ABSTRACT
To better diagnose and treat individuals at risk for age-related dementia and cognitive decline, it is
important to understand the differences between normal and pathological changes to the brain and their
different impacts on cognitive function. Furthermore, the presence of different cognitive trajectories across the
normal spectrum of brain aging presents a particularly challenging problem for cognitive science and clinical
treatment efficacy. The objective of this research proposal is to identify age-related changes to brain function
across cognitive trajectories in different types of learning. Although it has been long documented that humans
and other mammalian species exhibit behavioral shifts from ‘place/allocentric’ to ‘response-driven/body-
centered’ spatial navigation strategies in advanced age, it is unclear whether these shifts extend to strategy
use in other cognitive domains outside spatial learning. This response shift has been defined by shifting away
from hippocampus (HPC)-dependent ‘cognitive mapping’ strategies, and toward caudate nucleus/dorsal
striatum-dependent ‘stimulus-response’ strategies. Furthermore, the dorsomedial subregion of the dorsal
striatum (DMS), has been implicated in behavioral flexibility and age-related changes to goal-directed behavior.
These observations suggest overall age-related changes to network communication that reflect the relative
expression of HPC- versus DMS-dominant solutions. This proposal will test the central hypothesis that age-
related changes to learning strategy are a product of suboptimal, perseverative behavior that can manifest as
cognitive impairment in older adults across different behavioral tasks, that this deficit is reflected by altered
HPC-DMS network activity, and that the anterior cingulate cortex (ACC) plays a critical role in these dynamics.
To achieve the goals of this proposal we will first combine high density in vivo electrophysiology recorded from
the HPC and DMS during associative and spatial learning in young and aged animals. This aim will determine
whether aged impaired or unimpaired animals have differential coupling patterns between the HPC and DMS
compared to young, and in what cognitive contexts these differences arise. Second, we will determine the
contributions of the ACC on spatial learning in young and aged rodents combining neurophysiology, volumetric
mapping of immediate-early gene expression, and circuit manipulation using virally transfected designer
receptors. The findings of this proposal will begin to unravel a more complex view of memory-system
interaction and age-related cognitive decline, which will have implications for therapeutic strategies in treating
dementia and promoting cognitive health.
