Impact of COMT Val158Met‐polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val¹⁵⁸Met‐polymorphism in the Catechol‐O‐Methyl‐Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val¹⁵⁸Met‐polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS?) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val¹⁵⁸Met‐genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS? in Val/Val‐allele carriers but not in the other genotype groups. Val/Val‐allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met‐allele group in the contrast CS+ > CS?. In addition, psychophysiological‐interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met‐allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val‐allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val‐allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing. Hum Brain Mapp 36:1093–1101, 2015. © 2014 Wiley Periodicals, Inc.     

Neuroticism and extraversion moderate neural responses and effective connectivity during appetitive conditioning

Classical appetitive conditioning constitutes a basic learning process through which environmental stimuli can be associated with reward. Previous studies showed that individual differences in neuroticism and extraversion influence emotional processing and have been shown to modulate neural activity in subcortical and prefrontal areas in response to emotional stimuli. However, the role of individual differences in appetitive conditioning has so far not been investigated in detail. The aim of this study was to assess the association between neuroticism and extraversion with neural activity and connectivity during appetitive conditioning. The conditioned stimulus (CS) was either a picture of a dish or a cup. One stimulus (CS+) was paired with a monetary reward and the other stimulus (CS?) was associated with its absence while hemodynamic activity was measured by means of functional magnetic resonance imaging. A significant negative correlation of neuroticism scores with amygdala activity was observed during appetitive conditioning. Further, extraversion was positively associated with responses in the hippocampus and the thalamus. In addition, effective connectivity between the amygdala as a seed region and the anterior cingulate cortex, the insula, and the thalamus was negatively correlated with neuroticism scores and positively correlated with extraversion scores. The results may indicate a neural correlate for the deficits in appetitive learning in subjects with high neuroticism scores and point to a facilitating effect of extraversion on reward‐related learning. Hum Brain Mapp 37:2992–3002, 2016. © 2016 Wiley Periodicals, Inc .     

Serotonin transporter gene polymorphism (5‐HTTLPR) influences trait anxiety by modulating the functional connectivity between the amygdala and insula in Han Chinese males

A functional polymorphism (5‐hydroxytryptamine transporter linked polymorphic region [5‐HTTLPR]) in the promoter region of human serotonin transporter gene has been found to be associated with several dimensions of neuroticism and psychopathology, especially anxiety. However, the neural basis underlying the association between 5‐HTTLPR and anxiety is less clear. Here, we explored how 5‐HTTLPR influenced anxiety by modulating the spontaneous brain activities in Han Chinese. First, we found an association between 5‐HTTLPR and anxiety only in the male and not in the female population, where male S/S homozygotes had a significantly higher level of anxiety than male L allele carriers. Then, we examined how 5‐HTTLPR influenced anxiety at both regional and network levels in the brain at rest. At the regional level, we found a significantly higher fractional amplitude of low‐frequency fluctuations in the amygdala in male S/S homozygotes relative to male L allele carriers. At the network level, male S/S homozygotes showed a weaker resting‐state functional connectivity (RSFC) between the amygdala and various regions, including the insula, Heschl's gyrus, lateral occipital cortex, superior temporal gyrus, and hippocampus, and a stronger RSFC between the amygdala and various regions, including the supramariginal gyrus and middle frontal gyrus. However, at both levels, only was the amygdala–insula RSFC correlated with anxiety. Mediation analyses further revealed that the amygdala–insula RSFC mediated the association between 5‐HTTLPR and anxiety. In short, our study provided the first empirical evidence that the amygdala–insula RSFC served as the neural basis underlying the association between 5‐HTTLPR and anxiety, suggesting a potential neurogenetic susceptibility mechanism for anxiety. Hum Brain Mapp 36:2732–2742, 2015. © 2015 Wiley Periodicals, Inc.     

Heightened amygdala responsiveness in s‐carriers of 5‐HTTLPR genetic polymorphism reflects enhanced cortical rather than subcortical inputs: An MEG study

Short allele carriers (S‐carriers) of the serotonin transporter gene (5‐HTTLPR) show an elevated amygdala response to emotional stimuli relative to long allele carriers (LL‐homozygous). However, whether this reflects increased responsiveness of the amygdala generally or interactions between the amygdala and the specific input systems remains unknown. It is argued that the amygdala receives input via a quick subcortical and a slower cortical pathway. If the elevated amygdala response in S‐carriers reflects generally increased amygdala responding, then group differences in amygdala should be seen across the amygdala response time course. However, if the difference is a secondary consequence of enhanced amygdala–cortical interactions, then group differences might only be present later in the amygdala response. Using magnetoencephalography (MEG), we found an enhanced amygdala response to fearful expressions starting 40–50 ms poststimulus. However, group differences in the amygdala were only seen 190–200 ms poststimulus, preceded by increased superior temporal sulcus (STS) responses in S‐carriers from 130 to 140 ms poststimulus. An enhanced amygdala response to angry expressions started 260–270 ms poststimulus with group differences in the amygdala starting at 160–170 ms poststimulus onset, preceded by increased STS responses in S‐carriers from 150 to 160 ms poststimulus. These suggest that enhanced amygdala responses in S‐carriers might reflect enhanced STS‐amygdala connectivity in S‐carriers. Hum Brain Mapp 38:4313–4321, 2017. © 2017 Wiley Periodicals, Inc.     

5‐HTTLPR differentially predicts brain network responses to emotional faces

The effects of the 5‐HTTLPR polymorphism on neural responses to emotionally salient faces have been studied extensively, focusing on amygdala reactivity and amygdala‐prefrontal interactions. Despite compelling evidence that emotional face paradigms engage a distributed network of brain regions involved in emotion, cognitive and visual processing, less is known about 5‐HTTLPR effects on broader network responses. To address this, we evaluated 5‐HTTLPR differences in the whole‐brain response to an emotional faces paradigm including neutral, angry and fearful faces using functional magnetic resonance imaging in 76 healthy adults. We observed robust increased response to emotional faces in the amygdala, hippocampus, caudate, fusiform gyrus, superior temporal sulcus and lateral prefrontal and occipito‐parietal cortices. We observed dissociation between 5‐HTTLPR groups such that L_AL_A individuals had increased response to only angry faces, relative to neutral ones, but S′ carriers had increased activity for both angry and fearful faces relative to neutral. Additionally, the response to angry faces was significantly greater in L_AL_A individuals compared to S′ carriers and the response to fearful faces was significantly greater in S′ carriers compared to L_AL_A individuals. These findings provide novel evidence for emotion‐specific 5‐HTTLPR effects on the response of a distributed set of brain regions including areas responsive to emotionally salient stimuli and critical components of the face‐processing network. These findings provide additional insight into neurobiological mechanisms through which 5‐HTTLPR genotype may affect personality and related risk for neuropsychiatric illness. Hum Brain Mapp 36:2842–2851, 2015. © 2015 Wiley Periodicals, Inc.     

Association of the serotonin transporter promoter region polymorphism with biased attention for negative word stimuli

Background: Biased attention for emotional stimuli reflects vulnerability or resilience to emotional disorders. The current study examines whether the 5‐HTTLPR polymorphism is associated with attentional biases for negative word stimuli. Methods: Unmedicated, young adults with low current depression and anxiety symptoms (N=106) were genotyped for the 5‐HTTLPR, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5‐HTTLPR. Participants then completed a standard dot‐probe task that measured attentional bias toward anxiety, dysphoric, and self‐esteem words. Results: The L_AL_A allele group demonstrated an attentional bias away from negative word stimuli. This attentional bias was absent among the S/L_G carriers. Conclusions: These findings replicate previous work and suggest that 5‐HTTLPR L_A homozygotes possess a protective attentional bias that may decrease susceptibility to depression and anxiety. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

5‐HTTLPR moderates the association between interdependence and brain responses to mortality threats

While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5‐HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self‐report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5‐HTTLPR were scanned using fMRI while they performed a one‐back task on death‐related, death‐unrelated negative, and neutral words. Participants’ interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death‐related words in emotion‐related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5‐HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death‐related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157–6171, 2017. © 2017 Wiley Periodicals, Inc.     

Amygdala and nucleus accumbens involvement in appetitive extinction

Extinction of appetitive conditioning is regarded as an important model for the treatment of psychiatric disorders like addiction. However, very few studies have investigated its neural correlates. Therefore, we investigated neural correlates of appetitive extinction in a large human sample including all genders (N = 76, 40 females) to replicate and extend results from a previous study. During differential appetitive conditioning, one stimulus (CS+) was paired with the chance to win a monetary reward, whereas another stimulus (CS?) was not. During appetitive extinction on the next day, neither the CS+ nor the CS? were reinforced. After successful acquisition of appetitive conditioning, the extinction phase elicited significant reductions of valence and arousal ratings toward the CS+ and a significant reduction in skin conductance responses to the CS+ from early to late extinction. On a neural level, early extinction showed significant differential (CS+ ? CS?) activation in dACC and hippocampus, whereas involvement of the vACC and caudate nucleus did not replicate. The differential activation of amygdala and nucleus accumbens during late extinction was replicated, with the amygdala displaying significantly higher differential activation during the late phase of extinction as compared to the early phase of extinction. We show discernible signals for reward learning and extinction in subregions of amygdala and nucleus accumbens after extinction learning. This successful replication underlines the role of nucleus accumbens and amygdala in neural models of appetitive extinction in humans that was previously only based on animal findings.     

Thalamocortical interactions underlying visual fear conditioning in humans

Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to “entrainment” of brain oscillations at a predefined modulation frequency. Steady‐state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed‐regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans. Hum Brain Mapp 36:4592–4603, 2015. © 2015 Wiley Periodicals, Inc.     

Neuroimaging genetics: new perspectives in research on major depression?

Objective: Stress‐related changes in the hippocampus are influenced by genetic factors. To enhance our understanding of both the interaction between the brain, behaviour and genetics and of biological mechanisms in mood disorders neuroimaging genetics provide a good opportunity. Method: A MEDLINE search was conducted to identify articles on neuroimaging genetics in major depression (MD). Results: Hippocampal volumes were found to be associated with polymorphisms in the promotor region of the serotonin transporter (5‐HTTLPR) in patients with MD. Met‐allele carriers of the BDNF (val66met) polymorphism had smaller hippocampal volumes in both patients and healthy controls when compared with homozygous val‐allele carriers. Polymorphisms of the serotonin transporter (5‐HTTLPR) and 5‐HT1a receptor are associated with increased amygdala activation investigated with functional MRI in patients with MD. Conclusion: Genetic variants seem to modulate the effects of stress on hippocampal volumes as well as amygdala activity as well as the development of the brain.     

The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis

Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant‐induced mania: a systematic review and meta‐analysis.
Bipolar Disord 2010: 12: 702–706. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Antidepressant‐induced mania (AIM) has been associated with the serotonin‐transporter‐linked promoter region (5‐HTTLPR) polymorphism in some studies but not in others. We conducted a meta‐analysis of those studies and other studies of genetic predictors of AIM. Methods: MEDLINE‐based searches of genetic studies of AIM were conducted, and a meta‐analysis of six studies of 5‐HTTLPR was performed. Other polymorphisms were insufficiently studied to allow for meta‐analysis. Results: There was an association of the short (s) variant of 5‐HTTLPR and AIM [risk ratio (RR) = 1.35, 95% confidence interval (CI): 1.04–1.76, p = 0.02]. There was a higher frequency of s carriers (sl and ss genotypes) in those who developed AIM [RR = 1.38, 95% CI: 0.98–1.93), p = 0.06]. Conclusion: The 5‐HTTLPR polymorphism appears to have a moderate effect size association with AIM in patients with bipolar disorder.     

The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity

Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS−) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.     

Interaction of chronic stress with serotonin transporter and catechol‐O‐methyltransferase polymorphisms in predicting youth depression

Background: Investigations of gene–environment interaction (G×E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5‐HTTLPR) as a moderator of the stress–depression relationship. However, recent evidence for 5‐HTTLPR G×E in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol‐O‐methyltransferase (COMT) gene on the strength of 5‐HTTLPR G×E. Methods: A community sample of youth ( n =384) was genotyped for 5‐HTTLPR and COMT. A multi‐method, multi‐informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G×G×E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results: Significant three‐way interactions were observed for both depressive symptoms and diagnoses, such that 5‐HTTLPR G×E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5‐HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two‐way G×E was found for 5‐HTTLPR. Conclusions: Inconsistent 5‐HTTLPR G×E findings to date may be partly attributable to unmeasured epistatic effects between 5‐HTTLPR and COMT val158met. Identifying the conditions under which 5‐HTTLPR G×E is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

COMT Val158Met polymorphism influences the susceptibility to framing in decision‐making: OFC‐amygdala functional connectivity as a mediator

Individuals tend to avoid risk in a gain frame, in which options are presented in a positive way, but seek risk in a loss frame, in which the same options are presented negatively. Previous studies suggest that emotional responses play a critical role in this “framing effect.” Given that the Met allele of COMT Val158Met polymorphism (rs4680) is associated with the negativity bias during emotional processing, this study investigated whether this polymorphism is associated with individual susceptibility to framing and which brain areas mediate this gene–behavior association. Participants were genotyped, scanned in resting state, and completed a monetary gambling task with options (sure vs risky) presented as potential gains or losses. The Met allele carriers showed a greater framing effect than the Val/Val homozygotes as the former gambled more than the latter in the loss frame. Moreover, the gene–behavior association was mediated by resting‐state functional connectivity (RSFC) between orbitofrontal cortex (OFC) and bilateral amygdala. Met allele carriers showed decreased RSFC, thereby demonstrating higher susceptibility to framing than Val allele carriers. These findings demonstrate the involvement of COMT Val158Met polymorphism in the framing effect in decision‐making and suggest RSFC between OFC and amygdala as a neural mediator underlying this gene–behavior association. Hum Brain Mapp 37:1880–1892, 2016. © 2016 Wiley Periodicals, Inc .     

Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats

Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely‐moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS?) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS? trials during training and early extinction. In contrast, they were lower during CS+ than CS? trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS? trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.     

Serotonin transporter genotype 5HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies

We present results of a meta-analysis of gene-by-environment (G × E) studies involving the serotonin transporter genotype 5HTTLPR to evaluate empirical support for two competing conceptual frameworks in developmental psychopathology: diathesis-stress and differential susceptibility. From a diathesis-stress perspective, the cumulative negative effects of the short allele (ss and sl genotypes) and adverse environments on development have been stressed. From a differential-susceptibility perspective, carriers of the s allele are predicted to be more open to adverse as well as positive environments, for better and for worse. Studies with children and adolescents up to 18 years of age (N=9361) were included. We found 41 effect sizes (N=5863) for the association between negative environments and developmental outcomes with or without significant moderation by 5HTTLPR genotype and 36 effect sizes (N=3498) for the potentially 5HTTLPR-moderated association between positive environments and developmental outcomes. Five moderators were examined: age, ethnicity, genotyping (biallelic or triallelic) and methods used to assess environment and outcome. In the total set of studies, including studies with mixed ethnicities, we found that ss/sl carriers were significantly more vulnerable to negative environments than ll carriers, thus supporting the diathesis-stress model. In the Caucasian samples, however, ss/sl carriers also profited significantly more from positive environmental input than ll carriers. Associations between (positive or negative) environment and (positive or negative) developmental outcome were absent for ll carriers. The meta-analytic findings support the hypothesis that in Caucasian samples 5HTTLPR is a genetic marker of differential susceptibility. G × E interactions might be critically dependent on ethnicity.     

Neural correlates of subjective CS/UCS association in appetitive conditioning

Explicit knowledge of conditioned stimulus (CS)/unconditioned stimulus (UCS) associations is proposed as important factor in classical conditioning. However, while previous studies have focused on its roles in fear conditioning, it has been neglected in the context of appetitive conditioning. The present functional magnetic resonance study aimed to investigate neural activation and functional connectivity linked to subjective CS/UCS association in appetitive conditioning. In total, 85 subjects participated in an appetitive acquisition procedure in which a neutral stimulus (CS+) was paired with a monetary reward, while another neutral stimulus (CS‐) was never paired with the reward. Directly afterwards, subjective CS/UCS association was assessed by measuring the extent to which the CS+ was thought to be associated with the UCS compared to the CS‐. Close relationships were established between subjective CS/UCS association and activations in the primary visual cortex (V1) during the early phase of conditioning and in the striatum during the late conditioning phase. In addition, we observed inverse relationships between subjective CS/UCS association and both V1/ventromedial prefrontal cortex (vmPFC) and striatal/vmPFC connectivity. The results suggest the involvement of decoupling vmPFC connectivity in reward learning in general and the roles of attentional processes in the formation of the subjective CS/UCS association during the early phase and reward prediction during the late phase of appetitive conditioning.     

Contribution of the anterior cingulate cortex to laser-pain conditioning in rats

The emotional component of nociception is seldom distinguished from pain behavioral testing. The aim of the present study was to develop a behavioral test that indicates the emotional pain responses using the classical conditioning paradigm. The role of the anterior cingulate cortex (ACC) in the process of this pain conditioning response was also evaluated. In laser-pain conditioning, free moving rats were trained to associate a tone (conditioned stimulus, CS) and short CO₂ laser pulsation (unconditioned stimulus, US). Monotonous tone (800 Hz, 0.6 s) was delivered through a loud-speaker as CS. CO₂ laser pulses (5 W at 50 or 100 ms in duration) applied to the hind paw was adopted as US. The CS–US interval was 0.5 s. Laser-pain conditioning was developed during 40 CS–US pairings. CS and US pairing with 100-ms laser pulse stimuli was more effective in establishing conditioning responses than that of 50-ms stimuli. The conditioning responses remained, tested by presenting CS alone, immediate to and 24 h subsequent to training. The performance of laser-pain conditioning was significantly reduced after bilateral lesioning of the ACC. Similar results were also obtained by bilateral lesions of the amygdala. The conditioning responses were also diminished following morphine treatment. The association between a neutral stimulus and a noxious stimulus could be demonstrated in a Pavlovian conditioning test in free moving rats. Thus, the conditioned response may be employed as a measure of the emotional component of the nociception. It is also suggested that the ACC may play an important role in mediating this conditioning effect.     

BDNF Val66met and 5‐HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

Brain‐derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address this, we evaluated whether BDNF val66met was predictive of a putative marker of brain serotonin levels, serotonin 4 receptor (5‐HT₄) binding assessed with [¹¹C]SB207145 positron emission tomography, which has also been associated with the serotonin‐transporter‐linked polymorphic region (5‐HTTLPR) polymorphism. We applied a linear latent variable model (LVM) using regional 5‐HT₄ binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain‐wide and region‐specific genotype effects on 5‐HT₄ binding. Our data supported an LVM wherein BDNF val66met significantly predicted a LV reflecting [¹¹C]SB207145 binding across regions (P = 0.005). BDNF val66met met‐carriers showed 2–9% higher binding relative to val/val homozygotes. In contrast, 5‐HTTLPR did not predict the LV but S‐carriers showed 7% lower neocortical binding relative to LL homozygotes (P = 7.3 × 10^?6). We observed no evidence for genetic interaction. Our findings indicate that BDNF val66met significantly predicts a common regulator of brain [¹¹C]SB207145 binding, which we hypothesize reflects brain serotonin levels. In contrast, our data indicate that 5‐HTTLPR specifically affects 5‐HT₄ binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5‐HTTLPR on behavior and related risk for neuropsychiatric illness in humans. Hum Brain Mapp, 36:313–323, 2015. © 2014 Wiley Periodicals, Inc .     

The serotonin transporter polymorphism (5‐HTTLPR): allelic variation and links with depressive symptoms

Background: We compare the genotype distribution for the serotonin transporter polymorphism (5‐HTTLPR) in a sample of older Taiwanese adults with samples of various racial and ethnic groups collected in other studies. We also explore interactions among sex, stressors, and 5‐HTTLPR genotype on depressive symptoms in our sample. Methods: Using a nationally representative sample of 984 Taiwanese aged 53 and older, we model depressive symptoms as a function of 5‐HTTLPR genotype and two classes of stressors: lifetime trauma and recent major life events. We test two‐ and three‐way interactions among stressors, 5‐HTTLPR, and sex. >Results: This sample exhibits higher frequency of S/S and lower frequency of L/L genotype than Western samples, but the distribution is comparable to those in East Asian populations. Nearly 9% carry an allele (XL) that has rarely been reported in the literature. Although the gene–environment (G×E) interaction with recent major life events is not significant, our results suggest that trauma has a worse effect on depressive symptoms for those with S/S or S/L genotype than for those who do not carry the S allele (P<0.05). We find no evidence that this G×E interaction varies by sex. Conclusions: Previous studies of this G×E interaction have been inconclusive, perhaps because interactions between genotype and stressful events are more prominent under extreme stressors. Our findings underscore the need to move beyond a bi‐allelic parameterization of the 5‐HTTLPR polymorphism and raise questions about why East Asian populations exhibit low rates of depression despite a high frequency of the S allele. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.