Dataset Information

Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience-network.

ABSTRACT: Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N=74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter-associated CpG island of SLC6A4 from blood-derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra-network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility.

SUBMITTER: Muehlhan M

PROVIDER: S-EPMC6869056 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience-network.

Muehlhan Markus M Kirschbaum Clemens C Wittchen Hans-Ulrich HU Alexander Nina N

Human brain mapping 20150825 11

Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks ...[more]

PMID: 26303978

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Project description:Weight gain is often associated with the pleasure of eating food rich in calories. This idea is based on the findings that people with obesity showed increased neural activity in the reward and motivation systems of the brain in response to food cues. Such correlations, however, overlook the possibility that obesity may be associated with a metabolic state that impacts the functioning of reward and motivation systems, which in turn could be linked to reactivity to food and eating behaviour and weight gain. In a study involving 44 female participants [14 patients with obesity, aged 20-63 years (mean: 42, SEM: 3.2 years), and 30 matched lean controls, aged 22-60 years (mean: 37, SEM: 1.8 years)], we investigated how ventromedial prefrontal cortex seed-to-voxel resting-state connectivity distinguished between lean and obese participants at baseline. We used the results of this first step of our analyses to examine whether changes in ventromedial prefrontal cortex resting-state connectivity over 8 months could formally predict weight gain or loss. It is important to note that participants with obesity underwent bariatric surgery at the beginning of our investigation period. We found that ventromedial prefrontal cortex-ventral striatum resting-state connectivity and ventromedial-dorsolateral prefrontal cortex resting-state connectivity were sensitive to obesity at baseline. However, only the ventromedial prefrontal cortex-ventral striatum resting-state connectivity predicted weight changes over time using cross-validation, out-of-sample prediction analysis. Such an out-of-sample prediction analysis uses the data of all participants of a training set to predict the actually observed data in one independent participant in the hold-out validation sample and is then repeated for all participants. In seeking to explain the reason why ventromedial pre-frontal cortex-ventral striatum resting-state connectivity as the central hub of the brain's reward and motivational system may predict weight change over time, we linked weight loss surgery-induced changes in ventromedial prefrontal cortex-ventral striatum resting-state connectivity to surgery-induced changes in homeostatic hormone regulation. More specifically, we focussed on changes in fasting state systemic leptin, a homeostatic hormone signalling satiety, and inhibiting reward-related dopamine signalling. We found that the surgery-induced increase in ventromedial prefrontal cortex-ventral striatum resting-state connectivity was correlated with a decrease in fasting-state systemic leptin. These findings establish the first link between individual differences in brain connectivity in reward circuits in a more tonic state at rest, weight change over time and homeostatic hormone regulation.

Project description:IntroductionAlthough the putamen has a significant role in reward-seeking and motivated behaviors, including eating and food-seeking, minorities' diminished returns (MDRs) suggest that individual-level risk and protective factors have weaker effects for Non-Hispanic Black than Non-Hispanic White individuals. However, limited research is available on the relevance of MDRs in terms of the role of putamen functional connectivity on body mass index (BMI).PurposeBuilding on the MDRs framework and conceptualizing race and socioeconomic status (SES) indicators as social constructs, we explored racial and SES differences in the associations between putamen functional connectivity to the salience network and children's BMI.MethodsFor this cross-sectional study, we used functional magnetic resonance imaging (fMRI) data of 6473 9-10-year-old Non-Hispanic Black and Non-Hispanic White children from the Adolescent Brain Cognitive Development (ABCD) study. The primary independent variable was putamen functional connectivity to the salience network, measured by fMRI. The primary outcome was the children's BMI. Age, sex, neighborhood income, and family structure were the covariates. Race, family structure, parental education, and household income were potential moderators. For data analysis, we used mixed-effect models in the overall sample and by race.ResultsHigher right putamen functional connectivity to the salience network was associated with higher BMI in Non-Hispanic White children. The same association was missing for Non-Hispanic Black children. While there was no overall association in the pooled sample, a significant interaction was found, suggesting that the association between right putamen functional connectivity to the salience network and children's BMI was modified by race. Compared to Non-Hispanic White children, Non-Hispanic Black children showed a weaker association between right putamen functional connectivity to the salience network and BMI. While parental education and household income did not moderate our association of interest, marital status altered the associations between putamen functional connectivity to the salience network and children's BMI. These patterns were observed for right but not left putamen. Other/Mixed Race children also showed a pattern similar to Non-Hispanic Black children.ConclusionsThe association between right putamen functional connectivity to the salience network and children's BMI may depend on race and marital status but not parental education and household income. While right putamen functional connectivity to the salience network is associated with Non-Hispanic White children's BMI, Non-Hispanic Black children' BMI remains high regardless of their putamen functional connectivity to the salience network. This finding is in line with MDRs, which attributes diminished effects of individual-risk and protective factors for Non-Hispanic Black children to racism, stratification, and segregation.

Dataset Information

Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience-network.

Publications

Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience-network.

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