The serotonin transporter gene variants modulate acute stress‐induced hippocampus and dorsomedial prefrontal cortex activity during memory retrieval

Abstract

The short (s) allele of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is related to reduced serotonin transporter efficiency and an increased vulnerability to stress and mental disorders. In the present study, we investigated how 5-HTTLPR impacts on memory retrieval under stress and related neural activity by reanalyzing a small genetic neuroimaging data set. Twenty-seven healthy male volunteers participated in both the Trier Social Stress Test (TSST) and a respective control procedure and then their brain activity was measured with functional MRI (fMRI) while they performed an emotional-face-recognition task. Sixteen participants were carriers of the short allele (ss/sl carriers) and 11 were homozygous for the long allele (ll carriers). Genotype groups were compared with respect to stress-related physiological changes, memory performance, and brain activity. No significant genotypedependent effects on memory performance or cortisol levels were found. The ss/sl carriers showed significantly higher systolic and diastolic blood pressure than the ll carriers, independent of stress. The ss/sl carriers reported stronger stress-induced nervous mood than the ll carriers. Our fMRI data revealed that the ss/sl carriers showed significantly weaker left hippocampus activation and stronger dorsomedial prefrontal cortex (dmPFC) deactivation when retrieving memories under stress as compared with the ll carriers. Subsequent analyses revealed that the distinct hippocampal activation pattern in both genotypes was associated with stress-induced cortisol elevation, while the distinct dmPFC activation pattern in both genotypes was associated with stress-induced changes in reaction times. Our results thus add new evidence that serotonin signaling modulates neural activity in the hippocampus and dmPFC during memory retrieval under acute psychosocial stress.When confronted with a changing and stressful environment, humans show different levels of vulnerability to the stressful events and this vulnerability is codetermined by nature (such as genes) and nurture (such as learning experiences). For decades, a large body of research on the serotonin transporter (5-HTT) gene promotor polymorphism (serotonin-transporterlinked polymorphic region [5-HTTLPR]) has provided more and more evidence on gene-by-environment interactions.

5HTTLPR Genetic Variant and Major Depressive Disorder: A Review

“…5HTTLPR variant studies with biological and cognitive factors underlying depression, such as childhood trauma, attempted suicide, stress, and anxiety, have been reported in different populations, thus contributing to a better understanding of the disease. The S allele of 5HTTLPR increases the risk of depression only in stressed individuals [52,53]; therefore, it should not be widely generalizable, only observable in limited situations and modest sample size [52,54,55]. On the other hand, the L allele's increased transcriptional activity is considered protective against depression, yet it has been associated with suicide, nicotine dependence, and attention deficit hyperactivity disorder [54,55].…”

The association of the 5-HTTLPR polymorphism and the response to different stressors in healthy males

“…However, other studies found no effect of 5-HTTLPR (Duman and Canli 2015 ; Wüst et al 2009 ) and one even found higher cortisol levels in L allele carriers (Mueller et al 2011 ). Li et al ( 2019 ) found no effect on cortisol, but nervous mood as well as brain activity during memory performance under stress. Despite the inconsistency of single studies, a meta-analysis concluded that 5-HTTLPR has a small but significant effect on cortisol response with S allele carriers showing increased reactivity (Miller et al 2013a , b ).…”

Stress‐related psychological outcomes: Psychological and biological mechanisms, developmental aspects, and management

“…The study shows that the severity of a person's stress early in life predicts his/her cortisol response to stress in adulthood, which may contribute to the risk of certain stress‐related illnesses. Second, the study by Li, Tang, Gao, Thiel, and Wolf () on genes and neuroimaging is an important contribution. The authors used fMRI to measure the brain activities that different serotonin transporter gene (5‐HTTLPR) genotypes carry while performing an emotional face‐recognition task under the acute stress induced by the Trier Social Stress Test.…”