Aria W Tarudji, Brandon Z McDonald, Evan Curtis, Connor Gee, Forrest M Kievit
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引用次数: 0
Abstract
Heterogeneity associated with traumatic brain injury (TBI) outcomes necessitates validated controls to differentiate pathophysiological events from experimental methodology. While craniectomies are commonly used in TBI research, inadvertent dura disruption can result in structural deficits, impacting cellular function and neurobehavioral outcomes. Thus, there is a critical need to evaluate the effect of craniectomy on neurological outcomes to develop robust experimental controls and improve pre-clinical TBI research. In this study, craniectomy mice undergoing surgical and anesthetic intervention were assessed against naïve mice for neurological deficits and pathophysiological dysfunction. T2-weighted magnetic resonance imaging confirmed that no lesions or cavities were observed postcraniectomy. However, the cranial defect induced midline shifting over time, which might contribute to poorer behavioral outcomes in the novel object recognition assessment. Immunohistochemical analysis demonstrated an increase in GFAP and Iba1, indicating craniectomy elicited an inflammatory response. Indeed, neuroinflammation led to an increase in neuronal cell death, as measured by increases in α-II-spectrin breakdown products. However, craniectomy mice also presented with decreases in LC3BII and SQSTM1 expression, indicating an inhibition of autophagy. Last, craniectomy contributed to the altered expression of several tight junction proteins, including occludin and claudin-1/5, suggesting the blood-brain barrier was perturbed. Overall, the deficits associated with craniectomy preclude its use as an adequate sole control for TBI research, as craniectomy limits translational insights into the neurological changes observed in TBI. Additionally, these results support the need for the use of closed-head injury models where uninjured control mice do not show significant confounding minor injury patterns.
与创伤性脑损伤(TBI)结果相关的异质性需要经过验证的对照来区分病理生理事件和实验方法。虽然颅骨切除术通常用于TBI研究,但无意的硬脑膜破坏可能导致结构缺陷,影响细胞功能和神经行为结果。因此,有必要评估颅骨切除术对神经预后的影响,以建立健全的实验对照,并改善临床前TBI研究。在这项研究中,接受手术和麻醉干预的颅骨切除术小鼠与naïve小鼠的神经功能缺损和病理生理功能障碍进行了评估。t2加权磁共振成像证实颅骨切除术后未见病变或空腔。然而,随着时间的推移,颅骨缺陷会导致中线移位,这可能会导致新的物体识别评估中的行为结果较差。免疫组织化学分析显示GFAP和Iba1增加,表明颅骨切除术引起了炎症反应。确实,神经炎症导致神经元细胞死亡的增加,通过α- ii -谱蛋白分解产物的增加来测量。然而,颅骨切除术小鼠也表现出LC3BII和SQSTM1表达降低,表明自噬受到抑制。最后,颅骨切除术导致一些紧密连接蛋白的表达改变,包括occludin和claudin-1/5,表明血脑屏障受到干扰。总的来说,由于颅切除术限制了对TBI中观察到的神经系统变化的转化性见解,颅切除术相关的缺陷使其无法作为TBI研究的充分唯一对照。此外,这些结果支持使用闭合性头部损伤模型的必要性,其中未受伤的对照小鼠没有显示出明显的混淆轻微损伤模式。