Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction

T. Lin, A. Simchovitz, S. Shenhar-Tsarfaty, S. Vaisvaser, R. Admon, G. Hanin, M. Hanan, E. Kliper, Y. Bar-Haim, N. Shomron, G. Fernandez, G. Lubin, E. Fruchter, T. Hendler*, H. Soreq

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Article numbere801
JournalTranslational Psychiatry
Volume6
DOIs
StatePublished - 3 May 2016

Funding

FundersFunder number
German Research Foundation Trilateral Cooperation Program
Israel Center Of Research Excellence
Legacy Heritage Science Initiative
Netherland Brain Bank
Sagol network foundation
U.S. Department of DefenseW81XWH-11-2-0008
Seventh Framework Programme321501
European Research Council
Ministry of Science, Technology and Space3-11170
Israel Science Foundation378/11
Israeli Centers for Research Excellence51/11

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