COMT val158met predicts reward responsiveness in humans

A functional variant of the catechol‐O‐methyltransferase (COMT) gene [val158met (rs4680)] is frequently implicated in decision‐making and higher cognitive functions. It may achieve its effects by modulating dopamine‐related decision‐making and reward‐guided behaviour. Here we demonstrate that individuals with the met/met polymorphism have greater responsiveness to reward than carriers of the val allele and that this correlates with risk‐seeking behaviour. We assessed performance on a reward responsiveness task and the Balloon analogue risk task, which measure how participants (N = 70, western European, university and postgraduate students) respond to reward and take risks in the presence of available reward. Individuals with the met/met genotype (n = 19) showed significantly higher reward responsiveness, F_2,64 = 4.02, P = 0.02, and reward‐seeking behaviour, F(2,68) = 4.52, P = 0.01, than did either val/met (n = 25) or val/val (n = 26) carriers. These results highlight a scenario in which genotype‐dependent reward responsiveness shapes reward‐seeking, therefore suggesting a novel framework by which COMT may modulate behaviour.     

COMT Val158Met genotype is associated with reward learning: a replication study and meta‐analysis

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol‐O‐methyl transferase gene (COMT; rs4680, Val¹⁵⁸Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European‐American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European‐American participants (β = 0.20, t = 2.75, P < 0.01; ΔR² = 0.04). Moreover, a meta‐analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI ?0.11 to ?0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.     

Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning

Previous studies suggest that a single nucleotide polymorphism in the catechol‐O‐methyltransferase (COMT) gene (val158met) may modulate reward‐guided decision making in healthy individuals. The polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial × COMT genotype interaction (P = 0.047; η² = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias [response bias at block 3 ? block 1 (met/met > val/val: P = 0.028) and block 3 ? block 2 (met/met > val/val: P = 0.007)], suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk‐seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk‐seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia.     

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.     

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.     

Learning to Obtain Reward,but Not Avoid Punishment,Is Affected by Presence of PTSD Symptoms in Male Veterans: Empirical Data and Computational Model

Post-traumatic stress disorder (PTSD) symptoms include behavioral avoidance which is acquired and tends to increase with time. This avoidance may represent a general learning bias; indeed, individuals with PTSD are often faster than controls on acquiring conditioned responses based on physiologically-aversive feedback. However, it is not clear whether this learning bias extends to cognitive feedback, or to learning from both reward and punishment. Here, male veterans with self-reported current, severe PTSD symptoms (PTSS group) or with few or no PTSD symptoms (control group) completed a probabilistic classification task that included both reward-based and punishment-based trials, where feedback could take the form of reward, punishment, or an ambiguous “no-feedback” outcome that could signal either successful avoidance of punishment or failure to obtain reward. The PTSS group outperformed the control group in total points obtained; the PTSS group specifically performed better than the control group on reward-based trials, with no difference on punishment-based trials. To better understand possible mechanisms underlying observed performance, we used a reinforcement learning model of the task, and applied maximum likelihood estimation techniques to derive estimated parameters describing individual participants’ behavior. Estimations of the reinforcement value of the no-feedback outcome were significantly greater in the control group than the PTSS group, suggesting that the control group was more likely to value this outcome as positively reinforcing (i.e., signaling successful avoidance of punishment). This is consistent with the control group’s generally poorer performance on reward trials, where reward feedback was to be obtained in preference to the no-feedback outcome. Differences in the interpretation of ambiguous feedback may contribute to the facilitated reinforcement learning often observed in PTSD patients, and may in turn provide new insight into how pathological behaviors are acquired and maintained in PTSD.     

Post-training reward partially restores chronic stress induced effects in mice

Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in na?ve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in na?ve mice, whereas (3) in stressed mice sugar partially "normalized" the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory.     

No Association of the BDNF Val66met Polymorphism with Implicit Associative Vocabulary and Motor Learning

Brain-derived neurotrophic factor (BDNF) has been suggested to play a major role in plasticity, neurogenesis and learning in the adult brain. The BDNF gene contains a common val66met polymorphism associated with decreased activity-dependent excretion of BDNF and a potential influence on behaviour, more specifically, on motor learning. The objective of this study was to determine the influence of the BDNF val66met polymorphism on short-term implicit associative learning and whether its influence is cognitive domain-specific (motor vs. language). A sample of 38 young healthy participants was genotyped, screened for background and neuropsychological differences, and tested with two associative implicit learning paradigms in two different cognitive domains, i.e., motor and vocabulary learning. Subjects performed the serial reaction time task (SRTT) to determine implicit motor learning and a recently established associative vocabulary learning task (AVL) for implicit learning of action and object words. To determine the influence of the BDNF polymorphism on domain-specific implicit learning, behavioural improvements in the two tasks were compared between val/val (n = 22) and met carriers (val/met: n = 15 and met/met: n = 1). There was no evidence for an impact of the BDNF val66met polymorphism on the behavioural outcome in implicit short-term learning paradigms in young healthy subjects. Whether this polymorphism plays a relevant role in long-term training paradigms or in subjects with impaired neuronal plasticity or reduced learning capacity, such as aged individuals, demented patients or patients with brain lesions, has to be determined in future studies.     

Symbolic sequence learning is associated with cognitive–affective profiles in female FMR1 premutation carriers

This study examines implicit sequence learning impairments that may indicate at‐risk cerebellar profiles proposed to underlie some aspects of subtle cognitive and affective dysfunctions found among female fragile X mental retardation 1 (FMR1) premutation (PM)‐carriers. A total of 34 female PM‐carriers and 33 age‐ and intelligence‐matched controls completed an implicit symbolically primed serial reaction time task (SRTT) previously shown to be sensitive to cerebellar involvement. Implicit learning scores indicated a preservation of learning in both groups; however, PM‐carriers demonstrated poorer learning through significantly elevated response latencies overall and at each specific block within the symbolic SRTT. Group comparisons also revealed a core deficit in response inhibition, alongside elevated inattentive symptoms in female PM‐carriers. Finally, strong and significant associations were observed between poor symbolic SRTT performance and executive, visuospatial and affective deficits in the PM‐carrier group. These associations remained strong even after controlling motor speed, and were not observed in age‐ and intelligence quotient‐matched participants. The findings implicate cerebellar non‐motor networks subserving the implicit sequencing of responses in cognitive–affective phenotypes previously observed in female PM‐carriers. We contend that symbolic SRTT performance may offer clinical utility in future pharmaceutical interventions in female PM‐carriers .     

Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal

Nicotine withdrawal‐related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal‐related cognitive disruption. CNR1 polymorphisms comprising the ‘TAG’ haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal‐related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha‐1 power density across 17 electrodes. Seventy‐three Caucasian Non‐Hispanic smokers (≥15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal‐related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal‐related cognitive disruption.     

Evidence for plasticity genotypes in a gene–gene–environment interaction: the TRAILS study

The purpose was to study how functional polymorphisms in the brain derived neurotrophic factor gene (BDNF val66met) and the serotonin transporter gene linked promotor region (5‐HTTLPR) interact with childhood adversities in predicting Effortful Control. Effortful Control refers to the ability to regulate behavior in a goal‐directed manner and is an interesting endophenotype for psychopathology because of its heritability and the association of low Effortful Control with both internalizing and externalizing problems. In a longitudinal population‐based study Effortful Control was assessed with the parent version of the Early Adolescent Temperament Questionnaire at age 11. Pregnancy and delivery adversities and childhood events were assessed in a parent interview at age 11. Long‐term difficulties until age 11 were assessed with a parent questionnaire at age 13.5. Blood or buccal cells were collected at age 16 for genotyping the rs6265 and rs25531 SNPs and the 5‐HTTLPR length polymorphism. The study included 1032 complete data sets. Effortful Control was significantly predicted by the interaction between BDNF val66met, 5‐HTTLPR and childhood events. The BDNF val66met val/val–5‐HTTLPR l′/l′ genotype was unaffected by childhood events, while having either at least one BDNF val66met met or 5‐HTTLPR s′ allele (l′/l′‐met‐carrier; l′/s′‐val/val; s′/s′‐val/val) made children sensitive to childhood events. Predictions of Effortful Control by pregnancy and delivery adversities and long‐term difficulties were largely independent of genotype. We concluded that the l′/l′‐met‐carrier, l′/s′‐val/val and the s′/s′‐val/val genotypes showed greatest plasticity while the l′/l′‐val/val genotype was unaffected by childhood events.     

The Computational Development of Reinforcement Learning during Adolescence

Adolescence is a period of life characterised by changes in learning and decision-making. Learning and decision-making do not rely on a unitary system, but instead require the coordination of different cognitive processes that can be mathematically formalised as dissociable computational modules. Here, we aimed to trace the developmental time-course of the computational modules responsible for learning from reward or punishment, and learning from counterfactual feedback. Adolescents and adults carried out a novel reinforcement learning paradigm in which participants learned the association between cues and probabilistic outcomes, where the outcomes differed in valence (reward versus punishment) and feedback was either partial or complete (either the outcome of the chosen option only, or the outcomes of both the chosen and unchosen option, were displayed). Computational strategies changed during development: whereas adolescents’ behaviour was better explained by a basic reinforcement learning algorithm, adults’ behaviour integrated increasingly complex computational features, namely a counterfactual learning module (enabling enhanced performance in the presence of complete feedback) and a value contextualisation module (enabling symmetrical reward and punishment learning). Unlike adults, adolescent performance did not benefit from counterfactual (complete) feedback. In addition, while adults learned symmetrically from both reward and punishment, adolescents learned from reward but were less likely to learn from punishment. This tendency to rely on rewards and not to consider alternative consequences of actions might contribute to our understanding of decision-making in adolescence.     

Evidence of a diurnal rhythm in implicit reward learning

Many aspects of hedonic behavior, including self-administration of natural and drug rewards, as well as human positive affect, follow a diurnal cycle that peaks during the species-specific active period. This variation has been linked to circadian modulation of the mesolimbic dopamine system, and is hypothesized to serve an adaptive function by driving an organism to engage with the environment during times where the opportunity for obtaining rewards is high. However, relatively little is known about whether more complex facets of hedonic behavior – in particular, reward learning – follow the same diurnal cycle. The current study aimed to address this gap by examining evidence for diurnal variation in reward learning on a well-validated probabilistic reward learning task (PRT). PRT data from a large normative sample (N = 516) of non-clinical individuals, recruited across eight studies, were examined for the current study. The PRT uses an asymmetrical reinforcement ratio to induce a behavioral response bias, and reward learning was operationalized as the strength of this response bias across blocks of the task. Results revealed significant diurnal variation in reward learning, however in contrast to patterns previously observed in other aspects of hedonic behavior, reward learning was lowest in the middle of the day. Although a diurnal pattern was also observed on a measure of more general task performance (discriminability), this did not account for the variation observed in reward learning. Taken together, these findings point to a distinct diurnal pattern in reward learning that differs from that observed in other aspects of hedonic behavior. The results of this study have important implications for our understanding of clinical disorders characterized by both circadian and reward learning disturbances, and future research is needed to confirm whether this diurnal variation has a truly circadian origin.     

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain‐containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non‐reward response to a stimulus) produced by cocaine administration. Cocaine‐dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (P = 0.00006), ‘any drug effect’ (P = 0.0003) and ‘like’ (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.     

Modifying the role of serotonergic 5‐HTTLPR and TPH2 variants on disulfiram treatment of cocaine addiction: a preliminary study

Disulfiram is a cocaine pharmacotherapy that may act through increasing serotonin, benefiting patients with genetically low serotonin transporter levels (5‐HTTLPR, S′ allele carriers) and low serotonin synthesis (TPH2, A allele carriers). We stabilized 71 cocaine and opioid co‐dependent patients on methadone for 2 weeks and randomized them into disulfiram and placebo groups for 10 weeks. We genotyped the SLC6A4 5‐HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating disulfiram treatment for cocaine dependence. Cocaine‐positive urines dropped from 78% to 54% for the disulfiram group and from 77% to 76% for the placebo group among the 5‐HTTLPR S′ allele carriers (F = 16.2; df = 1,301; P < 0.0001). TPH2 A allele carriers responded better to disulfiram than placebo (F = 16.0; df = 1,223; P < 0.0001). Patients with both an S′ allele and a TPH2 A allele reduced cocaine urines from 71% to 53% on disulfiram and had no change on placebo (F = 21.6; df = 1,185; P < 0.00001).     

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.     

Attenuated stress‐evoked anxiety,increased sucrose preference and delayed spatial learning in glucocorticoid‐induced receptor‐deficient mice

The glucocorticoid‐induced receptor (GIR) is a stress‐responsive gene that is abundantly expressed in forebrain limbic regions. Glucocorticoid‐induced receptor has been classified as a Neuropeptide Y‐like receptor, however, physiological attributes have not been investigated. In this study, mice lacking GIR (?/?) were screened in various paradigms related to stress, anxiety, activity, memory, fear and reward. GIR ?/? mice elicited behavioral insensitivity to the anxiogenic effects of restraint stress. However, hypothalamic pituitary adrenal axis response to stress was not impacted by GIR deficiency. Increased preference for sucrose was observed in GIR ?/? mice suggestive of modulation of reward‐associated behaviors by the receptor. A delayed acquisition of spatial learning was also observed in GIR ?/? mice. There were no effects of genotype on the modulation of anxiety‐like behavior, activity, fear‐conditioning and extinction. Our data extend previous studies on GIR regulation by glucocorticoids and provide novel evidence for a role of GIR in reward, learning and the behavioral outcomes of stress .     

C957T polymorphism of the dopamine D2 receptor gene is associated with motor learning and heart rate

Genetic variants that are related to the dopaminergic system have been frequently found to be associated with various neurological and mental disorders. Here, we studied the relationships between some of these genetic variants and some cognitive and psychophysiological processes that are implicated in such disorders. Two single nucleotide polymorphisms were chosen: one in the dopamine D2 receptor gene (rs6277-C957T) and one in the catechol-O-methyltransferase gene (rs4680-Val158Met), which is involved in the metabolic degradation of dopamine. The performance of participants on two long-term memory tasks was assessed: free recall (declarative memory) and mirror drawing (procedural motor learning). Heart rate (HR) was also monitored during the initial trials of the mirror-drawing task, which is considered to be a laboratory middle-stress generator (moderate stress), and during a rest period (low stress). Data were collected from 213 healthy Caucasian university students. The C957T C homozygous participants showed more rapid learning than the T allele carriers in the procedural motor learning task and smaller differences in HR between the moderate- and the low-stress conditions. These results provide useful information regarding phenotypic variance in both healthy individuals and patients.     

Low‐density lipoprotein receptor‐related protein 1 variant interacts with saturated fatty acids in puerto ricans

Objective:

Low‐density lipoprotein receptor‐related protein 1 (LRP1) is a multifunctional endocytic receptor that is highly expressed in adipocytes and the hypothalamus. Animal models and in vitro studies support a role for LRP1 in adipocyte metabolism and leptin signaling, but genetic polymorphisms have not been evaluated for obesity in people.

Design and Methods:

We examined whether dietary fats (eg., saturated, polyunsaturated) modulated the association of LRP1 rs1799986 with anthropometric traits. We studied a population‐based sample of Puerto Ricans (n = 920, aged 45–74 y) living in the Boston area.We examined whether dietary fats (eg., saturated, polyunsaturated) modulated the association of LRP1 rs1799986 with anthropometric traits. We studied a population‐based sample of Puerto Ricans (n = 920, aged 45–74 y) living in the Boston area.

Results:

In multivariable linear regression models, we dichotomized saturated fat intake and found significant interaction terms between total saturated fatty acids and LRP1 rs1799986 genotype for BMI (P=0.006) and hip (P = 0.002). High intake of saturated fat was associated with higher BMI (P = 0.001), waist (P = 0.008) and hip (P=0.003) in minor allele carriers (CT+TT) compared to CC participants. Further analysis of dichotomized individual saturated fatty acids revealed that interactions were strongest for two individual longer chain fatty acids. High intake of palmitic acid (C16:0; P = 0.0007) and high stearic acid intake (C18:0; P = 0.005) were associated with higher BMI in T carriers. Interactions were not detected for polyunsaturated fatty acids.

Conclusions:

Gene–diet interactions at the LRP1 locus support the hypothesis that susceptibility to weight gain based on saturated fatty acids is modified by genotype and possibly by chain length. These results may facilitate the development of a panel of genetic candidates for use in optimizing dietary recommendations for obesity management.     

Neuropeptide‐S‐receptor deficiency affects sex‐specific modulation of safety learning by pre‐exposure to electric stimuli

Neuropeptide S (NPS) is a neuropeptide involved in the regulation of fear. Because safety learning is impaired in patients suffering from anxiety‐related psychiatric disorders, and polymorphisms of the human neuropeptide S receptor (NPSR) gene have also been associated with anxiety disorders, we wanted to investigate whether NPSR‐deficiency interferes with safety learning, and how prior stress would affect this type of learning. We first investigated the effect of pre‐exposure to two different types of stressors (electric stimuli or immobilization) on safety learning in female and male C57Bl/6 mice, and found that while stress induced by electric stimuli enhanced safety learning in males, there were no differences in safety learning following immobilization stress. To further investigate the role of the NPS system in stress‐induced modulation of safety learning, we exposed NPSR‐deficient mice to stress induced by electric stimuli 10 days before safety learning. In nonstressed male mice, NPSR‐deficiency enhanced safety learning. As in male C57Bl/6 mice, pre‐exposure to electric stimuli increased safety learning in male NPSR +/+ mice. This pre‐exposure effect was blocked in NPSR‐deficient male mice showing impaired, but still intact, safety learning in comparison to their NPSR +/+ and NPSR +/? littermates. There was neither a pre‐exposure nor a genotype effect in female mice. Our findings provide evidence that pre‐exposure to stress induced by electric stimuli enhances safety learning in male mice, and that NPSR‐deficiency prevents the beneficial effect of stress exposure on safety learning. We propose an inverted U‐shape relationship between stress and safety learning.