TITLE: The contribution of declines in functional connectivity to cognitive aging Competing Renewal of NIH/NIA R01AG049722 FOA type: PA-19-056: Abstract: The number of Americans over age 65 is projected to exceed 55 million when the next census results become available. Unfortunately, a large proportion of older adults will experience cognitive decline that interferes with their quality of life with many developing Alzheimer's disease. In fact, the estimated direct costs for patient care involving Alzheimer's disease and related dementias in the United States were estimated at $277 billion in 2018 and predicted to exceed $1 trillion by 2050. Thus, developing new strategies for improving late life cognition is vital. Both changes in the activity properties of individual neurons in the medial temporal lobe and prefrontal cortex, as well as aberrant organization and dynamics of functional connectivity across the brain have been linked to cognitive decline in old age and early Alzheimer's disease. Notably, however, differences in individual neurons that are the building blocks of network functional connectivity have not been linked to large- scale changes in the distributed brain networks that support cognition. Bridging spatial and temporal scales to understand the mechanisms of cognitive aging is critical for developing targeted interventions to improve cognitive function in aging and Alzheimer's disease. The long-term goal of this research program is to determine the mechanisms of altered network-level interactions that underlie cognitive dysfunction in advanced age and Alzheimer's disease. The primary objective of the current proposed competing renewal is to directly link the activity of perirhinal cortical (PER) neurons in the medial temporal lobe that project directly to the prefrontal cortex (PFC) to age-associated differences in large scale functional connectivity in the context of behavior. Through an innovative series of experiments that integrate advanced methodologies in imaging, functional anatomy, in vivo neurophysiology, and behavior, the central hypothesis that age-related changes in PER to PFC projection neurons leads to disrupted dynamics of the global connectivity, manifesting as cognitive impairments will be tested by pursuing the following specific aims: 1) Determine if altered PER-PFC projection neuron activity in aged animals mediates aberrant functional connectivity patterns, 2) Determine whether manipulating PER- PFC projection neuron activity alters network functional connectivity, and 3) Determine the oscillatory signatures of age-related changes in PER-PFC functional connectivity. Our rationale is that by elucidating how aging influences systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, because state-of-the-art imaging and neurophysiological techniques will be integrated with measures of behavioral deficits in young and aged ra...