Effects of HTR1A C(−1019)G on Amygdala Reactivity and Trait Anxiety

Abstract

Background 5-HT1A autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating 5-HT signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C(-1019)G) in the human 5-HT1A gene (HTR1A) represents one potential source of such inter-individual variability. Both in vitro and in vivo the -1019G blocks transcriptional repression leading to increased autoreceptor expression. Thus, the -1019G may contribute to relatively decreased 5-HT signaling at postsynaptic forebrain target sites via increased negative feedback. Objectives & Design To use imaging genetics to evaluate the effects of HTR1A C(-1019)G on amygdala reactivity in 89 healthy adults and employ path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that the -1019G, which potentially results in decreased 5-HT signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. Results Consistent with prior findings, the -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism impacting 5-HT signaling, namely the 5-HTTLPR. While there were no direct genotype effects on trait anxiety, the HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. Conclusions Our findings further implicate relatively increased 5-HT signaling, associated with genetic variation mediating increased 5-HT1A autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation impacts emergent behavioral processes related to psychiatric disease risk indirectly by biasing the response of underlying neural circuitries.

What is a representative brain? Neuroscience meets population science

“…Larger-scale studies of the type typically conducted by survey researchers and demographers often contain rich longitudinal measures of behavior and experience. Presently, it is rare for these types of data to be examined in dialogue with neuroimaging data [although a growing number of studies have scanned subsamples of participants within specific existing longitudinal or archival studies (64)(65)(66)]. One large-scale example that might be considered a model for integration of brain imaging into existing representative samples is the National Institutes of Health Pediatric MRI Database (NIH-PD) (6,67), which used populationbased sampling at six sites, based on the 2000 census data.…”

“…The key to this point is that using these sampling techniques, along with "piggybacking" on another study, means that neuroimaging studies need not necessarily be of large magnitude to yield large findings if sampled thoughtfully within the context of a larger study. Moreover, when piggybacked on another study, the neuroimaging data are enhanced through more precise (and often longitudinal) behavioral phenotypes at both the individual and macro level of behavioral analysis (6,64). Substantially more work is needed to broaden this understanding and to more fully integrate what is known about large-scale social phenomena with the individual level processes that yield these largerscale phenomena.…”

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…The G-allele of this SNP impairs the binding of the repressor, Nuclear Deaf-1 Related factor (NUDR), in a raphe cell line. Possibly as a result, G-allele carriers have higher levels of 5-HT1A autoreceptors, an increased risk for depression, and paradoxically, decreased amygdala reactivity (Albert and Lemonde, 2004;Fakra et al, 2009;Parsey et al, 2010). However, no study has assessed the brain region-specific impact of this polymorphism on 5-HT1A receptor expression during development.…”

Neural substrates of cognitive bias and anxiogenesis

“…These studies indicate that 5-HTTLPR (serotonin-transporter-linked polymorphic region) may be a susceptibility factor for affective disorders by biasing the functional reactivity of the human amygdala when challenged with stress and/or deficient cortical regulatory input [38]. A functional variation in the human 5-HT1A gene [39,40], polymorphism in the androgen receptor gene [41], and regulatory variant of human tryptophan hydroxylase-2 gene [42] have also been observed to bias the reactivity of the amygdala. Recently role of sleep quality on the relationships between amygdala reactivity and perceived stress among men has also been examined [36].…”

“…Thus, amygdala reactivity to anxiogenic stimuli appears to be central in the pathogenesis of anxiety disorders and many studies indicate that it is affected by a variety of factors [36][37][38][39][40][41][42]. These studies indicate that 5-HTTLPR (serotonin-transporter-linked polymorphic region) may be a susceptibility factor for affective disorders by biasing the functional reactivity of the human amygdala when challenged with stress and/or deficient cortical regulatory input [38].…”