Dietary reversal of cognitive impairment after traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）是年轻人和儿童死亡和残疾的主要原因。它每21秒发生一次，每年在美国折磨多达200万人。TBI是一种异质性损伤，其沉淀了传播严重的长期病理的连锁反应。边缘海马体是一种对学习和记忆至关重要的大脑结构，在TBI中经常受损。目前尚不清楚细胞代谢和神经递质功能的区域变化如何导致与TBI相关的认知障碍。然而，我们的初步数据表明，创伤后海马兴奋性的区域变化部分是由于代谢优先级的变化。我们的主要观察结果是，通常用于神经递质合成的特定氨基酸可能被转移到蛋白质合成和能量代谢中，从而扰乱了兴奋和抑制之间的必要平衡。重要的是，损伤后饮食给予支链氨基酸（BCAAs）导致全面的认知恢复。因此，我们提出了以下中心假设：支链氨基酸的饮食干预通过改善海马兴奋性的区域变化来恢复创伤后认知缺陷。为了验证这一假设，将在TBI小鼠模型中从分子水平到系统水平研究海马亚区的细胞代谢以及兴奋和抑制功能。更好地理解有助于我们成功进行饮食干预的时间窗口和机制，将有助于制定最有效的未来干预措施，以减轻这种破坏性（即认知障碍）病理。 创伤性脑损伤（TBI）是一个重大的公共卫生问题，对我们的医疗保健系统有重大影响。对TBI相关残疾的年度成本进行的经济分析从45亿美元的直接支出（医疗保健和服务）到206亿美元的伤害相关工作损失和残疾。我们的长期目标是继续制定一种有效、安全和耐受性良好的饮食干预措施，该干预措施可以从实验室迅速转化为临床，以改善TBI患者的认知功能障碍。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the primary cause of death and disability in young adults and children. It occurs every 21 seconds and afflicts up to two million people annually in the United States. TBI is a heterogeneous insult that precipitates a cascade of ripples that propagate severe long-lasting pathologies. The limbic hippocampus, a brain structure crucial for learning and memory is often damaged in TBI. It is still unknown how regional changes in cellular metabolism and neurotransmitter function contribute to cognitive impairment associated with TBI. However, our preliminary data suggest that post-traumatic regional shifts in hippocampal excitability are due in part to a change in metabolic priorities. Our key observation is that specific amino acids normally employed for neurotransmitter synthesis are potentially diverted to protein synthesis and catabolism for energy thus disturbing the necessary balance between excitation and inhibition. Significantly, dietary administration of branched chain amino acids (BCAAs) after injury results in comprehensive cognitive restoration. We have thus formulated the following CENTRAL HYPOTHESIS: Dietary intervention with branched chain amino acids restores posttraumatic cognitive deficit by ameliorating regional shifts in hippocampal excitability. To test this hypothesis, cellular metabolism, as well as excitatory and inhibitory function in hippocampal subregions will be studied from the molecular to the systemic level in a mouse model of TBI. Better understanding the temporal window and mechanism(s) contributing to our successful dietary intervention will enable the specific formulation of the most efficacious future intervention to alleviate this devastating (i.e. cognitive impairment) pathology. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to continue to formulate an efficacious, safe and well- tolerated dietary intervention that can be rapidly translated from the bench to the clinic to ameliorate cognitive dysfunction in TBI patients.