Normal memory requires a system of anatomically related brain structures in the medial temporal lobe (MTL) in primates, including the hippocampus, and the entorhinal, perirhinal and parahippocampal cortices. Although extensive MTL damage produces robust memory impairment, efforts to define the core memory processing functions of the hippocampus proper and, by extension, to define the contribution of hippocampal dysfunction to cognitive aging - have proved challenging. In a series of experiments we are testing the memory effects of MRI-guided excitotoxin lesions (N-methyl-D-aspartic acid) involving extensive damage restricted to the hippocampus. Our findings indicate that traditional assessments used to study global MTL amnesia fail to capture the key operating characteristics of memory mediated by the primate hippocampus. Ongoing efforts are therefore testing the related view that procedures emphasizing the component processes of episodic memory (e.g., the temporal organization of remembered events) will provide more sensitive measures of hippocampal integrity. These experiments are ultimately aimed at establishing assessments with optimal sensitivity for detecting the consequences of the relatively subtle changes in hippocampal integrity that are associated with aging, and for testing the efficacy of interventions intended to reverse age-related memory impairment. Related neuroimaging studies are currently underway in collaboration with the Comparative Medicine Section of the NIA-IRP and investigators at the National Institute on Drug Abuse. Scanning is carried using a Siemens Tim Trio 3T scanner, adapting procedures that yield reliable resting state BOLD signal in rats. Briefly, subjects are maintained under a carefully titrated twilight level of anesthesia during a series of structural, aterial spin labeling, and echo planar resting state scans. Vital physiological parameters (i.e., blood pressure, oxygen saturation, heart rate, etc.) are monitored continuously. Imaging, post-acquisition pre-processing and analysis are ongoing and preliminary results confirm a pattern of activity temporally correlated with a seed region in the posterior cingulate cortex distributed across frontal and cingulate cortices, comparable to previous descriptions of the default mode network in humans and monkeys. Parallel analyses currently in progress are among the first to directly test whether damage to the hippocampus is sufficient to disrupt distributed cortical network dynamics. Ultimately, these findings from an experimental lesion model will provide a valuable framework for interpreting the effects of aging on network functional connectivity. Complementing our in vivo studies, this project continues to yield unique opportunities for the quantitative morphometric analysis of relevant neural circuitry in relation to individual differences in the cognitive outcome of aging. Growing evidence points to changes in excitatory/inhibitory balance associated with cognitive decline as a precursor to neurodegenerative progression in the aged brain, and we are examining these early events by surveying the integrity of neurochemically identified neuronal subtypes in cortical and subcortical circuitry in behaviorally characterized young and aged monkeys. Taken together, these studies have the potential to help guide studies aimed at developing effective strategies for promoting optimally healthy cognitive aging.