It has been known for many years that normal episodic/declarative memory requires a system of anatomically related medial temporal lobe (MTL) structures, including the hippocampus, and the entorhinal, perirhinal and parahippocampal cortices. Although extensive MTL damage produces robust memory impairment, defining the specific memory processing function of the hippocampus proper has proved challenging. In a series of experiments we tested the memory effects in adult rhesus monkeys of magnetic resonance imaging (MRI) guided excitotoxin lesions (N-methyl-D- aspartic acid;NMDA) involving extensive, MRI-confirmed damage restricted to the hippocampus. All behavioral testing was post-operative and included a standardized version of the trial-unique, delayed nonmatching-to-sample (DNMS) visual recognition memory task, and a novel DNMS variant using a repeated set of discriminative stimuli across test sessions. We also tested subjects on the classic delayed response task, i.e., a procedure known to be sensitive to extensive MTL damage in monkeys, but that has not previously been examined in subjects with lesions restricted to the hippocampus. Relative to unoperated controls, damage to the hippocampus had no statistically reliable or numerically prominent effect on any of the neuropsychological assessments examined. These findings suggest that traditional tests, developed in the study MTL amnesia in monkeys, fail to capture the key operating characteristics of episodic/declarative memory mediated by the primate hippocampus. The significant implication is that alternate approaches will be needed to document the cognitive consequences of the relatively subtle hippocampal dysfunction associated with aging. These findings are scheduled for presentation at this year's annual Society of Neuroscience meeting (Zhang et al., 2012, Soc. Neurosci. Abstr.). Early life events potently influence development, contributing to adult individual differences in cognitive health, responses to stress, and disease susceptibility. At the other end of the lifespan, aging is often accompanied by declining capacities that compromise the quality of independent living, prominently involving cognitive function. Like early development, there is marked individual variability in neurocognitive aging, and defining the basis of different outcomes is a critical challenge. In an ongoing collaborative initiative with Dr. Stephen Suomi at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we have begun to bridge the traditionally distinct fields of early development and aging toward a lifespan perspective on neurocognitive health. The initial goal of the program is straightforward: to test the hypothesis that differential early rearing in infant monkeys - a manipulation known to substantially influence cognitive, biobehavioral and neurobiological development in childhood and adolescence - influences individual differences in cognitive function at the end of the lifespan. Preliminary indications are encouraging, suggesting that while the status of memory mediated by the MTL system appears relatively insensitive, early experience may substantially influence the effects of aging on working memory capacities mediated by the prefrontal cortex such that subjects reared in groups of young peers display relatively better outcome than age-matched individuals provided early maternal rearing. That the prefrontal cortex is more sensitive to early experience than the hippocampus has also been noted by other investigators using in vivo brain imaging analysis. Ongoing experiments aim to confirm and extend our initial findings by testing the same subjects on additional behavioral assessments of prefrontal cortex function. The effects of early life experience in other models are mediated, at least in part, by epigenetic regulation, and strategies currently in development in the present project, using an olfactory epithelium biopsy approach adapted from human studies, aim to test for a potential epigenetic contribution in aged monkeys. Ultimately, these results will be evaluated in relation to ongoing studies on the neurobiology of cognitive aging in monkeys, including quantitative morphometric analysis of relevant neural circuitry in behaviorally characterized subjects (Long et al., 2012, Soc. Neurosci. Abstr.).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000352-04
Application #
8552379
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$676,412
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2016) Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys. J Neurosci 36:901-10
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Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2014) Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci U S A 111:486-91
Hara, Yuko; Rapp, Peter R; Morrison, John H (2012) Neuronal and morphological bases of cognitive decline in aged rhesus monkeys. Age (Dordr) 34:1051-73
Hara, Yuko; Park, C Sehwan; Janssen, William G M et al. (2012) Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys. Neurobiol Aging 33:421.e17-28
Hara, Yuko; Punsoni, Michael; Yuk, Frank et al. (2012) Synaptic distributions of GluA2 and PKM? in the monkey dentate gyrus and their relationships with aging and memory. J Neurosci 32:7336-44
Shamy, Jul Lea; Habeck, Christian; Hof, Patrick R et al. (2011) Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys. Cereb Cortex 21:1559-73

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