Department of Neurosurgery, The First Affiliated Hospital, Neurosurgery Research Institute, Fujian Medical University, Fuzhou, Fujian, China.
Department of Neurosurgery, State Key laboratory of Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Shanghai Medical College, Fudan University Huashan Hospital, Institute of Brain Science, Fudan University, Shanghai, China.
CNS Neurosci Ther. 2023 Jul;29(7):1785-1804. doi: 10.1111/cns.14137. Epub 2023 Mar 7.
Stem cells offer a promising therapeutic strategy for patients with disorders of consciousness (DOC) after severe traumatic brain injury (TBI), but the optimal transplantation sites and cells are not clear. Although the paraventricular thalamus (PVT) and claustrum (CLA) are associated with consciousness and are candidate transplantation targets, few studies have been designed to investigate this possibility.
Controlled cortical injury (CCI) was performed to establish a mouse model of DOC. CCI-DOC paradigm was established to investigate the role of excitatory neurons of PVT and CLA in disorders of consciousness. The role of excitatory neuron transplantation in promoting arousal and recovery of consciousness was determined by optogenetics, chemogenetics, electrophysiology, Western blot, RT-PCR, double immunofluorescence labeling, and neurobehavioral experiments.
After CCI-DOC, neuronal apoptosis was found to be concentrated in the PVT and CLA. Prolonged awaking latency and cognitive decline were also seen after destruction of the PVT and CLA, suggesting that the PVT and CLA may be key nuclei in DOC. Awaking latency and cognitive performance could be altered by inhibiting or activating excitatory neurons, implying that excitatory neurons may play an important role in DOC. Furthermore, we found that the PVT and CLA function differently, with the PVT mainly involved in arousal maintenance while the CLA plays a role mainly in the generation of conscious content. Finally, we found that by transplanting excitatory neuron precursor cells in the PVT and CLA, respectively, we could facilitate awakening with recovery of consciousness, which was mainly manifested by shortened awaking latency, reduced duration of loss of consciousness (LOC), enhanced cognitive ability, enhanced memory, and improved limb sensation.
In this study, we found that the deterioration in the level and content of consciousness after TBI was associated with a large reduction in glutamatergic neurons within the PVT and CLA. Transplantation of glutamatergic neuronal precursor cells could play a beneficial role in promoting arousal and recovery of consciousness. Thus, these findings have the potential to provide a favorable basis for promoting awakening and recovery in patients with DOC.
干细胞为严重创伤性脑损伤（TBI）后意识障碍（DOC）患者提供了一种有前途的治疗策略，但最佳的移植部位和细胞尚不清楚。虽然室旁丘脑（PVT）和屏状核（CLA）与意识有关，是候选的移植靶点，但很少有研究设计来探讨这种可能性。
采用控制性皮质损伤（CCI）建立小鼠 DOC 模型。建立 CCI-DOC 范式，研究 PVT 和 CLA 兴奋性神经元在意识障碍中的作用。通过光遗传学、化学遗传学、电生理学、Western blot、RT-PCR、双免疫荧光标记和神经行为学实验，确定兴奋性神经元移植在促进觉醒和意识恢复中的作用。
CCI-DOC 后，发现 PVT 和 CLA 中神经元凋亡集中。PVT 和 CLA 破坏后，觉醒潜伏期延长，认知能力下降，提示 PVT 和 CLA 可能是 DOC 的关键核团。抑制或激活兴奋性神经元可改变觉醒潜伏期和认知表现，提示兴奋性神经元在 DOC 中可能发挥重要作用。此外，我们发现 PVT 和 CLA 的功能不同，PVT 主要参与觉醒维持，而 CLA 主要参与意识内容的产生。最后，我们发现分别在 PVT 和 CLA 中移植兴奋性神经元前体细胞，可以促进觉醒和意识恢复，主要表现为觉醒潜伏期缩短、意识丧失（LOC）持续时间减少、认知能力增强、记忆增强和肢体感觉改善。
在这项研究中，我们发现 TBI 后意识水平和内容的恶化与 PVT 和 CLA 内谷氨酸能神经元大量减少有关。移植谷氨酸能神经元前体细胞可能在促进觉醒和意识恢复方面发挥有益作用。因此，这些发现有可能为促进 DOC 患者的觉醒和恢复提供有利的基础。
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