Explorer Dopamine and memory dedifferentiation in aging

1 The dedifferentiation theory of aging proposes that a reduction in the specificity of neural 2 representations causes declines in complex cognition as people get older, and may reflect a 3 reduction in dopaminergic signaling. The present pharmacological fMRI study investigated episodic 4 memory-related dedifferentiation in young and older adults, and its relation to dopaminergic 5 function, using a randomized placebo-controlled double-blind crossover design with the agonist 6 Bromocriptine (1.25 mg) and the antagonist Sulpiride (400 mg). We used multi-voxel pattern 7 analysis to measure memory specificity: the degree to which distributed patterns of activity 8 distinguishing two different task contexts during an encoding phase are reinstated during memory 9 retrieval. As predicted, memory specificity was reduced in older adults in prefrontal cortex and in 10 hippocampus, consistent with an impact of neural dedifferentiation on episodic memory 11 representations. There was also a linear age-dependent dopaminergic modulation of memory 12 specificity in hippocampus reflecting a relative boost to memory specificity on Bromocriptine in 13 older adults whose memory was poorer at baseline, and a relative boost on Sulpiride in older better 14 performers, compared to the young. This differed from generalized effects of both agents on task 15 specificity in the encoding phase. The results demonstrate a link between ageing, dopaminergic 16 function and dedifferentiation in the hippocampus. 17