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Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

ABSTRACT: Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20-30 years) and 37 older (age 60-75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

SUBMITTER: Baeuchl C

PROVIDER: S-EPMC6505745 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Baeuchl Christian C Chen Hsiang-Yu HY Su Yu-Shiang YS Hämmerer Dorothea D Klados Manousos A MA Li Shu-Chen SC

PloS one 20190508 5

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects betwe ...[more]

PMID: 31067250

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Project description:Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described.To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.Randomized, placebo-controlled, before-after, crossover study.Clinical research center.Eighteen nonabstaining individuals with cocaine use disorders.Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects).Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire.Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections.These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.

Dataset Information

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Publications

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

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