Association of indoleamine 2,3 dioxygenase, brain derived neurotrophic factor and cellular senescence in type 2 diabetes mellitus with depression: a clinical approach.

BACKGROUND AND AIM: Type 2 diabetes mellitus (T2DM) and depression are often linked. Several studies have reported the role of molecular markers either in diabetes or depression. The present study aimed at molecular level profiling of Indoleamine-2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF) and cellular senescence in patients with type 2 diabetes with and without depression compared to individuals with healthy controls. METHODS: A total of 120 individuals diagnosed with T2DM were enlisted for the study, with a subset of participants with and without exhibiting depression. The gene expression analysis was done using quantitative real-time PCR. RESULTS: Indoleamine 2,3 dioxygenase (p < 0.001) and senescence genes (p < 0.001) were significantly upregulated, while brain derived neurotrophic factor (p < 0.01) was significantly downregulated in T2DM patients comorbid with and without depression when compared to healthy controls. CONCLUSION: Indoleamine 2,3 dioxygenase, Brain derived neurotrophic factor and cellular senescence may play a role in the progression of the disease. The aforementioned discoveries offer significant contributions to our understanding of the molecular mechanisms that underlie T2DM with depression, potentially aiding in the advancement of prediction and diagnostic methods for this particular ailment.

Olfactory genes affect major depression in highly educated, emotionally stable, lean women: a bridge between animal models and precision medicine.

Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

The association of FKBP5 gene polymorphism with genetic susceptibility to depression and response to antidepressant treatment- a systematic review.

BACKGROUND: Given the inconsistencies in current studies regarding the impact of FKBP5 gene polymorphisms on depression, arising from variations in study methods, subjects, and treatment strategies, this paper provides a comprehensive review of the relationship between FKBP5 gene polymorphisms and genetic susceptibility to depression, as well as their influence on response to antidepressant treatment. METHODS: Electronic databases were searched up to April 11, 2023, for all literature in English and Chinese on depression, FKBP5 gene polymorphisms, and antidepressant treatment. Data extraction and quality assessment were performed for key study characteristics. Qualitative methods were used to synthesize the study results. RESULTS: A total of 21 studies were included, with the majority exhibiting average to moderate quality. Six SNPs (rs3800373, rs1360780, rs9470080, rs4713916, rs9296158, rs9394309) were broadly implicated in susceptibility to depression, while rs1360780 and rs3800373 were linked to antidepressant treatment sensitivity. Additionally, rs1360780 was associated with adverse reactions to antidepressant drug treatment. However, these associations were largely unconfirmed in replication studies. CONCLUSIONS: Depression is recognized as a polygenic genetic disorder, with multiple genes contributing, each exerting relatively small effects. Future studies should explore not only multiple gene interactions but also epigenetic changes. Presently, research on FKBP5 in affective disorders remains notably limited, highlighting the necessity for further investigations in this domain.

Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia.

BACKGROUND: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies. METHODS: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets. RESULTS: We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data. CONCLUSIONS: Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety.

Purpose: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety. Methods: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations. Results: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression. Conclusions: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.

Biomarkers of Depression among Adolescent Girls: BDNF and Epigenetics.

Alterations in brain-derived neurotrophic factor (BDNF) expression have been suggested to mediate the influence of environmental factors on the emergence of depression through epigenetic modifications. However, research on this subject in the developmental population is lacking and the pathophysiology of adolescent depression remains unclear. We aimed to investigate the alterations in BDNF expression and global DNA methylation in depression among adolescent girls. Thirty female inpatients with the initial diagnosis of depression were assessed before and after the period of antidepressant treatment and compared with thirty age-matched healthy controls. The assessment involved BDNF and proBDNF serum levels, the BDNF gene exon IV promoter methylation, and global DNA methylation. The methylation level in the BDNF gene exon IV promoter was significantly lower in the studied group compared with the control and correlated negatively with the severity of depression. The test distinguished the studied group from the controls with a sensitivity of 37% and specificity of 90%. The differences were no longer present after the period of antidepressant treatment. No differences in the global DNA methylation, BDNF, and proBDNF levels were found. We concluded that decreased methylation in the BDNF exon IV promoter could be considered as a biomarker of a depression state among adolescent girls.

Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation.

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling.

Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour. We showed that increasing hippocampal NUDT6 results in depression-like behaviour in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acted by inducing inflammatory signalling, specifically by increasing S100 calcium binding protein A9 (S100A9) levels, activating nuclear factor-kappa B-p65 (NF-κB-p65), and elevating microglia numbers along with a reduction in neurogenesis. Our results suggest that NUDT6 could play a role in major depression by inducing a proinflammatory state. This is the first report of an antisense protein acting through a different mechanism of action than regulation of its sense protein. The opposite effects of NUDT6 and FGF2 on depression-like behaviour may serve as a mechanism to fine-tune affective behaviour. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behaviour, as well as in neuropsychiatric disorders. KEY POINTS: Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor-2 (FGF2), increases depression-like behaviour in rats. Hippocampal NUDT6 overexpression triggers a neuroinflammatory cascade by increasing S100 calcium binding proteinA9 (S100A9) expression and nuclear NF-κB-p65 translocation in neurons, in addition to microglial recruitment and activation. Hippocampal NUDT6 overexpression suppresses neurogenesis. NUDT6 exerts its actions without altering the levels or downstream signalling pathways of FGF2.

Night shift work, genetic risk, and the risk of depression: A prospective cohort study.

BACKGROUND: Genetic factors and night shift work both contribute to the risk of depression, but whether the association of night shift work with depression varies by genetic predisposition remains unclear. OBJECTIVES: To assess whether night shift work is associated with a higher risk of depression regardless of genetic predisposition. METHODS: We used data from the UK biobank of 247,828 adults aged 38-71 free of depression at baseline from March 13, 2006, to October 1, 2010. Genetic predisposition to depression was assessed using polygenic risk scores (PRS) weighted sums of genetic variant indicator variables and classified as low (lowest tertile), intermediate (tertile 2), and high (highest tertile). Night shift work exposures were collected using a touchscreen questionnaire and were divided into four categories. RESULTS: After a median follow-up of 12.7 years, 7315 participants developed depression. Compared with day workers, HRs (95 % CIs) of depression were 1.28 (1.19-1.38) for shift work, but never or rarely night shifts, 1.32 (1.20-1.45) for irregular night shifts, and 1.20 (1.07-1.34) for permanent night shifts. Considering lifetime employment and compared with never shift workers, >8 nights/month (HR: 1.40; 95 % CI: 1.19-1.66) and <10 years (HR: 1.30; 95 % CI: 1.09-1.54) of night shift work were associated with a higher risk of depression. In joint effect analyses, compared to participants with low genetic predisposition and day workers, the HRs (95 % CIs) of depression were 1.49 (1.32-1.69) in those with high genetic predisposition and shift work, but never or rarely night shifts, and 1.36 (1.20-1.55) for those with high genetic predisposition and irregular/permanent night shifts. In addition, there was neither multiplicative nor additive interaction between genetic predisposition and night shift work on the risk of depression. CONCLUSIONS: Night shift work was associated with an increased risk of depression regardless of genetic risk.

Ginsenoside Rk3 Regulates Tryptophan Metabolism along the Brain-Gut Axis by Targeting Tryptophan Hydroxylase and Remodeling the Intestinal Microenvironment to Alleviate Depressive-Like Behavior in Mice.

Depression is a neuropsychiatric disease that significantly impacts the physical and mental health of >300 million people worldwide and places a major burden on society. Ginsenosides are the main active ingredient in ginseng and have been proven to have various pharmacological effects on the nervous system. Herein, we investigated the antidepressant effect of ginsenoside Rk3 and its underlying mechanism in a murine model of depression. Rk3 significantly improved depression-like behavior in mice, ameliorated the disturbance of the hypothalamus-pituitary-adrenal axis, and alleviated neuronal damage in the hippocampus and prefrontal cortex of mice. Additionally, Rk3 improved the abnormal metabolism of tryptophan in brain tissue by targeting tryptophan hydroxylase, thereby reducing neuronal apoptosis and synaptic structural damage in the mouse hippocampus and prefrontal cortex. Furthermore, Rk3 reshaped the composition of the gut microbiota of mice and regulated intestinal tryptophan metabolism, which alleviated intestinal barrier damage. Thus, this study provides valuable insights into the role of Rk3 in the tryptophan metabolic cycle along the brain-gut axis, suggesting that Rk3 may have the potential for treating depression.

Single-cell RNA-sequencing of cellular heterogeneity and pathogenic mechanisms in paraquat-induced Parkinson's disease with depression.

Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases, and approximately one third of patients with PD are estimated to have depression. Paraquat (PQ) exposure is an important environmental risk factor for PD. In this study, we established a mouse model of PQ-induced PD with depression to comprehensively investigate cellular heterogeneity and the mechanisms underlying the progression of depression in the context of PD. We utilized single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of individual cells from model mice and characterize the gene expression profiles in each differentially expressed cell type. We identified a specific glutamatergic neuron cluster responsible for the development of heterogeneous depression-associated changes and established a comprehensive gene expression atlas. Furthermore, functional enrichment and cell trajectory analyses revealed that the mechanisms underlying the progression of PD with depression were associated with specific glutamatergic neurons. Together, our findings provide a valuable resource for deciphering the cellular heterogeneity of PD with depression. The suggested connection between intrinsic transcriptional states of neurons and the progression of depression can provide insight into potential biomarkers and specific targets for anti-depression treatment in patients with PD. SYNOPSIS: Our results obtained using model mice confirm the core effects of PQ exposure on glutamatergic neurons and their potential role in the development of PD with depression.

Association between maternal prenatal depressive symptoms and offspring epigenetic aging at 3-5 weeks.

Epigenetic clocks are emerging as tools for assessing acceleration and deceleration of biological age during childhood. Maternal depression during pregnancy may affect the biological aging of offspring and related development. In a low-income cohort of mother-child dyads, we investigated the relationship between prenatal maternal depressive symptoms and infant epigenetic age residuals, which represent the deviation (acceleration or deceleration) that exists between predicted biological age and chronological age. The epigenetic age residuals were derived from a pediatric-specific buccal epithelial clock. We hypothesized that maternal depressive symptoms, both sub-clinical and elevated (clinical level), would be associated with estimated biological age deceleration in offspring during early infancy. We analyzed data from 94 mother-child dyads using the Edinburgh Postnatal Depression Scale (EPDS) and DNA methylation derived from offspring buccal cells collected at 3-5 weeks of age. There was a significant non-linear association between the EPDS score and epigenetic age residual (ß = -0.017, 95% confidence interval: -0.03,-0.01, P = <0.01). The results indicated that infants of mothers with sub-clinical depressive symptoms had the lowest infant epigenetic age residuals while infants of mothers with no-to-low depressive symptoms had the highest and experienced biological age acceleration. Maternal depressive symptoms may influence the biological aging of offspring living in poverty.

The causal relationship between depression and obstructive sleep apnea: A bidirectional Mendelian randomization study.

OBJECTIVE: Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR). METHODS: Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators. RESULTS: The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (ORivw = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (ORivw = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (ORivw = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (ORivw = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA. CONCLUSION: These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA.

Cohort profile: BioMD-Y (biopsychosocial factors of major depression in youth) - a biobank study on the molecular genetics and environmental factors of depression in children and adolescents in Munich.

PURPOSE: BioMD-Y is a comprehensive biobank study of children and adolescents with major depression (MD) and their healthy peers in Germany, collecting a host of both biological and psychosocial information from the participants and their parents with the aim of exploring genetic and environmental risk and protective factors for MD in children and adolescents. PARTICIPANTS: Children and adolescents aged 8-18 years are recruited to either the clinical case group (MD, diagnosis of MD disorder) or the typically developing control group (absence of any psychiatric condition). FINDINGS TO DATE: To date, four publications on both genetic and environmental risk and resilience factors (including FKBP5, glucocorticoid receptor activation, polygenic risk scores, psychosocial and sociodemographic risk and resilience factors) have been published based on the BioMD-Y sample. FUTURE PLANS: Data collection is currently scheduled to continue into 2026. Research questions will be further addressed using available measures.

[The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression]. / Svyaz' polimorfizmov gena serotoninovogo transportera SLC6A4 s depressiei.

OBJECTIVE: To study the relationship of polymorphic variants of the SLC6A4 gene with depression among people aged 25-44 years in Novosibirsk. MATERIAL AND METHODS: Under the WHO program «MONICA-psychosocial (MOPSY)¼, a random representative sample of people aged 25-44 years from the population of the Oktyabrsky district of Novosibirsk (men n=725, mean age 43.4±0.4 years, response - 71.3%, women n=710, mean age 44.8±0.4 years, response - 72%). Depression was assessed using the MONICA-MOPSY psychosocial questionnaire. Every fourth respondent was examined for polymorphic variants of 5HTTLPR-VNTR SNP rs25531 A>G of the SLC6A4 gene. The study was carried out within the framework of the budget topic Reg. No. 122031700094-5. RESULTS: The high level of depression among people aged 25-44 was 12.8% (for men 9.1%, for women - 15.92%); the average level of depression occurred in 24.5% of the population (among men in 21.24%, among women in 26.76%) (χ2=17.071, df=2, p<0.001). The most common genotype of the SLC6A4 gene, among people aged 25--4 years old in Novosibirsk, was SLA - 43.29%, LALA - 26.53% - in second place, SS - 17.87% - third, LALG - 6 genotypes were less represented genotypes. 74%, SLG - 4.18%, LGLG - 1.39%. Carrying the SLA genotype (53.3% and 63.6%) increased the chance of developing both the average level of depression by 2.359 (95% CI 1.278-4.355) times, and depression in general by 1.933 (95% CI 1.142-3.271) times, compared with persons carrying the LALA genotype (32.0% and 46.9%), (χ2=7.674, df=1, p<0.01 and χ2=6.095, df=1, p<0.05). Persons carrying the LALG genotype (54.5%) also had a higher chance of developing a mean level of depression RR=2.929 (95% CI 1.039-8.261), compared with carriers of the LALA genotype (32.0%) (χ2=4.326, df =1, p<0.05) (p<0.05). CONCLUSION: Associative links between polymorphic variants of the SLC6A4 gene and depression have been established.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence.

BACKGROUND: The endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)-an enzyme that regulates endocannabinoid signaling-to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. METHODS: This study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9-11 years at Baseline, 11-13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. RESULTS: A significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p's<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p's>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p's>0.05). CONCLUSIONS: Our findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

Associations of depression and anxiety symptoms in childhood and adolescence with epigenetic aging.

BACKGROUND: Childhood anxiety and depression symptoms are potential risk factors for accelerated biological aging. In child and adolescent twins, we tested whether these symptoms were associated with DNA methylation (DNAm) aging, a measure of biological aging. METHODS: 276 twins (135 pairs, 6 singletons) had DNAm assayed from saliva in middle childhood (mean = 7.8 years). Residuals of five different DNAm age estimates regressed on chronological age were used to indicate accelerated aging. Anxiety and depression symptoms were assessed in middle childhood and early adolescence using the Child Behavior Checklist. Mixed effect regression was used to examine potential relationships between anxiety or depression symptoms, and accelerated DNAm age. MZ twin difference analysis was then utilized to determine if associations were environmentally-driven or due to genetic or shared-environment confounding. RESULTS: Anxiety and depression symptoms were not associated with accelerated DNAm aging in middle childhood. In early adolescence, only the Wu clock was significant and indicated that each one symptom increase in anxiety symptoms had an associated age acceleration of 0.03 years (~0.4 months; p = 0.019). MZ twin difference analysis revealed non-significant within-pair effects, suggesting genetic and shared environmental influences. LIMITATIONS: Sample is predominantly male and white. Generalizability to other populations may be limited. CONCLUSION: Accelerated DNAm aging of the Wu clock in middle childhood is associated with anxiety, but not depression, symptoms in early adolescence. Further, this association may be the result of shared genetic and environmental influences. Accelerated DNAm aging may serve as an early risk factor or predictor of later anxiety symptoms.

Neuroproteomics: Unveiling the Molecular Insights of Psychiatric Disorders with a Focus on Anxiety Disorder and Depression.

Anxiety and depression are two of the most common mental disorders worldwide, with a lifetime prevalence of up to 30%. These disorders are complex and have a variety of overlapping factors, including genetic, environmental, and behavioral factors. Current pharmacological treatments for anxiety and depression are not perfect. Many patients do not respond to treatment, and those who do often experience side effects. Animal models are crucial for understanding the complex pathophysiology of both disorders. These models have been used to identify potential targets for new treatments, and they have also been used to study the effects of environmental factors on these disorders. Recent proteomic methods and technologies are providing new insights into the molecular mechanisms of anxiety disorder and depression. These methods have been used to identify proteins that are altered in these disorders, and they have also been used to study the effects of pharmacological treatments on protein expression. Together, behavioral and proteomic research will help elucidate the factors involved in anxiety disorder and depression. This knowledge will improve preventive strategies and lead to the development of novel treatments.

Genetic influences on depression and selection into adverse life experiences.

Genome-wide association studies find that a large number of genetic variants jointly influence the risk of depression, which is summarized by polygenic indices (PGIs) of depressive symptoms and major depression. But PGIs by design remain agnostic about the causal mechanisms linking genes to depression. Meanwhile, the role of adverse life experiences in shaping depression risk is well-documented, including via gene-environment correlation. Building on theoretical work on dynamic and contingent genetic selection, we suggest that genetic influences may lead to differential selection into negative life experiences, forging gene-environment correlations that manifest in various permutations of depressive behaviors and environmental adversities. We also examine the extent to which apparent genetic influences may reflect spurious associations due to factors such as indirect genetic effects. Using data from two large surveys of middle-aged and older US adults, we investigate to what extent a PGI of depression predicts the risk of 27 different adversities. Further, to glean insights about the kinds of processes that might lead to gene-environment correlation, we augment these analyses with data from an original preregistered survey to measure cultural understandings of the behavioral dependence of various adversities. We find that the PGI predicts the risk of majority of adversities, net of class background and prior depression, and that the selection risk is greater for adversities typically perceived as being dependent on peoples' own behaviors. Taken together, our findings suggest that the PGI of depression largely picks up the risk of behaviorally-influenced adversities, but to a lesser degree also captures other environmental influences. The results invite further exploration into the behavioral and interactional processes that lie along the pathways intervening between genetic differences and wellbeing.

Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.