Molecular Mechanisms Regulating Age-Related Cognitive Decline in C. elegans

描述（由申请人提供）：秀丽隐杆线虫和人类一样，会随着年龄的增长而经历认知功能的衰退，但这些衰退的原因尚不清楚。我们建议确定与年龄相关的神经元功能变化，并区分那些功能有害的变化和那些可能是对衰老的适应性反应的变化。在我们的第一个目标中，我们将通过操纵候选基因确定长期联想记忆（LTAM）所需的基因，这些基因随着年龄的增长和功能的下降而变化，并随着年龄的增长而恢复功能。我们的第二个目标是鉴定参与LTAM的细胞，并描述它们在LTAM过程中的作用。此外，我们将评估细胞功能随年龄的变化。最后，我们将比较两种秀丽隐杆线虫痴呆模型在正常衰老和病理变化过程中的变化。与痴呆模型的比较将区分健康的和病理性的年龄依赖性变化。通过这些研究，特定成分对功能性认知的贡献将用于确定治疗干预的最佳目标，以治疗随年龄增长的认知衰退。

DESCRIPTION (provided by applicant): C. elegans, like humans, experience cognitive functional declines with age, but the cause of these declines are not yet known. We propose to identify age-related changes in neuronal function, and to distinguish those changes that are functionally deleterious from those that may be an adaptive response to aging. In our first Aim, we will identify the genes required for long-term associative memory (LTAM) that change with age and with decreased function, and rescue function with age through manipulation of candidate genes. Our second Aim focuses on the identification of the cells involved in LTAM, and the characterization of their roles in the LTAM process. Furthermore, we will assess changes in cellular function with age. Finally, we will compare changes during normal aging to pathological changes in two C. elegans models of dementia. Comparisons with models of dementia will distinguish healthy from pathological age-dependent changes. Through these studies, the contributions of specific components to functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age. PUBLIC HEALTH RELEVANCE: In our work, we propose to use the model organism C. elegans to discover genes whose changes in function are correlated with decline in cognitive ability with age. We have designed a test of long-term memory in this organism, and observe that the animals lose their ability to remember with age. Using this test and various molecular tools, we can study the genes and cells responsible for loss of memory with age and in neurodegenerative disease.