Neuronal Somatic Response to Traumatic Brain Injury

描述（由申请人提供）：这份修订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。与大多数关注局灶性改变的当代TBI文献不同，大多数研究都涉及到挫伤和血肿形成等大的破坏性病变，本研究探索了弥漫性TBI的可能性，没有局灶性病变或继发性损伤，引起了神经元体质膜或周围轴突附属物的弥漫性改变。具体来说，我们假设损伤力能够机械地穿透完整的质膜，造成持久或短暂的膜扰动，分别参与导致细胞死亡或膜重封和细胞恢复的进行性损伤。在其他的神经元群中，同样的损伤力也被设想为引起细胞周围轴切开术。假设这种tbi诱导的损伤转化为神经元体细胞扰动。然而，与已发表的文献相比，我们假设大多数神经元不会死亡。相反，他们经历了一种修复的尝试。这些前提将在两个很好的表征模型中进行探讨，即流体冲击和冲击加速度TBI。在损伤前后的不同时间点，通过在鞘内施用不同分子量/大小的示踪剂来评估质膜穿孔和再密封的可能性。使用现代立体学原理的定量研究将评估新皮层特定区域内参与这种复杂病理生物学的神经元数量。平行的LM免疫细胞化学和超微结构分析将提供直接评估膜完整性和相关的细胞骨架、细胞器或核变化，这些变化与细胞恢复或导致死亡的损伤进展相关。鞘内示踪剂将用于那些维持细胞周围轴切的神经元，以排除质膜激活的可能性，同时使用平行免疫细胞化学方法来了解这些轴切神经元是进展到细胞死亡，还是在重组和修复过程中经历短暂的扰动。总的来说，这些研究应该重塑我们对创伤性脑损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.