Dopaminergic mechanisms of reward memory in aging - PROJECT SUMMARY/ABSTRACT Aging is accompanied by reductions in multiple components of the dopamine system and concomitant declines in cognition. Alterations in dopamine signaling have been posited to be major drivers of age-related changes in multiple cognitive domains including reward processing, memory encoding and memory consolidation. Salient events, such as those associated with rewards, are more likely to be remembered later. Evidence from animal models has demonstrated that reactivation of neural activity contributes to prioritization of rewarding events. In recent human fMRI studies, activation patterns produced during specific task conditions persisted into periods of rest following the task, and the strength of this persistence is related to better memory performance. However, the exact mechanisms driving reinstatement of fMRI patterns remain unknown. The current project will test, for the first time in humans, whether greater dopamine release is related to reinstatement of fMRI activation patterns, and whether dopamine function impacts the relationship between reinstatement and reward memory. Endogenous dopamine release will be quantified in vivo in cognitively normal older adults using the positron emission tomography (PET) tracer [11C]raclopride and a within-subjects pharmacological protocol using the dopamine reuptake-inhibitor methylphenidate. fMRI pattern reinstatement will be measured using multi-voxel pattern analysis and a classifier algorithm to distinguish between fMRI patterns associated with high and low reward task conditions. Reinstatement of these patterns into periods of rest following the task will determine persistence of reward-related activation. This project will use a healthy aging sample where there is substantial inter-individual variability in all measures of interest and where defining the impact of suboptimal dopamine function is most clinically relevant. Analyses will include Alzheimer’s disease (AD)-related pathology (tau and β-amyloid) as covariates. Dopamine is rarely studied in the context of AD and accounting for pathology will allow for assessment of cognitive and neural effects that are specifically related to dopamine. Aim 1 will establish relationships between dopamine function and reward-related fMRI patterns during encoding. Aim 2 will link fMRI reinstatement, dopamine, and cognitive performance. We predict that individuals with the highest dopamine release will demonstrate distinct fMRI patterns for high versus low reward task conditions, suggesting that dopamine contributes to tuning and sharpening neural activity for reward-related events. The proposed project will allow the PI to train in (1) advanced neuroimaging, (2) reward processing in aging, (3) statistics, (4) scientific communication, and (5) mentorship. Dr. Anne Berry (sponsor) and Dr. Jacob Hooker (co-sponsor) have expertise in PET, fMRI, and aging. Brandeis University and the Massachusetts General Hospital provide exceptional faculty, neuroimaging facilities, and professional development opportunities. Completion of the proposed project and training plan will support the PI in successful pursuit of a career studying aging and neuromodulator systems.
