Age-related changes in midbrain dopaminergic regulation of the human reward system

Abstract

The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and rewardrelated neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[ 18 F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging.aging ͉ dopamine ͉ fMRI ͉ PET ͉ reinforcement S uccessful aging has become one of the most crucial public health challenges of our time. Achieving an understanding of age-related changes in the neurobiology of key brain circuits, such as the reward system, is an integral part of rising to this challenge. Detecting, predicting, and responding to reward information are fundamental capabilities of simple life forms that have evolved in humans into complex behavioral patterns, such as learning, motivation, and appetitive and hedonic activities, which remain essential as we age. A substantial body of data in animals indicates that dopamine is closely associated with reward processing (1-3), and that midbrain dopamine neurons send reward-related signals to postsynaptic sites, particularly the prefrontal cortex. In humans, although indirect evidence from pharmacological (4, 5) and clinical (6-8) studies also suggests a fundamental role of dopamine in reward processing, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, although the dopamine system is known to be particularly vulnerable to aging (9, 10), there has been no search for alterations in this predicted relationship in older humans. Here, by using 6-[ 18 F]fluoroDOPA ...

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