THE ANTERIOR CINGULATE CORTEX LINKS SEROTONIN TRANSPORTER GENETICS AND EMOTION PROCESSING
Authors: Kloebl *Manfred , Murgaš Matej , Reed Murray Bruce , Silberbauer Leo , Hartmann Annette M , Godbersen Godber Mathis , Hahn Andreas , Gryglewski Gregor , Rujescu Dan , Lanzenberger Rupert 
Published: February 2025

Abstract

Background
Selective serotonin reuptake inhibitors (SSRIs) target the serotonin transporter (SERT) and constitute the first line of pharmacological treatment of major depressive disorder (MDD). SSRIs also affect emotion processing and brain function in healthy individuals (1-4). Previous studies found increased amygdala activation after intake of the SSRI citalopram and related amygdala function during processing of negative emotions to SERT availability (5, 6). Furthermore, imaging genetics studies reported an influence of the SERT-linked promotor region (5-HTTLPR) polymorphisms on limbic system function, where the single nucleotide polymorphism rs25531 controls SERT expression (7-10).

Aims & Objectives
This study aimed to bridge the gaps between the genetic basis for SERT expression, the effect of SSRIs acting on the SERT and affecting emotion processing, and how this influences brain function.

Method
In a randomized, double-blind, crossover design, a large sample of 153 subjects (109 healthy, 44 with MDD) underwent simultaneous [11C]DASB PET/fMRI scans to assess brain activation and specific SERT binding potential (BPP). Subjects performed an emotion identification task containing fearful, happy, and neutral faces before and after receiving 8 mg citalopram or placebo IV. Genotyping was performed for 5- HTTLPR and rs25531. Lastly, we assessed attribution style as psychometric measure of emotion processing using the Internal, Personal and Situational Attributions Questionnaire – revised. We used SPM12 and the Sandwich Estimator toolbox for neuroimaging data as well as linear mixed models and mediation analysis for further testing. Appropriate multiplicity correction was applied.

Results
Independent of diagnosis, citalopram reduced the activation in the anterior cingulate cortex (ACC), cingulate sulcus, and superior temporal regions for fearful versus happy faces, as well as in the bilateral posterior insula for fearful versus neutral faces (ps = 0.0321-0.0025). Activation in the ACC cluster correlated with summarized striatal and thalamic BPP (r = -0.20, p = 0.0306), where striatal BPP mediated the influence of LA allele frequency of the 5-HTTLPR polymorphism under placebo (p = 0.0400). Lastly, the difference in ACC activation between citalopram and placebo correlated with the difference in self- versus other-attribution (r = -0.28, p = 0.0191).

Discussion & Conclusion
While an influence of the 5-HTTLPR polymorphism on limbic function, including the ACC, and emotion processing is well known (7, 8), SERT BPP has thus far only been related to amygdala and ACC connectivity (6). Our study thus closes this gap by showing a mediating role of SERT BPP on the influence of 5-HTTLPR genotype on ACC activation. Furthermore, our data suggests that the frequency of the LA allele might influence SERT expression and emotion processing rather than allele length or LA homozygosity (10, 11). A potential explanation for the increased ACC activation under citalopram for fearful versus happy faces corresponding to less self-attribution might lie in the previously shown predictive power of ACC activation during a similar task for escitalopram treatment response (12) and the proposed role of SSRIs in passive coping with depression (13).

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