Exercise-enhanced neurogenesis and functional recovery following TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是儿童和年轻人死亡的主要原因[1-6]，使许多患者（美国每年150万）出现严重的运动障碍和认知障碍[1-4，6]。TBI是一个重大的社会经济负担[2，7-9]。2000年，平民TBI患者的医疗费用超过600亿美元[3，4，10，11]。此外，据估计，超过30万名伊拉克和阿富汗战争退伍军人因战时简易爆炸装置的冲击波而遭受轻度创伤性脑损伤（mTBI）（占160万人的20%）。因此，mTBI是一个严重的公共卫生问题。目前，对这些TBI相关疾病没有有效的治疗方法。因此，开发治疗TBI后这些疾病的治疗方法将具有巨大的临床、社会和经济效益。最近的研究已经确定了成人大脑中的神经干/祖细胞（NSC）[14-17]。在整个成年期，新的神经元不断从NSC产生[18]。这些成年新生神经元是修复TBI后大脑损伤的潜在资源。此外，这些发现表明先天修复和/或可塑性机制存在于成人大脑中。然而，这些先天过程通常是不成功的，并且需要额外的干预来增加先天可塑性以成功修复TBI后受损的大脑。最近，研究表明，体育锻炼增强了成年海马体的神经发生，并适度改善了TBI后的功能表现[19-21]。这一发现表明，身体运动增强神经发生可能会诱导TBI后的患者。然而，到目前为止，运动增强的功能改善已被证明是温和的，仍然存在几个问题：1）体育锻炼是否增加NSC增殖或/和促进新生神经元存活？2)调节运动增强神经发生的分子和细胞机制是什么？3)运动增强神经发生是否能改善创伤性脑损伤患者的行为以及4）如何增加这种效应以进一步促进神经发生并潜在地大大改善TBI患者的行为？为了解决这些问题，本提案将研究调节运动增强神经发生的分子和细胞机制，并使用本研究中鉴定的分子进一步增加TBI后成年海马中运动增强的神经发生。这些研究的完成不仅将提供对介导运动增强神经发生的分子和细胞机制的见解，而且还可能提供一种潜在的方法来增加神经发生并促进TBI后的功能恢复。 公共卫生相关性：创伤性脑损伤（TBI）是儿童和年轻人死亡的主要原因，并代表着重大的社会经济负担。它使许多患者出现严重的认知障碍和癫痫。目前还没有有效的治疗这些疾病。本研究旨在探讨脑外伤后运动增强海马神经发生的分子和细胞机制，并为脑外伤后运动增强海马神经发生的功能恢复提供新的途径。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI), the leading cause of death in children and young adults [1-6], leaves many patients (1.5 million annually in the US) with substantial motor disabilities and cognitive impairments [1-4, 6]. TBI represents a significant socioeconomic burden [2, 7-9]. In 2000 civilian TBI patients incurred over $60 billion in medical costs [3, 4, 10, 11]. Furthermore, it is estimated that more than 300,000 Iraq and Afghanistan war veterans have sustained mild traumatic brain injury (mTBIs) from blast waves of wartime improvised explosive devices (20% of 1.6 million) [12, 13]. Therefore, mTBI is a serious public health problem. At present, there is no effective treatment for these TBI-associated disorders. Thus, the development of therapeutic approaches to treat these disorders following TBI would be of enormous clinical, social, and economic benefit. Recently research has identified neural stem/progenitor cells (NSCs) in the adult brain [14-17]. New neurons are continuously generated from NSCs throughout adulthood [18]. These adult-born new neurons are a potential resource for repairing damages in the brain following TBI. In addition, these findings suggest that innate repair and/or plasticity mechanisms exit in the adult brain. However, these innate processes are often unsuccessful, and additional interventions are required to increase the innate plasticity for successfully repairing the damaged brain following TBI. Recently, it has been shown that physical exercise enhanced neurogenesis in the adult hippocampus, and moderately improved its functional performance following TBI [19-21]. This finding suggests that physical exercise-enhanced neurogenesis might be induced in patients following TBI. However, so far exercise-enhanced functional improvement have proven to be moderate, and several questions still remain: 1) Does physical exercise increase NSC proliferation or/and promote newborn neuron survival?; 2) What are the molecular and cellular mechanisms that regulate exercise-enhanced neurogenesis?; 3) Does exercise-enhanced neurogenesis lead to behavioral improvements in patients following TBI?; and 4) How can this effect be increased to further boost neurogenesis and to potentially greatly improve the behaviorof TBI patients? To address these questions, this proposal will investigate the molecular and cellular mechanisms that regulate exercise-enhanced neurogenesis, and use the molecules identified in this study to further increase exercise-enhanced neurogenesis in the adult hippocampus following TBI. Completion of these studies will not only provide insights into the molecular and cellular mechanisms mediating exercise- enhanced neurogenesis, but also may provide a potential approach to increase neurogenesis and facilitate functional recovery following TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is the leading cause of death in children and young adults, and represents a significant socioeconomic burden. It leaves many patients with substantial cognitive impairments and epilepsy. Currently there is no effective treatment for these disorders. This proposal aims to investigate the molecular and cellular mechanisms underlying exercise-enhanced neurogenesis in the hippocampus following TBI, and to potentially find a novel approach to augment exercise-enhanced neurogenesis for functional recovery of patients following TBI.