Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. This project extends our prior work into the exact nature of age-related memory decline and into its neural bases. Like our prior project, this proposal draws heavily on animal models of aging and computational models of memory to test specific hypotheses about age-related memory decline. In our prior funding period, we focused almost exclusively on the hippocampus, demonstrating age- related disruptions in the hippocampal circuit that parallel those found in the rodent and demonstrating how these changes affect specific kinds of memory. In particular, we showed how the human hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. We also showed how this circuit is disrupted gradually over the course of aging and how this is linked to age-related loss of the detail or episodic components of a memory. One goal of the project is to build extensively on the behavioral tasks that we have pioneered and that are being widely adopted in the field so that we can develop and neurobiologically validate an entire suite of behavioral tasks that are maximally sensitive to hippocampal function and to age- related cognitive decline. As this loss is not confined to the hippocampus, but includes changes in the adjacent medial temporal lobe cortices and in the prefrontal cortex, we propose to examine in detail changes in these regions and in their interactions with the hippocampus. Here again we draw heavily on neurobiological findings from the rodent to test specific hypotheses about age-related changes in regions like the perirhinal cortex and to assess changes in the functional contributions of and interrelationship between hippocampal and prefrontal age-related changes in memory. Like our prior work, we propose to collect a comprehensive suite of behavioral and neuroimaging data from a large sample of adults. By collecting an extensive set of measures on each participant, we can examine interrelationships that would otherwise be impossible. In addition to our own specific questions and hypotheses, the extensive set of measures (which includes longitudinal assessment of participants from our prior work) will be valuable to other researchers. As before, we will make all components of the data widely available to others.

Public Health Relevance

The percentage of the world's population aged 65 and older is expected to be triple what it was several decades ago and double the current proportion, representing a huge demographic shift. The incidence of dementia (e.g., Alzheimer's Disease, Vascular Dementia, etc.) increases dramatically with age. Outside of dementia, there are also clear cognitive effects of age, particularly in the domain of memory. Understanding the neural mechanisms that underlie these age-related deficits is crucial for understanding the effects of aging and dementia, and paving the way to improve treatments for both normal and pathological changes in memory and for early prevention.

National Institute of Health (NIH)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wagster, Molly V
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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Bennett, Ilana J; Huffman, Derek J; Stark, Craig E L (2015) Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan. Cereb Cortex 25:2988-99
Reagh, Zachariah M; Yassa, Michael A (2014) Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans. Proc Natl Acad Sci U S A 111:E4264-73
Leal, Stephanie L; Tighe, Sarah K; Yassa, Michael A (2014) Asymmetric effects of emotion on mnemonic interference. Neurobiol Learn Mem 111:41-8
Huffman, Derek J; Stark, Craig E L (2014) Multivariate pattern analysis of the human medial temporal lobe revealed representationally categorical cortex and representationally agnostic hippocampus. Hippocampus 24:1394-403
Azab, Marwa; Stark, Shauna M; Stark, Craig E L (2014) Contributions of human hippocampal subfields to spatial and temporal pattern separation. Hippocampus 24:293-302
Borota, Daniel; Murray, Elizabeth; Keceli, Gizem et al. (2014) Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci 17:201-3
Reagh, Zachariah M; Roberts, Jared M; Ly, Maria et al. (2014) Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. Hippocampus 24:303-14
Leal, Stephanie L; Tighe, Sarah K; Jones, Craig K et al. (2014) Pattern separation of emotional information in hippocampal dentate and CA3. Hippocampus 24:1146-55
Roberts, Jared M; Ly, Maria; Murray, Elizabeth et al. (2014) Temporal discrimination deficits as a function of lag interference in older adults. Hippocampus 24:1189-96
Reagh, Zachariah M; Yassa, Michael A (2014) Repetition strengthens target recognition but impairs similar lure discrimination: evidence for trace competition. Learn Mem 21:342-6

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