This research program represents a multidisciplinary, integrated approach to understanding the effects of normal aging on a critical brain system that supports cognitive functions affected in humans as they age. We focus on brain aging in hippocampal/cortical circuits using male Long Evans rats, an outbred strain that exhibits individual differences in aging outcomes in well-characterized cognitive assessments. At older ages (24-28 month) cognitive impairment affects 50-60% of healthy rats in this population, while the remaining aged cohorts fall within the range of young adults (4-6 months). Research under this mechanism of support has identified alterations in the brain that are tightly coupled to these cognitive outcomes. Significant progress in the most recent funding period occurred in the use of experimental interventions to demonstrate the functional significance of altered network properties in circuitry comprised of the entorhinal cortex and its targets in the dentate gyrus (DG) and CA3 regions of the hippocampus. That research in the aged rodent model led to the successful use of a treatment in a proof-of-concept (POC) clinical study in elderly patients with amnestic mild cognitive impairment. Our proposed plans will build on our achievements, exploiting recent findings to embark on new lines of investigation to understand neurocognitive aging and modify aging outcomes. To that end, three Cores (Administrative, Animal Resource, and Bioinformatics/Data Management) will serve all of the participating investigators conducting research in three proposed projects. Proposed studies will build on an emerging consensus that the hippocampus integrates inputs from two interconnected, but anatomically distinct, pathways from the lateral and medial divisions of the entorhinal cortex (LEC and MEC) to create memory representations for the content of an experience within its spatiotemporal context. Accumulated findings in our model and from other sources suggest that deficient processing in the LEC stream contributes disproportionately to the condition of age-related cognitive impairment. Across-project tests of this hypothesis will examine evidence at the level of neural encoding, connectional circuits, and cellular/synaptic function, with all investigations conducted in behaviorally-characterized subjects. Our studies will harness new technology for experiments in aging brains, including optogenetics and whole cell recording methods to study entorhinal input from LEC and MEC onto granule cells in the DG and a recently developed retrovirus/rabies virus tracing system to test a novel hypothesis regarding the integration of newly generated DG neurons as a basis for individual differences in aging with and without cognitive impairment. Finally, we will further study functional mechanisms that may uniquely distinguish successful aging from young adult brains, including recruitment of greater inhibitory control over the entorhinal/DG/CA3 network as an adaptive signature in aged rats with preserved cognitive abilities on a par with young.
Aging is often accompanied by cognitive deficits and is also the major risk factor for Alzheimer's disease. This multi-component research program studies a rodent model of naturally occurring variation in cognitive aging, with the goal of understanding the neurobiological basis of impairment and preservation of brain function. Building on existing therapeutic progress, work within this program will continue to contribute to the development of effective therapeutic interventions for cognitive decline in aging.
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