Normal 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 are testing the memory effects in adult rhesus monkeys of magnetic resonance imaging (MRI) guided excitotoxin lesions (N-methyl-D- aspartic acid) involving extensive, MRI-confirmed damage restricted to the hippocampus (Zhang et al., Soc. Neurosci. Abstr, 2012). All behavioral testing is post-operative and includes 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 have also tested subjects on the classic delayed response task, i.e., a procedure known to be modestly 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 assessments, developed in the study MTL amnesia in monkeys, fail to capture the key operating characteristics of memory mediated by the primate hippocampus. Current studies are testing the corresponding prediction that procedures emphasizing the component processes of episodic memory (e.g., temporal organization) will provide enhanced sensitivity for documenting impairment that arises from the relatively subtle hippocampal dysfunction associated with aging. Early life events potently influence development and contribute to adult individual differences in cognitive health, reactivity to stress, and disease susceptibility. At the other end of the lifespan, aging is frequently 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 these different outcomes is a critical challenge. In an ongoing collaborative initiative, 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 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 suggest that while the status of memory mediated by the MTL system appears relatively insensitive, early experience may significantly influence the effects of aging on working memory capacities mediated by the prefrontal cortex. Experiments currently in progress are designed to confirm and extend that proposal by testing the same subjects on additional behavioral assessments of prefrontal cortex function. A new, collaborative project direction currently in development aims to identify the critical links between cognitive aging and the effects of early experience with neural network dynamics using MRI to examine resting state activity and functional connectivity in behaviorally characterized subjects. Ultimately, studies of this sort will enable direct comparisons with related human research in LBN and other IRP divisions, providing a valuable translational model for the development of potential interventions for age-related impairment. Complementing these efforts, this program also continues to yield a unique resource of brain material for the quantitative morphometric analysis of relevant neural circuitry in relation to individual differences in the cognitive outcome of aging (Hara et al., J. Neurosci., 2012).

National Institute of Health (NIH)
National Institute on Aging (NIA)
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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
Young, M E; Ohm, D T; Dumitriu, D et al. (2014) Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey. Neuroscience 274:33-43
Naugle, Michelle M; Nguyen, Long T; Merceron, Tyler K et al. (2014) G-protein coupled estrogen receptor, estrogen receptor α, and progesterone receptor immunohistochemistry in the hypothalamus of aging female rhesus macaques given long-term estradiol treatment. J Exp Zool A Ecol Genet Physiol 321:399-414
Ash, Jessica A; Rapp, Peter R (2014) A quantitative neural network approach to understanding aging phenotypes. Ageing Res Rev 15:44-50
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
Kim, Wook; Fiori, Jennifer L; Shin, Yu-Kyong et al. (2014) Pancreatic polypeptide inhibits somatostatin secretion. FEBS Lett 588:3233-9
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 PKMζ 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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