Neuronal Somatic Response to Traumatic Brain Injury

描述（由申请人提供）：本修订申请旨在探索创伤性脑损伤（TBI）病理生物学中相对未知的领域，重点是涉及脑弥漫性损伤的那些损伤。不像大多数当代TBI文献，其重点是局灶性变化，其中大部分涉及大的破坏性病变，如挫伤和血肿形成，本申请探讨了弥漫性TBI的潜力，不复杂的局灶性病变或继发性损伤，引起弥漫性变化的神经元体细胞质膜或体周轴突附件。具体而言，我们认为损伤力能够机械穿孔完整的质膜，引起持久或短暂的膜扰动，其可以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，同样的损伤力也可以引起体周轴突切断。据推测，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，我们认为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。这些前提下，将探讨在两个良好的特点模型TBI，流体冲击和冲击加速度TBI。将通过在损伤前和损伤后不同时间点鞘内给予不同分子量/大小的示踪剂来评估质膜穿孔和重新密封的可能性。使用现代体视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，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神经元维持周围轴突切断术，以排除质膜potation的潜力，同时使用平行的免疫细胞化学方法，以了解如果这样的轴突切断神经元进展到细胞死亡，而是经历短暂的扰动与重组和修复。总的来说，这些研究应该重塑我们对TBI复杂病理学的认识。

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.