Variation in TREK1 gene linked to depression-resistant phenotype is associated with potentiated neural responses to rewards in humans.
The TREK1 gene has been linked to a depression-resistant phenotype in rodents and antidepressant response in humans, but the neural mechanisms underlying these links are unclear. Because TREK1 is expressed in reward-related basal ganglia regions, it has been hypothesized that TREK1 genetic variation may be associated with anhedonic symptoms of depression. To investigate whether TREK1 genetic variation influences reward processing, we genotyped healthy individuals (n = 31) who completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Three genotypes previously linked to positive antidepressant response were associated with potentiated basal ganglia activity to gains, but did not influence responses to penalties or no change feedback. TREK1 genetic variations did not affect basal ganglia volume, and fMRI group differences were confirmed when accounting for self-report measures of anhedonia. In addition, the total number of "protective" TREK1 alleles was associated with stronger responses to gains in several other reward-related regions, including the dorsal anterior cingulate cortex, orbitofrontal cortex, and mesial prefrontal cortex. In control analyses, associations between basal ganglia responses to gains and functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes were also explored. Results revealed that TREK1 and DAT/COMT genotypes were independently related to basal ganglia responses to gains. These findings indicate that TREK1 genotypes are associated with individual differences in reward-related brain activity. Future studies in depressed samples should evaluate whether variation in neural responses to rewards may contribute to the association between TREK1 and antidepressant response in humans.
Dillon
Daniel G
DG
Department of Psychology, Harvard University, Cambridge, Massachusetts 02138, USA.
Bogdan
Ryan
R
Fagerness
Jesen
J
Holmes
Avram J
AJ
Perlis
Roy H
RH
Pizzagalli
Diego A
DA
D001479:Basal Ganglia / Q000033:anatomy & histology / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology*; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics* / Q000378:metabolism*; D012201:Reward; D017422:Sequence Analysis, DNA; D055815:Young Adult
D050483:Dopamine Plasma Membrane Transport Proteins; D024683:Potassium Channels, Tandem Pore Domain; C493214:SLC6A3 protein, human; C103742:potassium channel protein TREK-1; D002394:Catechol O-Methyltransferase