The contribution of declines in functional connectivity to cognitive aging

 描述(由申请人提供)：到2020年，65岁以上的美国人预计将达到5500万。因此，为了个人尊严以及因需要长期护理而产生的经济和公共卫生后果，必须保护这些人独立生活的能力。不幸的是，很大一部分老年人的记忆力下降，这干扰了他们的生活质量。然而，理解老年记忆障碍的神经生物学存在一个重大问题，因为记忆过程分布在整个大脑中，而且我们对这些结构如何相互作用的理解存在根本差距。这项拟议研究的长期目标是确定导致老年认知障碍的网络层面互动的变化。目前的建议的主要目标是确定内侧颞叶-前额叶功能连接的年龄相关变化，这是导致记忆缺陷的原因。将整合神经生理学、解剖学和行为分析的最先进方法来检验这一中心假设，即年龄相关的记忆损害表现为额叶前部和内侧颞叶回路跨区域相互作用的障碍，通过追求以下具体目标：1)皮质功能连接缺陷是否介导记忆损害，2)与年龄相关的脑周功能障碍是否影响海马区内的活动动力学，以及3)与年龄相关的额叶前部皮质活动减少是否影响鼻孔皮质的功能连接。我们的理论基础是，通过阐明衰老如何影响系统水平的动力学，我们将更好地处于开发广泛改善认知的干预措施的地位。这项拟议的研究具有创新性，因为最先进的神经解剖学测量和神经生理学技术将与年轻和老年大鼠行为缺陷的测量相结合，以探索局部功能障碍如何表现为网络损害或引发代偿机制。这些实验的成功完成的意义将是对功能连接和认知之间的联系提供前所未有的理解，这将使未来的干预性研究能够在衰老和神经退化的背景下恢复记忆网络的相互作用。

 DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, a large proportion of elderly people experience memory decline that interferes with their quality of life. Understanding the neurobiology of memory impairments in advanced age, however, presents a significant problem, as memory processes are distributed throughout the brain and a fundamental gap exists in our understanding of how these structures interact. The long-term goal of the proposed research is to determine the alterations in network-level interactions that underlie cognitive impairment in advanced age. The primary objective of the current proposal is to identify age-associated changes in medial temporal lobe-prefrontal functional connectivity that contributes to memory deficits. State-of-the-art methodologies in neurophysiology, anatomy and behavioral analysis will be integrated to test the central hypothesis that age-related memory impairments manifest from dysfunction in cross-regional interactions among prefrontal and medial temporal lobe circuits by pursuing the following specific aims: 1) Do deficits in cortical functional connectivity mediate memory impairments, 2) Does age-related perirhinal dysfunction impact activity dynamics within the hippocampus, and 3) Do age-related reductions in prefrontal cortical activity impact functional connectivity in the rhinal cortices. Our rationale is that by elucidating how aging influences systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, because state-of-the-art neuroanatomical measures and neurophysiological techniques will be integrated with measures of behavioral deficits in young and aged rats in order to probe how local dysfunction manifests as network impairments or elicits compensatory mechanisms. The significance of successful completion of these experiments will be to provide an unprecedented understanding of the association between functional connectivity and cognition that will enable future interventional studies aimed at restoring memory network interactions in the context of aging and neurodegeneration.