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.
The proposed research is relevant to public health because it will allow functional interactions among different brain regions involved in memory to be directly linked to behavioral measures in old age. By understanding how alterations in systems-level network function across the brain produce memory deficits, or elicit compensatory mechanisms, it will be possible to promote the development of interventions that broadly improve cognition and meet a mission of the NIA to advance our understanding of age-related cognitive decline.
