Serotonin transporter gene variation impacts innate fear processing: acoustic startle response and emotional startle

Abstract

Anxiety-related behaviors are closely linked to neural circuits relaying fear-specific information to the amygdala. Many of these circuits, like those underlying processing of innate fear, are remarkably well understood. Recent imaging studies have contributed to this knowledge by discriminating more detailed corticoamygdalar associations mediating processing fear and anxiety. However, little is known about the underlying molecular mechanisms. We used the acoustic startle paradigm to investigate the impact of molecular genetic variation of serotonergic function on the acoustic startle response and its fear potentiation. Startle magnitudes to noise bursts as measured with the eye blink response were recorded in 66 healthy volunteers under four conditions: presenting unpleasant and pleasant affective pictures as well as neutral pictures, and presenting the startle stimulus without additional stimuli as a baseline. Subjects were genotyped for functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-hydroxytryptamine transporter gene-linked region: 5-HTTLPR). Analyses of variance revealed a significant effect of 5-HTTLPR on overall startle responses across conditions. Carriers of the short (s) allele exhibited stronger startle responses than l/l homozygotes. However, we could not confirm our hypothesis of enhanced fear potentiation of the startle in s allele carriers. In conclusion, the results provide first evidence that the startle response is sensitive to genetic variation in the serotonin pathway. Despite some issues remaining to be resolved, the startle paradigm may provide a valuable endophenotype of fear processing and underlying serotonergic influences.

Decreased Density of the Platelet Serotonin Transporter in Pathological Gamblers

“…The most intriguing data, although not conclusive, suggest that a disturbance of the 5-HT system may trigger the onset of impulsive behaviour [17,18,50] . In addition, although much research is still required, some authors have already highlighted relationships between the SERT and personality traits [58] , aggressive features [15,59] , anxiety [41] , pharmacological response [43] and emotional states [38,39,42] .…”

“…Moreover, there exist also indications of changes of SERT in healthy subjects [38,39] which have been hypothesized to be linked to particular dimensions, such as anxiety or impulsivity [15,17,26,[40][41][42] , or to antidepressant response [43] . One study only has reported a decreased density of SERT in 16 PG patients, measured by means of tritiated clomipramine [44] , but this is not a specific ligand for SERT [45] .…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…102 Similar baseline functional differences are suggested by an acoustic startle study showing that s allele carriers have stronger baseline startle reaction, but do not differ in emotional startle potentiation from ll homozygotes. 103 Furthermore, a whole brain exploration indicates widespread structural and functional differences between s allele carriers and ll homozygotes in other brain regions: the s allele appears to be associated with reduced volume and grey matter density in several frontal-lobe regions, greater reactivity to negative emotional stimuli in the insula and striatum and stronger reactivity to positive emotional stimuli in the left frontal and posterior cingulate regions. 100 These results, contingent on replication, indicate that the 5-HTTLPR may have a pervasive effect on brain structure and function.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Early human studies investigating this relationship have focused greatly on the 5-HTTLPR variants, and their role in psychopathology, with many but not all studies reporting an association between the low-expressing s allele and increased trait anxiety (Lesch et al, 1996;Schinka et al, 2004;Sen et al, 2004), increased incidence and severity of major depressive disorder following a stressful life event (Caspi et al, 2003;Culverhouse et al, 2013;Karg et al, 2011;Munafo et al, 2009;Risch et al, 2009;Zalsman et al, 2006), and heightened behavioral reactivity to fearful stimuli (Armbruster et al, 2009;Brocke et al, 2006). A common 5-HTT-polyadenylation polymorphism reducing 5-HTT expression is associated with fear extinction recall deficits (Hartley et al, 2012;Yoon et al, 2013).…”