulation. Overall, the present study provides deeper insight into the propagation of injury within networks, demonstrating that together the initial activity, network structure, and post-injury activity levels contribute to the progressive changes in a neural circuit after mechanical trauma.

中文翻译：

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体外区域性神经退行性变：神经活动的保护作用

颅脑外伤是一个毁灭性的公共卫生问题，是全球第八大死亡原因。为了增进我们对细胞损伤如何影响神经回路功能的理解，我们开发了一种协议，可以精确地损伤体外神经网络中的单个神经元。我们使用高速钙成像来评估针对性微创伤后发生的神经活动和连接性的改变。我们的研究表明，机械损伤的神经元在微创伤后会失活，并最终重新整合到网络中。单神经元的重新整合取决于其在受伤之前的活动和网络中的初始连接：更多活跃和整合的神经元对微创伤的抵抗力更高，并且更有可能重新整合到网络中。微机械损伤导致受伤的和未受伤的神经元的子集在受伤后6小时神经元死亡。有趣的是，在线性判别分析中，损伤后的神经活动和网络参与与存活率相关（正确预测为77.3％，Wilks Lambda = 0.838）。基于此观察，我们调节了神经元的活性，以在微创伤后拯救神经元。与激活神经元相比，抑制神经元活性提供了更大的生存能力（ANOVA，事后Tukey HSD，p <.01，p <.01）。由于我们观察到微机械损伤后沉默的神经元导致线粒体钙积聚的显着减少，因此在急性期后通过阻断活性来挽救神经元部分是由线粒体能量介导的。全面的，