Previous research has implicated the regulation of serotonin to be important in the regulation of emotional activity, via a critical cortical-limbic circuit. Pezawas et al. (2005)
found that short 5-HTTLPR allele carriers had significant reduction in gray matter volume in the perigenual anterior cingulate (pACC) and the rostral anterior cingulate—regions of the prefrontal cortex previously implicated in affect regulation (Drevets, 2000
)—compared to long 5-HTTLPR allele homozygotes. Further, using fMRI to assess relative activation of the pACC and amygdala in response to negative stimuli (e.g., angry and scared facial expressions), short 5-HTTLPR allele carriers had less functional coupling between the pACC and the amygdala. The “uncoupling” of this emotion circuit may explain why short 5-HTTLPR allele carriers have greater amygdala responses to emotional stimuli (e.g., Hariri et al., 2005
Similarly, Heinz et al. (2005)
reported that a region of the prefrontal cortex more dorsal and rostral to the pACC was over-activated in short 5-HTTLPR allele carriers than long 5-HTTLPR homozygotes when presented with emotional images. Activation of the ventromedial prefrontal cortex region was positively correlated with amygdala activation, suggesting a compensatory effort to regulate exaggerated amygdala responses of the short allele carriers. This heightened amygdala response in short 5-HTTLPR allele carriers likely applies to a variety of emotional stimuli, as the amygdala also responds to positive stimuli (Cunningham et al., 2008
), as well as novel, salient, and ambiguous stimuli (Whalen, 2007
A similar pattern of functional connectivity has been uncovered in men possessing the low-expressing allele of the MAOA u-VNTR (MAOA-L) (Buckholtz et al., 2008
). The MAOA-L allele is associated with increased levels of 5-HT, and the functional network of ventromedial prefrontal cortex, rostral cingulate, and amygdala has been shown to be both functionally and structurally compromised during an emotional arousal task among MAOA-L allele carriers. Taken together, these results suggest that alterations in 5-HT concentrations during development may affect critical pathways for emotion regulation by altering white matter microarchitecture (Buckholtz and Meyer-Lindenberg, 2008
). This is further supported by the critical role 5-HT plays in the modulation of axonal guidance during development (Bonnin et al., 2007
These studies indicate that the 5-HTTLPR polymorphism is associated with biased processing of emotional information, likely resulting from altered functional connectivity within a corticolimbic circuit (Munafo et al., 2008
). Critical components of this circuit include the amygdala, subgenual anterior cingulate cortex, and the prefrontal cortex, which are involved in the experience, expression and regulation of emotion. Therefore, individual differences in the microarchitecture of white matter fiber tracts that connect cortical and limbic regions could strongly affect ability to cognitively regulate emotional information. Despite several findings indicating that the 5-HTTLPR is associated with reduced functional coupling between areas of the prefrontal cortex and amygdala, no prior research has directly tested this possibility by examining whether the 5-HTTLPR is associated with individual differences in the white matter (WM) pathways that connect these regions.
In this study, we have documented a strong inverse association between number of low-expressing 5-HTTLPR alleles and the WM micro-architecture of a frontal-limbic circuit that plays a critical role in the regulation of emotional reactivity. As number of low expressing 5-HTTLPR alleles increased, FA values in the left frontal region of the uncinate fasciculus decreased. Lower FA values in the uncinate fasciculus, a critical WM tract that connects regions of the prefrontal cortex to the amygdala, may contribute to the heightened amygdala reactivity and poorer functional coupling between the prefrontal cortex and amygdala (Pezawas et al., 2005
) observed among carriers of the low expressing 5-HTTLPR allele. Future work that assesses whether WM micro-architecture mediates the association between 5-HTLPR polymorphism and neural responses to emotional stimuli is needed to confirm this hypothesis.
Importantly, reduced FA values in the left frontal region of the uncinate fasciculus were observed among a sample of healthy, non-depressed, non-medicated women. Therefore, the results from the current study are likely associated with vulnerability to depression (e.g., Caspi et al., 2003
), rather than a symptomatic outcome of altered mood state. Further, it is intriguing that FA differences were specific to the UF in the left frontal regions. This is consistent with previous research indicating altered activity in left prefrontal cortex is associated with vulnerability to depression (Davidson et al., 2002
), although additional research is needed to determine whether the laterality of these effects are replicated in a larger sample.
We also documented a strong association between age and FA values specifically in the bilateral frontal regions of the uncinate fasciculus. This finding corresponds with work showing FA values in prefrontal regions (including those associated with attention, motor skills, and cognitive ability) increase with age as prefrontal myelination develops (Barnea-Goraly et al., 2005
). Given the high rates of depression observed among adolescents, particularly girls (Hankin et al., 1998
), alterations in the development of the uncinate fasciculus may play an important role in the onset of depression. Consistent with this possibility, the 5-HTTLPR polymorphism appears to be an important predictor of depression vulnerability among adolescent girls (Eley et al., 2004
Several limitations of this study should be noted. First, our sample size was modest and exclusively female—a replication study with a larger sample of men and women is needed. Third variable explanations, such as the possibility that the 5-HTTLPR promoter polymorphism is in linkage disequilibrium with another functional genetic marker or the possibility of population stratification, should also be considered as explanations for the observed effects. Our sample was racially heterogeneous, but we found no differences in allele frequencies for the minority groups, so they were collapsed together for analysis. Although we found no evidence that race or ethnicity predicted FA values in any of the regions we examined, future work with larger samples should consider the races separately, as there are known allele frequency differences for African and Asian races, or consider using genomic controls.
Finally, it will be critically important for future work to determine whether impairments in the development of the uncinate fasciculus (and other white matter pathways involved in the regulation of emotion) predict future onset of depression. Consistent with this possibility, this is the first demonstration of an association between the 5-HTTLPR polymorphism, a gene that has been linked with depression vulnerability (Caspi et al., 2003
), and the white matter morphology of the uncinate fasciculus.