The contribution of declines in functional connectivity to cognitive aging

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 rats in order to probe how
local dysfunction impacts larger scale network dynamics to provoke compensation or propagate impairment. The
significance of successful completion of these experiments will be to provide an unprecedented understanding
of the association between alterations at the level of single cells and brain wide functional connectivity, and how
this relates to cognitive function in old age and the early stages of Alzheimer's disease.

Grant Number: 5R01AG049722-08
NIH Institute/Center: NIH
Principal Investigator: SARA BURKE