The objective of this research program is to understand the basis of memory impairments that result from normal aging. While empirical focus on the hippocampus is justified because of this structure's critical role in memory, the extent to which changes in upstream cortico-hippocampal inputs contribute to these age-related behavioral deficits is unknown. The perirhinal cortex is at the highest level of the ventral visual processing stream. It carries polymodal sensory information to the hippocampus, is extensively reciprocally connected with it, and is critical for memory in its own right. The entorhinal cortex sends massive projections to the hippocampus. The cells in the medial portion exhibit distinct grid-like firing fields that repeat at regular spatial intervals and appear to provide the path integration mechanism the hippocampus uses to anchor rapidly changing episodes of experience during navigation or across contexts. The experiments proposed in the present application are guided by three primary aims.
Aim 1 is to understand how age affects memory and information processing characteristics of hippocampal and perirhinal cortical networks. Three hypotheses are tested concerning the consequences that altered perirhinal-hippocampal interactions may have on mnemonic function: a) that older monkeys will show changes in perirhinal cell population dynamics that reflect either a perceptual defect or a defect in information storage capacity;b) that the old monkey hippocampus will periodically send inappropriate activity patterns through hippocampal back-projections to perirhinal cortex which could result in altered stimulus retrieval;c) that old monkey perirhinal cells will be slower to develop stimulus-stimulus associations, and less robust development of hippocampal cell firing patterns across temporal gaps.
Aim 2 is to understand how associative recollection of experience is impacted by aging and level of motor engagement. Experiments under this aim will explore whether age has an impact on hippocampal associations of events in unique locations or behavioral contexts. The hypothesis is that old monkeys will show faulty retrieval of hippocampal network patterns when path integration operations are engaged in open space (using telemetry), and that the global network activity state will be altered in both age groups when the animals are restrained.
Aim 3 is to understand how aging may alter the internal dynamics of, and interactions between, the medial entorhinal cortex and hippocampus. Two hypotheses are tested: a) that the medial entorhinal cortex grid cell network structure is disrupted during aging, and contributes to map retrieval failures noted in hippocampal ensembles in old rats;and b) that the output code from the hippocampus to deep layers of entorhinal cortex is altered in the aged rat, contributing to faulty memory consolidation processes. Understanding how bi-directional interactions between the hippocampus, perirhinal cortex and entorhinal cortex are altered by the aging process should contribute substantively to the development of therapeutic or preventative treatments for cognitive decline in the elderly.

Public Health Relevance

The outcome of the proposed project will have a significant impact on our understanding of the neural basis of episodic and semantic memory and how specific brain regions contribute to age-associated memory deficits. This is a prerequisite for successful development of therapeutic or preventative treatments for cognitive decline in the elderly, and will provide new approaches to studying, and ultimately ameliorating, memory disorders arising from other sources, such as developmental disorders, stress, drug abuse and brain trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG003376-30
Application #
8663748
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wagster, Molly V
Project Start
1990-09-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
30
Fiscal Year
2014
Total Cost
$674,882
Indirect Cost
$80,325
Name
University of Arizona
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Engle, James R; Machado, Christopher J; Permenter, Michele R et al. (2016) Network Patterns Associated with Navigation Behaviors Are Altered in Aged Nonhuman Primates. J Neurosci 36:12217-12227
Wiegand, Jean-Paul L; Gray, Daniel T; Schimanski, Lesley A et al. (2016) Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability. J Neurosci 36:5650-60
Thomé, A; Gray, D T; Erickson, C A et al. (2015) Memory impairment in aged primates is associated with region-specific network dysfunction. Mol Psychiatry :
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Burke, Sara N; Maurer, Andrew P; Nematollahi, Saman et al. (2014) Advanced age dissociates dual functions of the perirhinal cortex. J Neurosci 34:467-80
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Roberson, Erik D; Defazio, R Anthony; Barnes, Carol A et al. (2012) Challenges and opportunities for characterizing cognitive aging across species. Front Aging Neurosci 4:6
Burke, S N; Maurer, A P; Hartzell, A L et al. (2012) Representation of three-dimensional objects by the rat perirhinal cortex. Hippocampus 22:2032-44
Thome, Alexander; Erickson, Cynthia A; Lipa, Peter et al. (2012) Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task. Hippocampus 22:2000-11

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