Aging is the single greatest risk factor for the development of many neurodegenerative disorders, including Alzheimers disease. However, defining the features of brain aging, distinct from disease, that mediate poor neurocognitive outcomes has proved challenging on the basis of human investigation alone. Old world macaques provide an exceptionally valuable model in this regard, displaying many features of brain and cognitive organization similar to the humans, but in the absence of developing frank neurodegenerative disease. One ongoing line of investigation in this program has aimed to survey the effects of aging on neurochemically specific neuronal populations that are positioned influence excitatory/inhibitory balance in circuitry critical for normal neuropsychological function. A recent study of this sort used state-of-the-art methods to quantify the numbers of neurons in two inhibitory interneuron populations in the dorsolateral prefrontal cortex (i.e., parvalbumin and somatostatin positive) in young adult monkeys, and in aged animals with documented deficits in working memory. The prefrontal cortex is strongly implicated in age-related decline in executive function, but the potential role of changes in inhibitory tone in the primate brain has received limited attention. Initial results point to a regionally specific change, restricted to the dorsal bank of the principal sulcus, consisting of an unexpected age-related increase in the number of immunopositive cells in both interneuron populations. Previous studies have demonstrated that reverberating circuit activity important for working memory is diminished in the aged prefrontal cortex, and our findings may point to a circuit basis for this effect. Whether these changes are a component of broader disruption in inhibitory systems, including GABAergic basal forebrain projections to the prefrontal cortex and other neocortical targets, is under active investigation. Our perspective is that cellular and circuit-specific changes in the aged brain ultimately give rise to disrupted neural network interactions that comprise the proximal basis of cognitive decline. We are testing this view taking advantage of advanced in vivo neuroimaging. These investigations are conducted in collaboration with the Neuroimaging Research Branch at National Institute on Drug Abuse, where animals are lightly anesthetized and scanned in a 3T scanner using a variety of techniques, including sequences for examining cerebral blood flow (i.e., pseudo-continuous arterial spin labeling; pASL), and resting state functional connectivity (rs-FC). Ongoing analysis suggests that rs-FC with seed regions in either the dorsolateral prefrontal cortex or the anterior cingulate is increased in aging across a distributed network of areas including temporal, insular, frontal and posterior cingulate cortices. Significant increases in cerebral blow flow, measured by pASL - a presumptive marker of excess activity - were also detected in the aged hippocampus. The long-term aim is to document the progression of network change longitudinally in relation to the status of cognitive function, in order to determine whether the observed changes represent a failed compensatory response, or a direct driver of cognitive impairment. Ultimately, studies of this sort will establish a valuable resource of neural network signatures for measuring the effects of interventions intended to promote healthy brain and cognitive aging.
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