Many studies have found that hypothalamic-pituitary-adrenal (HPA) axis abnormalities are related to the pathophysiology of major depressive disorder (MDD) and cognitive functioning. Our aim was to assess the influence of genetic polymorphisms and methylation levels in three different promoter regions throughout the glucocorticoid receptor (GR) gene NR3C1 on cognitive performance in MDD. Plausible interactions with childhood adversity and mediation relationships between genetic and epigenetic variables were explored.

The sample included a total of 64 MDD patients and 82 healthy controls. Child maltreatment and neurocognitive performance were assessed in all participants. HPA negative feedback was analyzed using the dexamethasone suppression test after the administration of 0.25mg of dexamethasone. A total of 23 single-nucleotide polymorphisms were genotyped, and methylation levels at several CpGs in exons 1D, 1F and 1H of the GR gene were measured.

Results show that, beyond the influence of other covariables, NR3C1 single-nucleotide polymorphisms and methylation levels predicted performance in executive functioning and working memory tasks. No significant interactions or mediation relationships were detected.

Results suggest that genetic variations and epigenetic regulation of the GR gene are relevant factors influencing cognitive performance in MDD and could emerge as significant biomarkers and therapeutic targets in mood disorders and other stress-related disorders.

Adults with symptoms of anxiety, depression, or PTSD and a history of adverse childhood experiences (ACEs) may experience more severe symptoms than those without ACEs. The identification of mechanisms linking ACEs to later mental health problems may provide salient treatment targets to improve outcomes. Several biological markers (cortisol, inflammation, allostatic load, DNA methylation, and telomere length) that are indicative of functional variation in stress response systems, have been hypothesized as potential mechanisms linking ACEs to later mental health outcomes. Much of the evidence supporting this hypothesis examines isolated pairwise associations between variables and it is unclear whether statistical tests of mediation support these conclusions. It is also unclear how much of the extant research has used theory to guide mediation analyses, which may be a salient factor in the recognition of a mechanism. This scoping review surveyed research conducting mediation analysis examining the indirect effect of any of these five biological markers on the relationship between ACEs and anxiety, depression, or PTSD. It further surveyed the use of theory in these analyses. Pubmed and seven electronic databases were searched: (1) APA PsychInfo (2) CINAHL Plus (3) Health Source: Nursing/Academic Edition (4) MEDLINE (5) Psychology and Behavioral Sciences Collection (6) Science and Technology Collection, and (7) SocINDEX. A total of 16 articles were identified. The majority of studies examined depression as an outcome and the statistical significance of indirect effects were mixed across mediators. Common theoretical models and frameworks were consistent with life course theory and evolutionary or developmental perspectives.

Social Anxiety Disorder (SAD) involves fear of negative evaluation and social avoidance, impacting quality of life. Early life adversities (ELA) are recognized as risk factors for SAD. Previous research indicated inconsistent alterations in resting state functional connectivity (RSFC) in SAD, particularly in the prefrontal cortex and precuneus. This study investigated the interaction between SAD and ELA at the RSFC level. Functional magnetic resonance imaging (fMRI) was conducted on 120 participants (aged 19-48). Four groups were formed: low/ high ELA controls (n = 49, n = 22) and low/ high ELA SAD participants (n = 30, n = 19). Seed-based correlation analyses (SCA) and multi-voxel pattern analysis (MVPA) were applied. A network in which ELA moderates the neural correlates of SAD during the resting state was identified, involving key nodes like the subgenual anterior cingulate cortex, left middle frontal gyrus, and an area in the calcarine fissure/precuneus. Five distinct interaction patterns of SAD and ELA were observed, showcasing opposite RSFC patterns in individuals with SAD based on ELA experience. Results remained significant when controlled for general anxiety and depression measures. Emotional aspects of ELA played a significant role in these interactions. These findings stress the necessity of considering primarily emotional ELA as covariate in neuroimaging studies investigating SAD and potentially also other psychiatric disorders, addressing inconsistencies in prior research. The left middle frontal gyrus emerges as a link in the SAD-ELA interaction during resting state and anxiety-relevant stimulation. Longitudinal studies, starting from childhood, are needed to understand ELA's impact on brain function and to identify potential neuromarkers for SAD predisposition post-ELA exposure.

To analyze and interpret why some individuals are resilient to ELS while others are susceptible, resulting in psychiatric outcome later in life, with a focus on the role of DNAm of the NR3C1 gene as a mediating mechanism between ELS and the risk of psychiatric outcomes. We hypothesized that a high level of mental resilience to ELS, expressed as lower incidence of psychiatric outcomes, was associated with attenuated NR3C1 DNAm levels.

The first authors conducted a systematic search on PubMed to identify primary research studies. Abstract were screened and full-text were reviewed to assess the eligibility for inclusion. Consensus on assessment was reached after discussion of eligibility criteria. Studies were sorted based on whether they investigated the association between ELS and NR3C1 DNAm in 1) individuals exposed compared to unexposed to ELS both without a psychiatric outcome or in 2) individuals exposed to ELS with a psychiatric outcome compared to exposed individuals without a psychiatric outcome.

Seven studies met the eligibility criteria. The results were inconsistent; two studies supported our hypothesis, two studies indicated that increased NR3C1 DNAm mediated resilience to ELS, and three studies found no association.

Hypnotherapy has a potential role in modulating attention bias to treat social anxiety disorder (SAD). This study aimed to verify whether hypnotherapy can reduce social anxiety by changing attentional bias. The primary objective of our study is to explore the influence of hypnosis on various aspects of attention processes, specifically focusing on how it affects attention bias and social anxiety.

This study included 69 participants with SAD who were assigned to three groups based on their scores on the Liebowitz Social Anxiety Scale (LSAS). The experimental group (n = 23) received a hypnosis treatment once a week, for a total of six sessions, while the control group (n = 23) and the baseline group (n = 23) did not receive any treatment. To evaluate whether hypnosis could alleviate SAD and attention bias towards threatening stimuli, we employed questionnaires and an odd-one-out task accompanied by electroencephalography (EEG) recordings.

Under the attention sensitivity conditions, the experimental group exhibited a reduced N170 and LPP at the posttest stage, and a similar N170 and LPP reduction under the attention disengagement conditions. Notably, the symptom improvements were positively correlated with the reduction in N170 and LPP amplitude across conditions.

Hypnosis treatment modulates the early face processing and late emotional evaluation of threat-related stimuli in SAD patients. These findings suggest that N170 and LPP are important biomarkers for the treatment of SAD.

Recent work showed an association of prefrontal dysfunctions in patients with Major Depressive Disorder (MDD) and social stress induced rumination. However, up to date it is unclear which etiological features of MDD might cause prefrontal dysfunctions. In the study at hand, we aimed to replicate recent findings, that showed prefrontal activation alterations during the Trier Social Stress Test (TSST) and subsequently increased stress-reactive rumination in MDD compared to healthy controls. Moreover, we aimed to explore the role of adverse childhood experiences and other clinical variables in this relationship. N = 55 patients currently suffering from MDD and n = 42 healthy controls (HC) underwent the TSST, while cortical activity in areas of the Cognitive Control Network (CCN) was measured via functional near-infrared spectroscopy (fNIRS). The TSST successfully induced a stress reaction (physiologically, as well as indicated by subjective stress ratings) and state rumination in all subjects with moderate to large effect sizes. In comparison to HC, MDD patients showed elevated levels of state rumination with large effect sizes, as well as a typical pattern of reduced cortical oxygenation during stress in the CCN with moderate effect sizes. Self-reported emotional abuse and social anxiety were moderately positively associated with increased stress-reactive rumination. Within the MDD sample, emotional abuse was negatively and social anxiety positively associated with cortical oxygenation within the CCN with moderate to large effect sizes. In conclusion, our results replicate previous findings on MDD-associated prefrontal hypoactivity during stress and extends the research toward specific subtypes of depression.

Social anxiety disorder (SAD) and panic disorder (PD) are prevalent anxiety disorders characterized by a complex interplay of genetic and environmental factors. Both disorders share overlapping features and often coexist, despite displaying distinct characteristics. Childhood life adversity, overall stressful life events, and genetic factors contribute to the development of these disorders. DNA methylation, an epigenetic modification, has been implicated in the pathogenesis of these diseases. In this study, we investigated whether whole-genome DNA methylation risk scores (MRSs) for SAD risk, severity of social anxiety, childhood life adversity, PD risk, and overall stressful life events were associated with SAD or PD case‒control status. Preliminary epigenome-wide association studies (EWASs) for SAD risk, severity of social anxiety, and childhood life adversity were conducted in 66 SAD individuals and 77 healthy controls (HCs). Similarly, EWASs for PD risk and overall stressful life events were performed in 182 PD individuals and 81 HCs. MRSs were calculated from these EWASs. MRSs derived from the EWASs of SAD risk and severity of social anxiety were greater in PD patients than in HCs. Additionally, MRSs derived from the EWASs of overall stressful life events, particularly in PD individuals, were lower in SAD individuals than in HCs. In contrast, MRSs for childhood life adversity or PD risk were not significantly associated with PD or SAD case‒control status. These findings highlight the epigenetic features shared in both disorders and the distinctive epigenetic features related to social avoidance in SAD patients, helping to elucidate the epigenetic basis of these disorders.

Externalizing problems among adolescents are prevalent, which are associated with a range of maladaptive developmental outcomes. Existing studies investigated the influence of childhood trauma, and attentional control on and how sensory processing sensitivity (SPS) is related to adolescents' externalizing problems. However, it is unknown whether attentional control plays a mediating role in the relationships between childhood trauma and adolescents' externalizing problems, and whether SPS plays a moderating role in these relationships. The present study examined these issues with a six-month-interval longitudinal study design.

A total of 1933 junior school students (Grade 7, Mage = 12.82, 47.7 % girls) from a large follow-up project in a city of eastern China participated in the study. After half a year (wave 2), the data of 1890 participants (Grade 8) were collected. The Childhood Trauma Questionnaire (CTQ), Attentional Control Scale (ACS-C), Highly Sensitive Child Scale (HSCS), and the Child Behavior Checklist (CBCL-YSR) were administered to the participants to assess their childhood trauma, attentional control, SPS, and externalizing problems in two waves. The immediate and longitudinal moderated mediation models were utilized to investigate the relationships among these factors.

Childhood trauma significantly and positively predicted adolescents' externalizing problems. Attentional control played an immediate and longitudinal mediating role in the relationship between childhood trauma and externalizing problems. SPS moderated the relationship between childhood trauma and adolescents' attentional control. Childhood trauma had a greater effect on the attentional control of adolescents with SPS levels.

This study suggests that childhood trauma might impair adolescents' attentional control and then increase their externalizing problems. The influence of childhood trauma on attentional control is more serious among adolescents with lower SPS levels. Therefore, decreasing and preventing childhood trauma and building a warm nurturing environment might be beneficial to improving adolescents' attentional control ability and then reduce their externalizing problems.

Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear.

C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated.

Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection.

The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.

Anxiety disorders (ADs) are extremely common psychiatric conditions that frequently co-occur with other physical and mental disorders. The pathophysiology of ADs is multifaceted and involves intricate connections among biological elements, environmental stimuli, and psychological mechanisms. Recent discoveries have highlighted the significance of epigenetics in bridging the gap between multiple risk factors that contribute to ADs and expanding our understanding of the pathomechanisms underlying ADs. Epigenetics is the study of how changes in the environment and behavior can have an impact on gene function. Indeed, researchers have found that epigenetic mechanisms can affect how genes are activated or inactivated, as well as whether they are expressed. Such mechanisms may also affect how ADs form and are protected. That is, the bulk of pharmacological trials evaluating epigenetic treatments for the treatment of ADs have used histone deacetylase inhibitors (HDACi), yielding promising outcomes in both preclinical and clinical studies. This review will provide an outline of how epigenetic pathways can be used to treat ADs or lessen their risk. It will also present the findings from preclinical and clinical trials that are currently available on the use of epigenetic drugs to treat ADs.

Academic pressure is a prevalent stressor among Chinese adolescents and is often linked to anxiety symptoms, although the underlying mechanism remains unclear. This study aimed to investigate the association between NR3C1 gene methylation, academic pressure, and anxiety symptoms among Chinese adolescents.

This nested-case control study included 150 adolescents (boys: 38.7%; baseline age: 12-17 years) from a school-based longitudinal study of Chinese adolescents. Cases (n = 50) were defined as those with anxiety symptoms at both baseline and follow-up, while controls (n = 100) were randomly selected from those without anxiety symptoms at both timepoints. The cases and controls were 1:2 matched by age. Academic pressure, anxiety symptoms, and potential covariates were measured using a self-report questionnaire. Peripheral whole blood samples were collected from each participant for the detection of cortisol level (i.e., morning serum cortisol level) and DNA methylation. The methylation analysis included a total of 27 CpG units at the NR3C1 promoter region.

The final adjusted models showed that students with heavy academic pressure at baseline were at a higher risk of anxiety symptoms at follow-up compared to those with mild academic pressure (β estimate: 6.24 [95% CI: 3.48 ~ 9.01]). After adjusting for covariates, the methylation level of one CpG unit (NR3C1-16 CpG10) in NR3C1 differed significantly between cases and controls (F = 6.188, P = 0.014), and the difference remained significant after correction for multiple testing (P < 0.025). The adjusted regression models showed that moderate (β estimate = 0.010 [95% CI: 0.000 ~ 0.020], P = 0.046) and heavy (β estimate = 0.011 [95% CI: 0.001 ~ 0.020], P = 0.030) academic pressure were significantly associated with the methylation level of NR3C1-16 CpG 10. Further mediation analysis demonstrated that the association of academic pressure and anxiety symptoms was significantly mediated by the methylation of NR3C1-16 CpG 10 (β estimate for indirect effect = 0.11 [95% CI: 0.005 ~ 0.32]; indirect/total effect = 8.3%).

The present study suggests that NR3C1-16 CpG 10 DNA methylation might be a potential mechanism that partially explains the lasting effects of academic pressure on subsequent anxiety symptoms among adolescents. Further studies with larger sample sizes are recommended to replicate this finding.