Neural circuit disruption by diffuse brain injury: basis for morbidity & therapy

描述（由申请人提供）：我们的长期目标是开发有效的药理学和康复治疗策略，促进脑损伤回路的适应性重组，以减轻弥漫性创伤性脑损伤（TBI）后的神经功能障碍（发病率）。为了实现这些目标，我们将利用我们在弥漫性脑损伤大鼠中观察到的一种新的、可重复的、迟发性神经功能缺损，类似于脑损伤幸存者的躁动。与未受伤的大鼠面部胡须刺激的舒缓和安抚性质相反，脑损伤的大鼠对胡须刺激的反应是畏缩、冻结和保护眼肌垫。这种异常行为伴随着轴突损伤、神经元萎缩、持续性炎症和神经可塑性，使得触须刺激激活常规体感触须电路之外的脑区域。目前的建议测试的假设，弥漫性脑损伤引起的炎症驱动适应不良的结构可塑性负责异常行为反应的胡须刺激。由脑损伤的躯体感觉须电路提供的模型系统提供了一种简化的方法来处理弥漫性TBI的复杂性，以解决与创伤后发病率相关的病理和修复机制。将评价弥漫性脑损伤成年雄性大鼠中的该回路的（目的1）由触须刺激引起的异常行为，（目的2）慢性神经病理学、神经元活化和回路重组，以及（目的3）导致回路重组和发病的神经炎症驱动的神经可塑性反应。抗炎治疗方案可以提供临床相关干预，以防止电路重新布线和发病。行为，解剖，功能和治疗方法的创新组合，针对脑损伤的躯体感觉须电路，解决了与受伤的大脑中不受调节的结构可塑性相关的潜在机制。揭示这些过程可以指导治疗以减轻神经功能障碍的发作、缩短持续时间和/或促进其解决。这个回路的结果最终可以扩展到啮齿动物的其他回路，然后是人类，以改善数百万TBI幸存者和其他可能患有进行性神经退行性疾病的人的生活质量。 公共卫生相关性：目前的建议集中在弥漫性脑损伤幸存者经历的持续发病率，对他们来说，治疗方案是有限的。在弥漫性脑损伤大鼠中，对触须刺激的异常反应将被用作识别与体感触须电路中断相关的病理和修复机制的工具。通过开发、验证和实施一种离散的创伤后发病的动物模型，可以在重塑啮齿动物和人类的第一个脑损伤回路、然后是其他脑损伤回路方面取得重大进展。

DESCRIPTION (provided by applicant): Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals, we will exploit a novel, reproducible, late-onset neurological deficit that we have observed in the diffuse brain-injured rat, analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats, brain- injured rats react to whisker stimulation by cowering, freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage, neuronal atrophy, persistent inflammation and neuroplasticity, such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI, to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation, (Aim 2) chronic neuropathology, neuronal activation and circuit reorganization, and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral, anatomical, functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset, reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors, for whom treatment options are limited. In diffuse brain-injured rats, aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing, validating and implementing an animal model of one discrete post-traumatic morbidity, significant advancements can be made towards reshaping first one, then other, brain- injured circuits in rodents and man.