Abstract
Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome–neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.
Highlights
Posttraumatic stress disorder (PTSD) is a severely debilitating psychiatric condition, especially in combat soldiers at high risk for trauma or chronic stress exposure.[1,2] PTSD, develops only in a subset of those experiencing such events,[3] pointing to individual differences in vulnerability and resiliency
We selected the rs17228616 single-nucleotide polymorphism (SNP) in the noncoding region of the AChE gene to investigate gene– environment brain interactions as those are reflected in posttraumatic stress symptoms (PTSS)
This was achieved by combining genotype and brain transcript tests with functional magnetic resonance imaging (fMRI) measurements of amygdala and ventromedial prefrontal cortex (vmPFC) responses to emotional stimuli in a military population at high risk for chronic stress exposure, known to impact the development of stressrelated symptoms.[1,29]
Summary
Posttraumatic stress disorder (PTSD) is a severely debilitating psychiatric condition, especially in combat soldiers at high risk for trauma or chronic stress exposure.[1,2] PTSD, develops only in a subset of those experiencing such events,[3] pointing to individual differences in vulnerability and resiliency. Human studies demonstrate that increases in ACh signaling contribute to stress-related illnesses, such as major depression.[31] As the rs17228616 polymorphism is related to excessive brain AChE hydrolytic activity,[15] we surmised that the AChE gene is close to its maximal expression capacity in individuals with the minor allele This would limit their ability to react to a changing environment by overproducing AChE to suppress the induced stress.
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