Serotonin transporter genotype modulates cognitive reappraisal of negative emotions: a functional magnetic resonance imaging study

A functional polymorphism within the serotonin transporter gene (5-HTTLPR) has been reported to modulate emotionality and risk for affective disorders. The short (S) allele has less functional efficacy than the long (L) allele and has been associated with enhanced emotional reactivity. One possible contributing factor to the high emotionality in S carriers may be inefficient use of cognitive strategies such as reappraisal to regulate emotional responses. The aim of the present study was to test whether the 5-HTTLPR genotype modulates the neural correlates of emotion regulation. To determine neural differences between S and L allele carriers during reappraisal of negative emotions, 15 homozygous S (S′/S′) and 15 homozygous L (L′/L′) carriers underwent functional magnetic resonance imaging (fMRI), while performing an instructed emotion regulation task including downregulation, upregulation and passive viewing of negative emotional pictures. Compared to L′/L′ allele carriers, subjects who carry the S′/S′ allele responded with lower posterior insula and prefrontal brain activation during passive perception of negative emotional information but showed greater prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. The current results support and extend previous findings of enhanced emotionality in S carriers by providing additional evidence of 5-HTTLPR modulation of volitional emotion regulation.     

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S′ allele carriers relative to L_AL_A individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S′ carriers exhibited a more negative association relative to L_AL_A individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.     

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.     

Robust BOLD Responses to Faces But Not to Conditioned Threat: Challenging the Amygdala's Reputation in Human Fear and Extinction Learning

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain''s “fear center”, but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition (n = 98; 68 female) and extinction learning (n = 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS⁺)], the other one was never followed by a shock (CS^–), and participants were instructed to learn these contingencies. Results revealed widespread responses to the CS⁺ compared with the CS^– in the fear network, including anterior insula, midcingulate cortex, thalamus, and bed nucleus of the stria terminalis, but not the amygdala, which actually responded stronger to the CS^–. Results were independent of spatial smoothing, and of individual differences in trait anxiety and conditioned pupil responses. In contrast, robust amygdala activation distinguished faces from houses, refuting the idea that a poor signal could account for the absence of effects. Moving forward, we suggest that, apart from imaging larger samples at higher resolution, alternative statistical approaches may be used to identify cross-species similarities in fear and extinction learning.SIGNIFICANCE STATEMENT The science of emotional memory provides the foundation of numerous theories on psychopathology, including stress and anxiety disorders. This field relies heavily on animal research, which suggests a central role of the amygdala in fear learning and memory. However, this finding is not strongly corroborated by neuroimaging evidence in humans, and null findings are too easily explained away by methodological limitations inherent to imaging deep brain structures. In a large nonclinical sample, we find widespread BOLD activation in response to learned fear, but not in the amygdala. A poor signal could not account for the absence of effects. While these findings do not disprove the involvement of the amygdala in human fear learning, they challenge its typical portrayals and illustrate the complexities of translational science.     

Memory consolidation of fear conditioning: Bi-stable amygdala connectivity with dorsal anterior cingulate and medial prefrontal cortex

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of memory consolidation of fear conditioning is not well understood. To address this question, we measured brain activity and the changes in functional connectivity following fear acquisition using resting-state functional magnetic resonance imaging. The amygdala–dorsal anterior cingulate cortex (dACC) and hippocampus–insula functional connectivity were enhanced, whereas the amygdala–medial prefrontal cortex (mPFC) functional coupling was decreased during fear memory consolidation. Furthermore, the amygdala–mPFC functional connectivity was negatively correlated with the subjective fear ratings. These findings suggest the amygdala functional connectivity with dACC and mPFC may play an important role in memory consolidation of fear conditioning. The change of amygdala-mPFC functional connectivity could predict the subjective fear. Accordingly, this study provides a new perspective for understanding fear memory consolidation.     

Serotonin transporter gene polymorphism (5-HTTLPR), environmental conditions,and developing negative emotionality and fear in early childhood

Studies on neural and behavioral correlates of the serotonin transporter gene polymorphism (5-HTTLPR) strongly suggested interaction effects between the 5-HTTLPR genotype and environmental conditions on infant emotionality development. However, empirical studies that involve human infants are rare. The present study thus analyzed the interaction of the 5-HTTLPR genotype with the quality of maternal parenting behavior on the development of negative emotionality and fear in infancy. In a sample of 69 healthy firstborn infants, negative emotionality and fear were assessed at 4, 8, and 12 months using a multi-method approach. The quality of previous parenting has been operationalized as the quality of the mother–infant attachment relationship measured by the strange situation procedure at 18 months. Corresponding to hypotheses, to their caregiver insecurely attached infants who were homozygous for the s-variant of the 5-HTTLPR genotype developed a high level of negative emotionality and fear. The results thus are in line with the experimental results in the non-human primate model and point to a more pronounced susceptibility of s/s carrying infants to early rearing experiences. An erratum to this article can be found at     

Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

BACKGROUND: Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. METHODS: Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS: Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. CONCLUSIONS: The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.     

The 5-HTTLPR Polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder

Background

Impulsivity belongs to the key features of Borderline Personality Disorder (BPD). It has been linked to altered serotoninergic neurotransmission and, genetically, to an over-representation of the short (S) allele of the serotonin transporter promoter-linked polymorphic region polymorphism (5-HTTLPR). On the other hand, serious life events (SLE) are of major importance in the development of BPD. However, the inter-relations between SLEs, impulsivity, and 5-HTTLPR are not understood.

Method

159 BPD patients from Germany were included in this study. Impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). We analysed (1) the effects of SLEs on impulsivity; and (2) modulating effects of the 5-HTTLPR polymorphism on the effects of SLEs on impulsivity.

Results

Regression analyses confirmed a decreasing effect of childhood sexual abuse, the cumulative SLE-related reactions and the impairment by SLEs on BIS sum score. Regarding BIS sum score, all SLEs except for rape were associated with a decrease of impulsivity in SS/SL carriers and an increase of BIS sum score in LL carriers.

Conclusions

This study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD patients. Clinical and research implications are discussed.     

The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism

The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case–control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery–Åsberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.     

Association between serotonin transporter genotype,brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13–19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.     

Social anxiety modulates amygdala activation during social conditioning

Aversive social learning experiences might play a significant role in the aetiology of social anxiety disorder. Therefore, we investigated emotional learning and unlearning processes in healthy humans using a social conditioning paradigm. Forty-nine healthy subjects participated in a 2-day fMRI differential conditioning protocol. Acquisition and extinction were conducted on Day 1 and extinction recall on Day 2. BOLD responses, ratings and skin conductance responses were collected. Our data indicate successful conditioning and extinction on the neural and subjective level. As a main result, we observed a positive correlation of social anxiety and conditioning responses on the subjective level (valence and fear) as well as on the neural level with significant CS⁺/CS⁻ differentiation in the left amygdala and the left hippocampus. Further, significant CS⁺/CS⁻ differentiation in the left amygdala was found during extinction and was associated with lower scores in social anxiety. During extinction recall, we found a tendentially negative correlation of social anxiety and CS⁺/CS⁻ differentiation in the vmPFC. In sum, we were able to show that social anxiety is related to conditionability with socially threatening stimuli. This could point to an important aspect in the aetiology of social anxiety disorder.     

Gray matter volumetric correlates of dimensional impulsivity traits in children: Sex differences and heritability

Previous research investigated the cerebral volumetric correlates of impulsivity largely in moderate‐sized samples and few have examined the distinct correlates of dimensions of impulsivity, sex differences, or heritability of the correlates. Here, we performed voxel‐based morphometry analysis of data (n = 11,474; 5,452 girls, 9–10 years) curated from the Adolescent Brain Cognition Development project. In a linear regression with all five UPPS‐P subscores as regressors and age in months, total intracranial volume, study site, and scanner model as covariates, higher levels of lack of premeditation, and sensation seeking were correlated with larger cortical and subcortical gray matter volumes (GMVs). In contrast, higher positive urgency was correlated with smaller GMVs in many of the same regions. The dimensional impulsivity traits also involved distinct volumetric correlates, with, for instance, sensation seeking and positive urgency specifically implicating bilateral caudate head/mid‐cingulate cortex and bilateral lateral orbitofrontal cortex/left precentral gyrus, respectively. Boys relative to girls scored higher in all impulsivity dimensions. Girls relative to boys showed significantly stronger positive and negative correlations between sensation seeking and insula, putamen, and inferior frontal gyrus (IFG) GMVs and between positive urgency and cingulate cortex, insula, and IFG GMVs, respectively. With a subsample of twins, the dimensional impulsivity traits were weakly to moderately heritable in both girls and boys, and the GMV correlates were highly heritable in girls and boys combined. These findings collectively suggest shared and nonshared as well as sex differences in the cerebral volumetric bases of dimensional impulsivity traits and may facilitate research of externalizing psychopathology in children.     

BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall

Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition ‘and’ extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS− comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes.     

Cerebellar Contributions to Different Phases of Visceral Aversive Extinction Learning

The cerebellum is increasingly recognized to contribute to non-motor functions, including cognition and emotion. Although fear conditioning has been studied for elucidating the pathophysiology of anxiety, the putative role of the cerebellum is still unknown. Fear conditioning could also be important in the etiology of chronic abdominal pain which often overlaps with anxiety. Hence, in this exploratory analysis, we investigated conditioned anticipatory activity in the cerebellum in a visceral aversive fear conditioning paradigm using functional magnetic resonance imaging. We extended and reanalyzed a previous dataset for different learning phases, i.e., acquisition, extinction, and reinstatement, utilizing an advanced normalizing method of the cerebellum. In 30 healthy humans, visual conditioned stimuli (CS⁺) were paired with painful rectal distensions as unconditioned stimuli (US), while other visual stimuli (CS^?) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. During acquisition, posterolateral cerebellar areas including Crus I, Crus II, and VIIb and parts of the dentate nucleus were activated in response to the CS⁺ compared to the CS^?. During extinction, activation related to CS⁺ presentation was detected in Crus I, Crus II, IV, V, VI, VIIb, IX, and vermis. Neural correlates of reinstatement were found in Crus I, Crus II, IV, V, and IX. We could show for the first time that the cerebellum is involved in abdominal pain-related associative learning processes. Together, these findings contribute to our understanding of the cerebellum in aversive learning and memory processes relevant to the pathophysiology of chronic abdominal pain.     

The association of 5-HTTLPR genotype and depressive symptoms is moderated by physical activity

The s allele serotonin transporter polymorphic region (5-HTTLPR) is associated with a number of physiological mechanisms that may increase the risk of elevated depressive symptoms. However, reports of a relationship between serotonin transporter polymorphic region (5-HTTLPR) genotype and depressive symptoms have thus far been inconclusive. This heterogeneity of results suggests that other factors may be moderating the relationship between 5-HTTLPR and depressive symptoms. Higher levels of physical activity are associated with lower levels of depressive symptoms. Mechanisms responsible for this association include alterations of the serotonergic system and the hypothalamic-pituitary axis. The aim of the current study was to measure the moderating effect of physical activity on the relationship between 5-HTTLPR genotype and depressive symptoms. Participants, ages 18-23, provided a saliva sample for DNA analysis and completed questionnaires to assess depressive symptoms and physical activity. A hierarchical multiple regression analysis was conducted to examine the moderating effect of physical activity on the relationship between 5-HTTLPR genotype and depressive symptoms. Analysis revealed a significant interaction between 5-HTTLPR and physical activity (p = .010). At low levels of physical activity, individuals with at least one s allele had significantly higher levels of depressive symptoms compared to ll individuals (p = .011). This finding provides preliminary support for a moderating effect of physical activity on the relationship between 5-HTTLPR and depressive symptoms.     

A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.     

Association analysis between gene variants of the tyrosine hydroxylase and the serotonin transporter in borderline personality disorder

Abstract

objectives. For patients with borderline personality disorder (BPD), we previously reported an independent effect of the catechol-o-methyl-transferase (COMT) low-activity (Met¹⁵⁸) allele and an interaction with the low-expression allele of the deletion/insertion (short/long or S/L, resp.) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR). The purpose of the present study was to extend these findings to the tyrosine hydroxylase (TH) Val⁸¹Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L polymorphism incorporating the recently described functional A/G SNP within the long allele of the 5-HTTLPR (rs25531) as well as the variable number of tandem repeat (VNTR) polymorphism within intron 2 of the serotonin transporter gene (STin2). Methods. In 156 Caucasian BPD patients and 152 healthy controls, we tested for association between BPD and the TH Val⁸¹Met SNP, the 5-HTTLPR/rs25531 polymorphism, the STin2, the interaction of the TH Val⁸¹Met SNP with the tri-allelic 5-HTTLPR/rs25531, the interaction of the TH Val⁸¹Met SNP with STin2. Results. Between BPD patients and controls, we observed a slight over-representation of the TH Met⁸¹Met genotype in BPD patients compared to controls, but no statistically significant differences in genotype distribution of the individual markers after adjusting for multiple testing. Logistic regression analysis showed a lack of interaction between the TH Val⁸¹Met and the 5-HTTLPR/rs25531 as well as between the TH Val⁸¹Met and the STin2 polymorphism. Conclusions. These data do not suggest independent or interactive effects of the TH Val⁸¹Met, the 5-HTTLPR/rs25531, or the STin2 polymorphisms in BPD.     

The 5‐HTTLPR polymorphism is associated with altered hemodynamic responses during appetitive conditioning

Background: Current models suggest that a variation in the promoter region of the serotonin transporter gene (5‐HTTLPR) is associated with altered amygdala reactivity not only towards negative but also towards positive stimuli, which has been neglected in the past. This association may possibly convey an elevated vulnerability for psychopathology like abuse, craving, and relapses. Since appetitive conditioning is a crucial mechanism in the pathogenesis of these psychiatric disorders, the identification of specific factors contributing to interindividual variation is important. Methods: In the present study (N = 86), an appetitive conditioning paradigm was conducted, in which a neutral stimulus (CS+) was associated with appetitive stimuli, while a second stimulus (CS?) predicted their absence. Subjects were genotyped according to the 5‐HTTLPR genotype. Results: As the main result, we report a significant association between the 5‐HTTLPR genotype and hemodynamic responses. Individuals with the s‐allele displayed elevated conditioned bilateral amygdala activity in contrast to l/l‐allele carriers. Further, increased hemodynamic responses in s‐allele carriers were also found in the extended emotional network including the orbitofrontal cortex, the thalamus, and the ventral striatum. Conclusion: The present findings indicate an association of the 5‐HTTLPR and altered conditioned responses in appetitive conditioning. Further, the findings contribute to the ongoing debate on 5‐HTTLPR dependent hemodynamic response patterns by emphasizing that s‐allele carriers are not exclusively biased towards fearful, but also towards positive stimuli. In conclusion, our results imply that s‐allele carriers might be better described as hyper‐reactive towards salient stimuli, which may convey vulnerability for the development of psychiatric disorders. Hum Brain Mapp 34:2549–2560, 2013. © 2012 Wiley Periodicals, Inc.     

Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression

CONTEXT: Genetic moderation of the depression-inducing effects of stressful life events (SLEs) has been reported, but findings suggest that genes may not moderate the effects of SLEs per se but instead may moderate the risk of depression associated with the stable tendency to develop negative emotions in response to minor environmental experiences. OBJECTIVE: To examine whether a functional polymorphism of the serotonin transporter gene (5-HTTLPR) moderates the association between negative affectivity (neuroticism) and depression and to what degree this can explain previous findings involving SLEs. DESIGN: A prospective cohort study involving 1 baseline and 4 follow-up measurements in 15 months analyzing change in self-reported depressive symptoms across time as a function of negatively attributed SLEs, neuroticism, 5-HTTLPR, and their interactions. SETTING: General community. PARTICIPANTS: A population-based sample of 374 ethnically homogeneous young adult female twins. MAIN OUTCOME MEASURE: A continuous score of self-reported depressive symptoms. RESULTS: The depressogenic effect of SLEs in the 3 months before interview was significantly greater in women with 2 short (S) alleles compared with women with 1 or none. However, this effect disappeared after accounting for the effect of SLEs conditional on neuroticism. Similarly, the depressogenic effect of neuroticism was progressively greater with number of S alleles, and this was unchanged after accounting for the effect of neuroticism conditional on SLEs. CONCLUSIONS: Genotype x environment interactions in depression may be more productively interpreted by involving mechanisms more proximal to psychological experience itself. The probability that stress-related cognitive vulnerabilities for depression result in symptom formation may be moderated by a neurobiologic phenotype characterized by altered processing of negative emotions associated with variation in 5-HTTLPR.     

Association between stressful life events and grey matter volume in the medial prefrontal cortex: A 2‐year longitudinal study

Stressful life events (SLEs) in adulthood are a risk factor for various disorders such as depression, cancer or infections. Part of this risk is mediated through pathways altering brain physiology and structure. There is a lack of longitudinal studies examining associations between SLEs and brain structural changes. High‐resolution structural magnetic resonance imaging data of 212 healthy subjects were acquired at baseline and after 2 years. Voxel‐based morphometry was used to identify associations between SLEs using the Life Events Questionnaire and grey matter volume (GMV) changes during the 2‐year period in an ROI approach. Furthermore, we assessed adverse childhood experiences as a possible moderator of SLEs‐GMV change associations. SLEs were negatively associated with GMV changes in the left medial prefrontal cortex. This association was stronger when subjects had experienced adverse childhood experiences. The medial prefrontal cortex has previously been associated with stress‐related disorders. The present findings represent a potential neural basis of the diathesis‐stress model of various disorders.