Shany Edelman

Epigenetic and Genetic Factors Predict Women's Salivary Cortisol following a Threat to the Social Self

Evidence suggests that the reactivity of the Hypothalamus-Pituitary-Adrenal axis (HPAA) is modulated by both genetic and environmental variables. Of special interest are the underlying molecular mechanisms driving gender differences to psychosocial stressors. Epigenetic mechanisms that sculpt the genome are ideal candidates for mediating the effects of signals on the HPAA. In the current study, we analyzed by pyrosequencing, bisulfite-treated buccal DNA from male and female university students who participated in the Trier Social Stress Test (TSST). A linear regression model was used to ascertain the effects of sex, CpG methylation and genes on stress response. Total cortisol output (area under the curve, AUC) was significantly predicted by glucocorticoid receptor (NR3C1) exon 1F methylation (averaged across 39 CpG sites) solely in female subjects. A single CpG site located in the exon 1F noncanonical nerve growth factor-inducible protein A (NGFI-A) transcription factor was a highly significant predictor of AUC in female subjects. Additionally, variations in the estrogen receptor alpha (ESR1) and the serotonin transporter promoter (5-HTTLPR) genes were independent additive predictors of AUC. The full model accounted for half of the variance (50.06%) in total cortisol output. Notably, this is the first demonstration that epigenetic changes at the GR exon 1F correlate with HPAA reactivity. These findings have important implications for understanding the molecular mechanisms underlying gender differences in stress-related disorders and underscore the unique value of modeling both epigenetic and genetic information in conferring vulnerability to stress.

Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy.

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions.

Behavioral and cognitive effects of the n-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: initial findings

The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in ≥ 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co-agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426&rank=1; NCT02051426.

Hemisphere asymmetry in schizophrenia as revealed through line bisection, line trisection, and letter cancellation

Individuals with schizophrenia are known to demonstrate reduced or reversed brain asymmetry. While much is known regarding anatomical brain asymmetry, little is known about how this affects the individual at the functional level. Based on the known leftward bias in normal individuals, the aim of this study was to explore whether any difference in this function would be noted in schizophrenia. This study therefore investigated the phenomenon of functional asymmetry in schizophrenia patients by means of the following tasks: line bisection, line trisection (assessing hemifield spatial neglect) and letter cancellation (assessing contralateral visuospatial exploration). Forty-five schizophrenia inpatients maintained on antipsychotic medication were evaluated. Transections were measured for accuracy, lateralization, and directional bias. In the line bisection task subjects indicated no pseudo-neglect, thus differing from a normal, leftward bias. In the line trisection there was a significant preference to perform the ambiguous instruction on the right side, with no consistent bias in accuracy. Irrespective of conditions, in the letter cancellation task there was always a significant tendency to succeed on the left third compared to the right third. Results may support findings in schizophrenia indicating decreased or altered function of the left hemisphere.

The dopamine D4 receptor gene shows a gender-sensitive association with cognitive empathy: evidence from two independent samples.

Increasing evidence points to a role of dopaminergic pathways in modulating social behavior. Specifically, a polymorphic region in the third exon of the Dopamine D4 receptor (DRD4) has been associated with a host of social behaviors, often in an environment-sensitive manner. Empathy is thought to be an important motivator of prosocial behaviors and can be seen as multifaceted, combining cognitive empathy (CE) and emotional empathy (EE). In the current study, we analyzed the association between DRD4 and the 2 aspects of empathy, as well as the effect of gender on this association. In Study 1, a large sample of adult participants (N = 477) was inventoried for general empathy, CE, and EE and genotyped for the DRD4 exon 3 polymorphism. Women scored higher than men on all empathy measures and no main effect of genotype was observed. It is important that a significant interaction between genotype and gender emerged specifically for CE, with women carriers of the 7R-allele scoring higher than noncarriers, whereas in men 7R-carriers scored lower than -7R. Notably, these findings were replicated in an independently recruited sample (N = 121) in Study 2. The current report shows that the DRD4 exon3 polymorphism is associated with CE and the direction of the association is gender-sensitive.

Hypnotizability and Sensorimotor Gating: A Dopaminergic Mechanism of Hypnosis

Abstract Dopaminergic mechanisms have been theorized to influence hypnotizability and sensorimotor gating. In this study, the authors investigated an association between sensorimotor gating, as measured by prepulse inhibition (PPI), and hypnotizability, as assessed by the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). They found an inverse correlation between the SSHS:C and PPI. This finding, which replicates an earlier study, provides further evidence for a dopaminergic basis for hypnotizability and suggests additional avenues for research, including a method for possibly enhancing hypnotizability through pharmacological interventions.

The Dopamine D4 Receptor (DRD4) Exon 3 VNTR Contributes to Adaptive Personality Differences in an Italian Small Island Population

The search for evolutionary forces shaping the diversity of human personality traits encouraged studies that have found that islanders are relatively closed and introverted, with little interest in the external world. The ‘personality gene flow’ hypothesis was proposed to explain the mechanism underlying this difference, suggesting that the frequency of alleles that influence islander personality traits might progressively increase in the gene pools on islands because of selective emigration of individuals not displaying these alleles. We genotyped 96 individuals from the Italian mainland and 117 from Giglio Island, whose residents were previously assessed regarding their personality traits. We genotyped three polymorphisms: the dopamine D4 receptor (DRD4) exon 3 repeat region, the serotonin–transporter SLC6A4 5–HTTLPR indel and the dopamine transporter SLC6A3 DAT1 3′UTR repeat region. Only the DRD4 exon 3 repeat was hypothesised to show varying allele frequencies because this polymorphism could be associated with human migration and personality traits such as extraversion, openness and novelty seeking. As predicted, no differences in allele frequencies were found for the SLC6A4 and SLC6A3 polymorphisms, whereas significant differences were observed in the frequency of the DRD4 exon 3 alleles. The DRD4.2 repeat was more common in mainlanders, as expected, whereas the DRD4.7 allele was over–represented among islanders who never emigrated. This last result contradicts the suggested association of this allele with long–distance migrations. We suggest that emigration might have caused gene flow out the island that resulted in somewhat unpredictable changes in the frequencies of specific alleles, thus influencing islander personality traits. Copyright

Hypnotizability Is Associated With a Protective but Not Acquisitive Self-Presentation Style

Abstract Self-presentation refers to the behavioral strategies a person adopts to convey desired social images of oneself to other people. The Concern for Appropriateness Scale (CAS) measures a defensive and fearful social approach aimed at avoiding social threats whereas the Revised Self-Monitoring Scale (RSMS) measures an active and flexible social approach aimed at gaining power and status. In this study, a significant correlation was found between hypnotizability, as measured by the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) scores and CAS (r = .43, p = .002) but not between hypnotizability and RSMS (r = .070, p = .631). These results suggest that a protective self-presentation style may incline certain individuals to cooperate with hypnotic suggestions.

P.1.023 Association between oxytocin receptor single nucleotide polymorphism rs2254298 and prepulse inhibition in healthy subjects

and the 5-HT1A BPND in the hippocampus. Post-hoc t-tests were performed for significant results. The level of significance was set to p< 0.05, SPSS 18.0. was used for statistical analyses. Results: Three of the tested BDNF SNPs showed a significant association with the 5-HT1A BPND in the hippocampus (rs10501087: F(2,43) = 3.782, p = 0.031; rs60760775: F(2,43) = 3.435, p = 0.041; rs10767664: F(2,43) = 5.534, p = 0.007). The three other tested SNPs retrieved no significant association (rs1491850, rs1491851, rs61888800). Carriers of the C-allele of the rs10501087 (mean BPND: 5.47±0.96), the T-allele of the rs60760775 (mean BPND: 5.47±0.96) and the T-allele of the rs10767664 (5.14±0.88) displayed highest binding in the hippocampus. All results survived correction using the Fisher’s least significant difference (LSD) procedure in accordance with the “closed test principle”. Conclusion: In accordance with previous preclinical investigations suggesting a strong interaction between BDNF and serotonergic neurotransmission we detected an association between SNPs of BDNF and the 5-HT1A binding potential in the hippocampus [2]. As the 5-HT1A receptor was shown to be altered in several psychiatric disorders this association might be of clinical relevance and broaden the understanding about functional relationships on a neuromolecular level implicated in their pathophysiology [3]. It is thus conceivable that functional polymorphisms of BDNF might contribute to an increased neurobiological vulnerability for psychiatric disorders via direct influence on the 5-HT1A receptor in addition to previously suggested mechanisms.

The Role of Oxytocin in Neuropsychiatric Disorders: Concepts and Mechanisms

The role of oxytocin in the pathophysiology and treatment of major neuropsychiatric disorders has recently received increased attention. Although oxytocin has an established role as a circulating hormone involved in parturition and lactation, it also acts as a neurotransmitter and neuromodulator. Oxytocin receptors are found in several brain areas such as amygdala, nucleus accumbens and hippocampus, which have been heavily implicated in the pathophysiology of schizophrenia, depression and anxiety disorders. Converging lines of evidences suggest that oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Moreover, oxytocin alleviates anxiety and impacts on fear conditioning and extinction and on social reward systems. Furthermore, recent data suggest that oxytocin has neuroprotective effects by increasing the resistance of fetal neurons to insults during delivery. Due to its influence upon a wide range of behaviors and its antistress neuroprotective properties the role of oxytocin-related dysfunctions and therapeutics are presently assessed in major neuropsychiatric disorders. In this chapter we will review and summarize some of the mechanisms and concepts relevant to the role of oxytocin in the pathophysiology and therapeutics of neuropsychiatric disorders.