Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans

Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning

Emerging ecophenotype: reward anticipation is linked to high-risk behaviours after sexual abuse.

This is the final version. Available from Oxford University Press via the DOI in this record. Adolescents frequently engage in high-risk behaviours (HRB) following childhood sexual abuse (CSA). Aberrant reward processes are implicated in HRB, and their underlying fronto-striatal networks are vulnerable to neurodevelopmental changes during adversity representing a promising candidate for understanding links between CSA and HRB. We examined whether fronto-striatal responses during reward anticipation and feedback (i) are altered in depressed adolescents with CSA compared to depressed, non-abused peers and (ii) moderate the relationship between CSA and HRB irrespective of depression. Forty-eight female adolescents {14 with CSA and depression [CSA +  major depressive disorder (MDD)]; 17 with MDD but no CSA (MDD); 17 healthy, non-abused controls} completed a monetary reward task during functional magnetic resonance imaging. No differences in fronto-striatal response to reward emerged between CSA + MDD and MDD. Critically, high left nucleus accumbens activation during reward anticipation was associated with greater HRB in CSA + MDD compared to MDD and controls. Low left putamen activation during reward feedback was associated with the absence of HRB in CSA + MDD compared to MDD. Striatal reward responses appear to play a key role in HRB for adolescents with CSA irrespective of depression, providing initial support for a CSA ecophenotype. Such information is pivotal to identify at-risk youth and prevent HRB in adolescents after CSA.Brain and Behaviour Research FoundationWellcome TrustNational Institute of Mental HealthNational Institute of Mental Healt

Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.National Institutes of Health (U.S.) (Javits Merit Grant R01 NS025529)United States. Office of Naval Research (N000140710903)National Parkinson Foundation (U.S.) (Lynn Diamond Fellowship

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Affective regulation of cognitive-control adjustments in remitted depressive patients after acute tryptophan depletion

Negative affect in healthy populations regulates the appraisal of demanding situations, which tunes subsequent effort mobilization and adjustments in cognitive control. In the present study, we hypothesized that dysphoria in depressed individuals similarly modulates this adaptation, possibly through a neural mechanism involving serotonergic regulation. We tested the effect of dysphoria induced by acute tryptophan depletion (ATD) in remitted depressed patients on conflict adaptation in a Simon task. ATD temporarily lowers the availability of the serotonin precursor L-Tryptophan and is known to increase depressive symptoms in approximately half of remitted depressed participants. We found that depressive symptoms induced by ATD were associated with increased conflict adaptation. Our finding extends recent observations implying an important role of affect in regulating conflict-driven cognitive control

Worth the ‘EEfRT’? The Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia

Background: Of the putative psychopathological endophenotypes in major depressive disorder (MDD), the anhedonic subtype is particularly well supported. Anhedonia is generally assumed to reflect aberrant motivation and reward responsivity. However, research has been limited by a lack of objective measures of reward motivation. We present the Effort-Expenditure for Rewards Task (EEfRT or ‘‘effort’’), a novel behavioral paradigm as a means of exploring effort-based decision-making in humans. Using the EEfRT, we test the hypothesis that effort-based decision-making is related to trait anhedonia. Methods/Results: 61 undergraduate students participated in the experiment. Subjects completed self-report measures of mood and trait anhedonia, and completed the EEfRT. Across multiple analyses, we found a significant inverse relationship between anhedonia and willingness to expend effort for rewards. Conclusions: These findings suggest that anhedonia is specifically associated with decreased motivation for rewards, and provide initial validation for the EEfRT as a laboratory-based behavioral measure of reward motivation and effort-base

Face Coding Is Bilateral in the Female Brain

Background: It is currently believed that face processing predominantly activates the right hemisphere in humans, but available literature is very inconsistent. Methodology/Principal Findings: In this study, ERPs were recorded in 50 right-handed women and men in response to 390 faces (of different age and sex), and 130 technological objects. Results showed no sex difference in the amplitude of N170 to objects; a much larger face-specific response over the right hemisphere in men, and a bilateral response in women; a lack of face-age coding effect over the left hemisphere in men, with no differences in N170 to faces as a function of age; a significant bilateral face-age coding effect in women. Conclusions/Significance: LORETA reconstruction showed a significant left and right asymmetry in the activation of the fusiform gyrus (BA19), in women and men, respectively. The present data reveal a lesser degree of lateralization of brain functions related to face coding in women than men. In this light, they may provide an explanation of the inconsistencies in the available literature concerning the asymmetric activity of left and right occipito-temporal cortices devoted to fac