Neural correlates of epigenesis

Abstract

The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals' level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.amygdala ͉ emotion ͉ environment ͉ gene ͉ hippocampus A dverse life events can reveal profound interindividual differences, rousing resilience in some and exposing susceptibility to mood disorders, including depression, in others. Diathesis-stress models have sought to explain these individual differences in terms of genetic predispositions interacting with environmental factors (1). Behavioral genetic studies have supported these models (2), with current work focusing on molecular and neural mechanism that may underlie these associations.Dysfunction of the serotonin (5-hydroxytryptophan, 5-HT) system is implicated in mood disorders, and variation within serotonergic genes has been associated with negative emotional traits such as neuroticism and harm avoidance (3). For example, higher scores in these traits are associated with a common short variant of a repetitive sequence in the transcriptional control region of the 5-HT transporter gene (5-HTT, SERT, SLC6A4), which results in low 5-HT uptake function (4). Two metaanalyses have concluded that presence of the short variant of this repeat (5-HTT-linked polymorphic region, 5-HTTLPR) is associated with higher levels of neuroticism or harm avoidance (5, 6). Although neuroticism itself is a risk factor for depression (7), the link between 5-HTTLPR genotype and depression has been more tenuous, suggesting that 5-HTTLPR genotype does not have a consistent main effect on depression but instead may be moderated through other variables (8).Caspi et al. (9) conducted a 23-year longitudinal study in a large sample of individuals who were genotyped for the 5-HTTLPR. They found that carriers of the 5-HTTLPR short variant showed more depressive symptoms, diagnosed depression, and suicidality as a function of stressful life events than individuals homozygous for the 5-HTTLPR long variant, thus demonstrating a significant gene-by-environment (...

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

“…Using MRI perfusion imaging, Canli and colleagues found support for increased resting activity in the left amygdala and the hippocampus. 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.…”

“…(2003) appears plausible as it is supported by quantitative population genetics studies, 5 neurophysiological investigations 102 and experimental studies in animals. 26 The majority of replication studies have provided results consistent with such effect (Table 1).…”

“…As a more direct functional probe of the G Â E interaction, Canli and colleagues 102 explored the interacting effects of stressful life events and 5-HTTLPR genotype on the brain function at rest and in reaction to emotional stimuli. They found that number of stressful life events was associated with higher left amygdala and hippocampus perfusion at rest, and lower relative reactivity to neutral stimuli in s allele carriers compared to ll homozygotes.…”

Interaction of Serotonin Transporter Gene-Linked Polymorphic Region and Stressful Life Events Predicts Cortisol Stress Response

“…Among younger adults, the interaction between 5-HTTLPR genotype and life stress was significant only when the analysis focused on SLEs that had occurred in the first 5 years of life: individuals homozygous for the L A allele exhibited a negative correlation between the number of SLEs during the first 5 years of life and peak cortisol response to social stress, whereas carriers of the S allele exhibited a positive correlation. Strikingly, a very similar pattern was reported by Canli et al (2006), who in an imaging study observed a negative correlation between SLEs and amygdala activation in homozygous L allele carriers and a positive correlation in S allele carriers (Canli et al, 2006), although these analyses did not separate early SLEs from other SLEs.…”

Stop the sadness: Neuroticism is associated with sustained medial prefrontal cortex response to emotional facial expressions

“…The time-course and order of block presentations in the current task also limited our analysis by only being able to use neutral as a baseline condition. We have previously reported on individual differences in resting (fixation) brain activity (Canli et al, 2005(Canli et al, , 2006). In the current series of analysis, we were interested in identifying temporal changes in activity and therefore chose neutral as a baseline based on the comparable timecourse of this condition compared to each of the emotional conditions (4 18-second blocks).…”