The influence of dopamine on cognitive flexibility is mediated by functional connectivity in young but not older adults

Dopaminergic signaling in striatum is strongly implicated in executive
functions including cognitive flexibility. However, there is a paucity of
multimodal research in humans defining the nature of relationships between
endogenous dopamine, striatal network activity, and cognition. Here, we
measured dopamine synthesis capacity in young and older adults using the
PET tracer 6-[18F]fluoro-L-m-tyrosine, and examined its relationship with
cognitive performance and functional connectivity during an fMRI study of
task switching. Aging is associated with alteration in dopamine function
including profound losses in dopamine receptors, but an apparent elevation
in dopamine synthesis. A compensatory benefit of upregulated dopamine
synthesis in aging has not been established. Across young and older
adults, we found that cognitive flexibility (low behavioral switch cost)
was associated with stronger task-related functional connectivity within
canonical fronto-striato-thalamic circuits connecting left inferior
frontal gyrus, dorsal caudate nucleus (DCA) and ventral lateral/ventral
anterior thalamic nuclei. In young adults, functional connectivity
mediated the influence of DCA dopamine synthesis capacity on switch
cost.  For older adults, these relationships were modified such
that DCA synthesis capacity and connectivity interacted to influence
switch cost. Older adults with most elevated synthesis capacity maintained
the pattern of connectivity-cognition relationships observed in youth,
whereas these relationships were not evident for low synthesis older
adults. Together, these findings suggest a role of dopamine in tuning
striatal circuits to benefit executive function in young adults, and
clarify the functional impact of elevated dopamine synthesis capacity in
aging.