Dietary reversal of cognitive impairment after traumatic brain injury

饮食逆转脑外伤后认知障碍

• 批准号: 8478216
• 负责人: Akiva S Cohen
• 金额: $ 34.03万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478216
• 关键词: Amino Acids; Area; Basic Science; Brain; Branched-Chain Amino Acids; Caring; Catabolism; Cause of Death; Child; Clinic; Clinical; Cognitive; Cognitive deficits; Data; Diet; Dietary Intervention; Direct Expenditure; Drug Formulations; Economics; Equilibrium; Future; Glutamates; Goals; Healthcare Systems; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Injury; Intervention; Learning; Mediating; Medical; Memory; Metabolic; Metabolism; Methodology; Molecular; Neurotransmitters; Outcome; Pathology; Patients; Physiological; Protein Biosynthesis; Public Health; Research; Services; Structure; Synapses; Synaptic Transmission; Testing; Translating; Traumatic Brain Injury; United States; Work; cost; dentate gyrus; disability; effective therapy; gamma-Aminobutyric Acid; hippocampal subregions; in vivo; mouse model; neurotransmitter metabolism; presynaptic; public health relevance; restoration; young adult

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.

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，在美国每年有多达200万人遭受折磨。创伤性脑损伤是一种异质性的损伤，它会引发一连串的涟漪，传播严重的长期疾病。大脑边缘海马体，一个对学习和记忆至关重要的大脑结构，经常在创伤性脑损伤中受损。目前尚不清楚细胞代谢和神经递质功能的局部变化如何导致与脑外伤相关的认知障碍。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分解代谢中，从而扰乱了兴奋和抑制之间的必要平衡。值得注意的是，在损伤后膳食中添加支链氨基酸（BCAAs）可导致全面的认知恢复。因此，我们制定了以下中心假设：支链氨基酸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，我们将从分子水平到系统水平研究脑损伤小鼠模型中海马亚区的细胞代谢以及兴奋和抑制功能。更好地理解时间窗口和机制有助于我们成功的饮食干预，将使我们能够制定出最有效的未来干预措施，以减轻这种毁灭性的（即认知障碍）病理。