Abstract
The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD.
Highlights
The default mode network (DMN) is a coherent network of spontaneous neural activity that is enhanced during tasks involving internal mentation such as autobiographical memory, self-referential thinking and mind-wandering (Mason et al, 2007; Spreng et al, 2009; Andrews-Hanna, 2012)
We recently examined the effects of blast exposure and mild traumatic brain injury on DMN connectivity using the cohort on which this report was based (N = 134) and found blast exposure to be associated with reduced connectivity in the bilateral primary somatosensory and motor cortices; associations between posttraumatic stress disorder (PTSD) and DMN connectivity were not thoroughly examined (Robinson et al, 2015)
When the seven candidate single nucleotide polymorphisms (SNPs) were entered in the second block of the analysis, results showed a significant main effect of rs130058 (HTR1B) on connectivity between the posterior cingulate cortex (PCC) and right angular gyrus with carriers of the A allele tending to show reduced connectivity within this region compared to others
Summary
The default mode network (DMN) is a coherent network of spontaneous neural activity that is enhanced during tasks involving internal mentation such as autobiographical memory, self-referential thinking and mind-wandering (Mason et al, 2007; Spreng et al, 2009; Andrews-Hanna, 2012). Analyses revealed significant negative associations between levels of 5-HT1A heteroreceptors and BOLD signal in the dorsal medial prefrontal cortex (mPFC) and PCC suggesting a modulatory influence of these receptors on DMN connectivity in these regions. Administration of a 5-HT2A/5-HT2C receptor agonist has been shown to decrease coupling between the mPFC and the PCC (Carhart-Harris et al, 2012), and serotonin reuptake inhibitors (SSRI) reduce pairwise connectivity between several regions of the DMN in healthy subjects (van de Ven et al, 2013; Klaassens et al, 2015) Together, these findings point to a possible modulatory influence of serotonin signaling on DMN activity. There are no individual SNPs or SNP haplotypes that offer perfect proxies for the traditional 5-HTTLPR genotypes so we could not examine it in this study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
