Neuronal Somatic Response to Traumatic Brain Injury

描述(申请人提供)：这份修改后的申请旨在探索创伤性脑损伤(TBI)病理生物学中一个相对未知的领域，重点关注那些涉及大脑弥漫性损伤的损伤。不同于大多数当代的脑外伤文献聚焦于局灶性改变，其中大多数涉及挫伤和血肿形成等大的破坏性损害，该应用探索了弥漫性脑损伤的潜力，即弥漫性脑损伤，而不是局灶性损害或二次损伤，引起神经元体细胞质膜或坐骨周围轴突附件的弥漫性改变。具体地说，我们假设损伤的力能够机械地穿孔完整的质膜，引起持久的或瞬时的膜扰动，这两种扰动分别参与导致细胞死亡或膜重新密封和细胞恢复的进行性损伤。在其他神经元群体中，同样的损伤力量也被认为会引起坐骨神经周围轴突切断。推测这种由脑损伤引起的损伤可转化为神经元体细胞的扰动。然而，与已发表的文献相反，我们假设大多数神经元不会死亡。相反，他们经历了一次修复性的尝试。这些前提将在两个具有良好特征的TBI模型中进行探索，即流体冲击和冲击加速TBI。质膜穿孔和再封闭的可能性将通过在损伤前和损伤后不同时间点鞘内注射不同分子质量/大小的示踪剂来评估。伴随着使用现代体视学原理的定量研究将评估在新皮质的特定区域内参与这种复杂病理生物学的神经元的数量。并行的光镜免疫细胞化学和超微结构分析将提供对细胞膜完整性和与细胞恢复或导致死亡的损伤进展相关的相关细胞骨架、细胞器或核变化的直接评估。鞘内示踪剂将用于那些接受坐骨神经周切断术的神经元，以排除质膜凹陷的可能性，同时使用平行的免疫细胞化学方法来了解这些轴突切断的神经元是否进展到细胞死亡，或者更确切地说，经历一过性的重组和修复扰动。总而言之，这些研究应该重塑我们对脑外伤复杂病理生物学的认识。

DESCRIPTION (provided by applicant): This amended application seeks to explore a relatively unchartered area in the pathobiology of traumatic brain injury (TBI) focusing on those injuries involving diffuse damage to the brain. Unlike the majority of contemporary TBI literature which focuses on focal change, most of which entails large destructive lesions such as contusion and hematoma formation, this application explores the potential that diffuse TBI, not complicated by focal lesions or secondary insult, evokes diffuse changes in either the neuronal somatic plasma membrane or perisomatic axonal appendages. Specifically, we posit that the forces of injury are capable of mechanically porating the intact plasma membrane causing either enduring or transient membrane perturbations that can respectively participate in progressive damage leading to cell death or membrane resealing and cell recovery. The same forces of injury are also envisioned to evoke, in other populations of neurons, perisomatic axotomy. It is posited that this TBI-induced damage translates into neuronal somatic perturbation. However, in contrast to published literature, we posit that most neurons do not die. Rather they undergo a reparative attempt. These premises will be explored in two well characterized models of TBI, fluid percussion and impact acceleration TBI. The potential for plasma membrane poration and resealing will be assessed via different molecular in weight/size tracers administered intrathecally at various time points pre and post injury. Companion quantitative studies using the principles of modern stereology will assess the numbers of neurons involved in this complex pathobiology within specific domains of the neocortex. Parallel LM immunocytochemical and ultrastructural analyses will provide for the direct assessment of membrane integrity and related cytoskeletal, organelle or nuclear changes that correlate either with cell recovery or a progression of damage leading to death. Intrathecal tracers will be used in those neurons sustaining perisomatic axotomy to exclude the potential for plasma membrane potation, while using parallel immunocytochemical approaches to understand if such axotomized neurons progress to cell death or rather undergo transient perturbation with reorganization and repair. Collectively, these studies should reshape our appreciation of the complex pathobiology of TBI.