Data_Sheet_1_Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder.docx

<p>Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD.</p

Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear

<p>The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus–unconditioned stimulus (CS–US) contingency at different stages of the experiment. Information about the CS–US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS–US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.</p

Interactive effect of <i>DRD4</i> genotype and maternal sensitivity at 6 months predicting externalizing behaviors at 18 months.

<p><b>A.</b> CBCL Externalizing behaviors for European-ancestry toddlers at 18 months. <i>DRD4</i> 7R carriers or non-carriers, with mothers with high or low sensitivity (median split) at 6 months. <b>B.</b> Linear regression slopes of CBCL Externalizing behaviors at 18 months by Maternal Sensitivity at 6 months are depicted separately for 7R-allele carriers and non-carriers, controlled for maternal age, child sex, child ancestry, and maternal depression. Regions of significance (RoS) are highlighted in the graph (shaded area). Only the lower bound of Maternal Sensitivity falls within the RoS (i.e. significant <i>DRD4</i> differences in child externalizing behaviors are not seen in children with mothers expressing high sensitivity) consistent with a diathesis-stress model.</p

Exploratory Analyses: Linear regression of effect of DRD4 genotype, maternal sensitivity, and their interaction on 18 month child DSM-problems subscales (Achenbach CBCL)^§.

<p>Exploratory Analyses: Linear regression of effect of DRD4 genotype, maternal sensitivity, and their interaction on 18 month child DSM-problems subscales (Achenbach CBCL)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160473#t003fn003" target="_blank">^§</a>.</p

Demographics of sample.

<p>Demographics of sample.</p

Replication Analysis: Linear regression of effect of DRD4 genotype, maternal sensitivity, and their interaction on 18 month child Externalizing Behavioral problems (Achenbach CBCL)^§.

<p>Replication Analysis: Linear regression of effect of DRD4 genotype, maternal sensitivity, and their interaction on 18 month child Externalizing Behavioral problems (Achenbach CBCL)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160473#t002fn003" target="_blank">^§</a>.</p

Data_Sheet_1_A DRD2/ANNK1–COMT Interaction, Consisting of Functional Variants, Confers Risk of Post-traumatic Stress Disorder in Traumatized Chinese.doc

<p>Objective: Post-traumatic stress disorder (PTSD) is a trauma- and stress-related psychiatric syndrome that occurs after exposure to extraordinary stressors. The neurotransmitter dopamine (DA) plays important roles in neurobiological processes like reward and stress, and a link between PTSD and the dopaminergic system has been reported. Thus, the investigation of an association between PTSD and gene–gene interaction (epistasis) within dopaminergic genes could uncover the genetic basis of dopamine-related PTSD symptomatology and contribute to precision medicine.</p><p>Methods: We genotyped seven single nucleotide polymorphisms (SNPs) of three dopaminergic genes DRD2/ANNK1 (rs1800497 and rs1801028), COMT (rs6269, rs4633, rs4818 and rs4680) and DBH (rs1611115), in a Chinese predominantly adult cohort that had been exposed to an earthquake (156 PTSD cases and 978 controls).</p><p>Results: Statistical genetics analysis identified a DRD2/ANNK1–COMT interaction (rs1800497 × rs6269), which is associated with PTSD diagnosis (P_interaction = 0.0008055 and P_corrected = 0.0169155). Single-variant and haplotype-based subset analyses showed that rs1800497 modulates the association directions of both the rs6269 G allele and the rs6269-rs4633-rs4818-rs4680 haplotype G-C-G-G. The interaction (rs1800497 × rs6269) was replicated in a Chinese young female cohort (32 cases and 581 controls, P_interaction = 0.01329).</p><p>Conclusions: Rs1800497 is related to the DA receptor D2 density and rs6269-rs4633-rs4818-rs4680 haplotypes affect the catechol O-methyltransferase level and enzyme activity. Thus, the interaction was inferred to be at protein–protein and DA activity level. The genotype combinations of the two SNPs indicate a potential origin of DA homeostasis abnormalities in PTSD development.</p

Differences in brain activation in response to fearful faces during appraisal tasks in probable PTSD and non-PTSD groups at two weeks and three months after MVC.

<p>(A) Appraisal of fearful faces vs. neutral faces reveals greater activation in dmPFC (sagittal and axial views) and vmPFC (sagittal view) in the probable PTSD group compared to the non-PTSD group at two weeks. (B) Activation in dmPFC at two weeks after MVC was significantly positively correlated with PCL scores at three months across both groups. (C) Changes over time in dmPFC activation and PCL scores from two weeks to three months were positively correlated in the probable PTSD group. (D) The same contrast reveals greater activation in the probable PTSD group compared to the non-PTSD group in left IC at three months. (E) Activation in left IC was positively correlated with PCL scores at three months across both groups. (F) Summary of significant differences in activation of appraisal of fearful faces between groups at both time points. Initial cut-off voxel level Z > 2.3 (P < 0.01), with whole brain FWE correction at the cluster level of P<0.05.</p

Volume of left SFG.

<p>(A) parcellation of left SFG (shaded in gray) in FreeSurfer partially overlaps with location of the dmPFC activation cluster. (B) Volume of left SFG at two weeks and three months after MVC. *: indicates significant effect of time by group interaction. #: indicates significant decrease in left SFG volume in probable PTSD group over time. The error bars indicate the standard error of the mean.</p

Demographics and symptoms of probable PTSD and non-PTSD groups.

<p>Demographics and symptoms of probable PTSD and non-PTSD groups.</p