摘要：

目的: 探讨骨窗封闭对中重型颅脑创伤小鼠模型的影响。方法: 采用控制性皮质撞击法分别构建中型和重型颅脑创伤小鼠模型，随机分为中型颅脑创伤骨窗封闭组（中型骨窗封闭组，50只）、中型颅脑创伤骨窗未封闭组（中型骨窗未封闭组，50只）、重型颅脑创伤骨窗封闭组（重型骨窗封闭组，50只）、重型颅脑创伤骨窗未封闭组（重型骨窗未封闭组，50只），监测颅内压，测定脑组织含水量和脑水肿体积，采用改良神经功能缺损评分（mNSS）评估神经功能缺损程度，Morris水迷宫实验评估空间学习能力和记忆力，Nissl染色评估大脑皮质和海马CA1区神经元损伤程度。结果: 颅内压监测，无论中型还是重型颅脑创伤模型小鼠骨窗封闭组与骨窗未封闭组颅内压差异均有统计学意义（P = 0.007，0.000），模型制备后不同观察时间点颅内压差异亦有统计学意义（P = 0.000，0.000），其中，中型骨窗封闭组模型制备后第1天颅内压高于中型骨窗未封闭组（P = 0.009），重型骨窗封闭组第1天（P = 0.000）和第3天（P = 0.038）颅内压高于重型骨窗未封闭组；模型制备后第7天中型骨窗封闭组（P = 0.000，0.000）和重型骨窗封闭组（P = 0.000，0.008）颅内压均低于第1天和第3天，第3天亦低于第1天（P = 0.000，0.000），仅第7天中型骨窗未封闭组颅内压低于第1天（P = 0.031）。脑组织含水量测定显示，重型骨窗封闭组模型制备后第1天（P = 0.028）、第3天（P = 0.023）和第7天（P = 0.023）脑组织含水量均低于重型骨窗未封闭组。脑水肿体积测定，无论中型还是重型颅脑创伤模型小鼠骨窗封闭组脑水肿体积均小于骨窗未封闭组（P = 0.021，0.037）。神经功能缺损程度评估，无论中型还是重型颅脑创伤模型小鼠骨窗封闭组与骨窗未封闭组模型制备后不同观察时间点mNSS评分差异均具有统计学意义（P = 0.000，0.001），其中，模型制备后第7天中型骨窗封闭组（P = 0.002）、中型骨窗未封闭组（P = 0.013）、重型骨窗封闭组（P = 0.009）mNSS评分均低于第1天，重型骨窗封闭组（P = 0.006）和重型骨窗未封闭组（P = 0.002）mNSS评分低于第3天。Morris水迷宫实验，重型骨窗封闭组小鼠平台潜伏期长于（P = 0.045）、目标象限停留时间短于（P = 0.025）重型骨窗未封闭组。Nissl染色显示，对于中型颅脑创伤模型小鼠，骨窗封闭组大脑皮质神经元Nissl小体密度减少，染色变浅；海马CA1区神经元Nissl小体密度减少，染色变浅，形态模糊。对于重型颅脑创伤模型小鼠，骨窗封闭组大脑皮质神经元Nissl小体染色变浅，染色模糊，可见较多异染颗粒；海马CA1区神经元胞体水肿，Nissl小体染色模糊。结论: 中型颅脑创伤模型小鼠，骨窗封闭虽在急性期增高颅内压，但对脑水肿程度、神经功能和认知功能无明显影响；重型颅脑创伤模型小鼠，骨窗封闭可导致颅内压升高、空间学习能力和记忆力减退，但可减轻脑水肿程度，应根据研究目的选择是否进行骨窗封闭。

关键词: 脑损伤, 创伤性, 减压颅骨切除术, 颅内压, 脑水肿, Morris水迷宫试验, 虎斑小体, 疾病模型, 动物

Abstract:

Objective: To investigate the effect of bone window closure on moderate to severe traumatic brain injury (TBI) in mice by controlled cortical impact (CCI). Methods: A total of 200 healthy male mice were divided into 2 groups for moderate and severe TBI.Fifty were randomly selected from each group for bone window closed, and the remaining 50 were not closed.The intracranial pressure (ICP) was monitored, the water content of brain tissue and the volume of cerebral edema were measured, the degree of neurological impairment was assessed by modified Neurological Severity Score (mNSS), and the spatial learning ability and memory were evaluated by Morris water maze test.Nissl staining assessed the degree of neuronal damage in the cerebral cortex and CA1 region of the hippocampus. Results: For ICP, there were differences in ICP between the bone window closed group and the unclosed group in both the moderate and severe TBI (P = 0.007, 0.000). There were also significant differences in ICP at different observation time points after modeling (P = 0.000, 0.000). The ICP on 1 d of the moderate bone window closed group was higher than that in the moderate bone window unclosed group (P = 0.009), 1 d (P = 0.000) and 3 d (P = 0.038) of the severe bone window closed group was higher than that of the severe bone window unclosed group.On 7 d, the ICP in the moderate bone window closed group (P = 0.000, 0.000) and the severe bone window closed group (P = 0.000, 0.008) was lower than that on 1 and 3 d, and the ICP on 3 d was also lower than that on 1 d (P = 0.000, 0.000). The ICP in the moderate bone window unclosed group on 7 d was lower than that on 1 d (P = 0.031). The water content of brain tissue was lower on 1 d (P = 0.028), 3 d (P = 0.023) and 7 d (P = 0.023) in severe bone window closed group than that of severe bone window unclosed group. The volume of brain edema in the bone window closed group was smaller than that in the bone window unclosed group (P = 0.021, 0.037). In the evaluation of the degree of neurological impairment, there were differences in mNSS scores at different observation time points between the bone window closed group and the bone window unclosed group (P = 0.000, 0.001). On 7 d, the mNSS scores of the moderate bone window closed group (P = 0.002), the moderate bone window unclosed group (P = 0.013) and the severe bone window closed group (P = 0.009) were all lower than those on 1 d. The mNSS scores of the severe bone window closed group (P = 0.006) and the severe bone window unclosed group (P = 0.002) were all lower than those of 3 d. Morris water maze test showed that the platform latency of mice in the severe bone window closed group was longer than that in the severe bone window unclosed group (P = 0.045), and the target quadrant residence time was shorter than that in the severe bone window unclosed group (P = 0.025). Nissl staining showed compared with the moderate bone window unclosed group, the density of Nissl bodies in cerebral cortex neurons was decreased, the staining was lighter, and the density of Nissl bodies in cerebral cortex neurons of CA1 region of hippocampus was decreased, the Nissl staining was lighter and the shape was blurred in the moderate bone window closed group. In severe TBI model mice, compared with the bone window unclosed group, the density of Nissl bodies in cerebral cortex and hippocampal CA1 region of the bone window closed group was decreased, the staining was blurred, and more metachromic particles appeared, hippocampal CA1 region body edema, the Nissl staining blurred. Conclusions: In moderate TBI model mice, bone window closure increases ICP in the acute stage, but has no significant effect on the degree of cerebral edema, neurological function and cognitive function. In severe TBI model mice, bone window closure can lead to increased ICP and decreased spatial learning ability and memory, but it can reduce the degree of brain edema and improve neurological function. It is suggested that bone window closure should be selected according to the purpose of the study.

Key words: Brain injuries, traumatic, Decompressive craniectomy, Intracranial pressure, Brain edema, Morris water maze test, Nissl bodies, Disease models, animal