Normal aging in primates often leads to impaired cognitive function, particularly in working memory (WM), which begins to decline in middle-age. Cognitive changes correlate with structural and functional changes to neurons and white matter pathways in the prefrontal cortex (PFC), a brain area that is a key player in WM. However, we currently lack a mechanistic understanding of how the changes at the single-cell and pathway level impact network function and thus WM performance. Moreover, the prefrontal cortex is only one node in a distributed network of brain regions that contributes to WM, and aging also alters these other ?particularly fronto-parietal and visual? areas and long-range inter-areal connections. The central goal of this project is to advance our understanding of the computational and neural mechanisms underlying WM as well as the age- related changes to this executive function in the rhesus monkey model of normal aging. Specifically, we will test the hypothesis that WM arises through coordinated interaction of visual and fronto-parietal brain regions, and that aging-related decline in WM results from changes to both local circuit dynamics and inter-area communication. Our interdisciplinary approach will combine psychophysical, anatomical and physiological experiments with theory and computational modeling, taking advantage of the complementary expertise of the collaborating laboratories. The proposed research has the following specific aims:
Aim 1 : Identify aging effects on individual neurons, white matter pathways and resting state fMRI activity in fronto-parietal and visual cortices.
Aim 2 : Develop a multi-area computational neural network model in which WM function emerges from interacting distributed circuits.
Aim 3 : Model-based interpretation and experimental validation of the neuronal mechanisms underlying age-related WM decline.
related to the NIA mission: This project will reveal mechanisms underlying WM and selective age-related changes to WM due to neuronal dysfunction and predict mechanisms that may compensate for these changes to restore function at the cellular, circuit and cognitive level and the quality of life. It thus has broad implications for strategies to enhance brain function in the rapidly increasing population of normally aging individuals. Unique to this proposal is our use of state-of-the-art multiscale anatomical, physiological, and computational approaches in behaviorally characterized rhesus monkeys. These data are critically needed for targeted therapies to prevent detrimental structural and functional brain changes in normal aging. Public distribution of these data will also provide a unique and invaluable resource for the neuroscience community supported by the NIA. RELEVANCE (See instructions): This project addresses the mission of the NIA -to enhance the understanding of mechanisms of cognitive aging and the quality of life of our aging population? by studying the mechanisms of changes to cognitive function in rhesus monkeys. Through a detailed interrogation of the intricate web of brain changes associated with cognitive decline together with sophisticated computational modeling, this project will provide unique data needed for targeted approaches to enhance the brain health, vitality and productivity of aging individuals.
