Examining the contributions of cognitive load and anterior cingulate cortex activity on striatal-hippocampal network coupling in age-related cognitive decline - 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.
