Depressive Phenotype Research Articles

Risk factors for the intergenerational transmission of depression in women and girls: Understanding neural correlates of major depressive disorder and the role of early-onset maternal depression.

Deficits in neural reward processing have been implicated in the etiology of depression and have been observed in high-risk individuals. However, depression is a heterogeneous disorder,and not all depressed individuals exhibit blunted neural reward response, suggesting the need to examine more specific depression phenotypes. Early-onset depression, a well-defined phenotype, has been associated with greater intergenerational transmission of depression and appears more closely linked to neural reward processing deficits. The present study examined whether a maternal history of early-onset depression was associated with neural reward response among mothers and their daughters. Mothers with and without a history of depression, as well as their biological, adolescent daughters (N = 109 dyads), completed a monetary reward guessing task while electroencephalogram was collected. Analyses focused on the Reward Positivity (RewP), an event-related potential following reward receipt. Adjusting for current depressive symptoms, maternal early-onset depression was associated with a blunted RewP in the mothers and a numerically smaller RewP in their never-depressed, adolescent daughters. Maternal adult-onset depression was not statistically associated with a blunted RewP in mothers or daughters. Thus, a blunted RewP appears to be a trait-like vulnerability marker for depression that emerges before depression onset and relates to more specific depression phenotypes (e.g., early-onset depression). These findings have implications for early identification of individuals at risk of depression and for developing more targeted interventions.

An examination of plasma autoantibodies against voltage gated calcium channels in schizophrenia

Autoantibodies targeting the central nervous system have been shown to induce psychiatric symptoms resembling schizophrenia. Concurrently, genetic studies have characterised a number of risk variants associated with schizophrenia although their functional implications are largely unknown. Any biological effects of functional variants on protein function may potentially be replicated by the presence of autoantibodies against such proteins. Recent research has demonstrated that the R1346H variant in the CACNA1I gene coding for the Cav 3.3 protein results in a synaptic reduction of Cav3.3 voltage gated calcium channels and, consequently, sleep spindles, which have been shown to correlate with several symptom domains in patients with schizophrenia. The present study measured plasma levels of IgG against two peptides derived from CACNA1I and CACNA1C, respectively, in patients with schizophrenia and healthy controls. The results demonstrated that increased anti-CACNA1I IgG levels were associated with schizophrenia but not associated with any symptom domain related to the reduction of sleep spindles. In contrast to previously published work indicating that inflammation may be a marker for a depressive phenotype, plasma levels of IgG against either CACNA1I or CACNA1C peptides were not associated with depressive symptoms, suggesting that anti-Cav3.3 autoantibodies may function independently of pro-inflammatory processes.

Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

Depression is one of the common non-motor symptoms of Parkinson’s disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 μg/mL in the drinking water) for 10 weeks. From the 10th week, BoNT/A (10 U·kg−1·d−1) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1β in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses.BoNT/A ameliorates depressive-like behavior, and reverses synapse loss mediated by classical complement pathway-initiated microglia engulfment as well as alleviates microglia-mediated proinflammatory response in the reserpine-induced Parkinson’s disease mouse model.

A sex-specific genome-wide association study of depression phenotypes in UK Biobank.

There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date, no studies seek to identify sex-specific markers and pathways. In this study, we performed a sex-stratified genome-wide association analysis for broad depression with the UK Biobank total participants (N = 274,141), including only non-related participants, as well as with males (N = 127,867) and females (N = 146,274) separately. Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. We identified 11 loci passing genome-level significance (P < 5 × 10-8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific polygenic risk scores (PRSs) for broad depression outperformed total and the opposite sex PRSs in the prediction of broad major depressive disorder. These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.

Long-lasting and sex-dependent effects of late lactational maternal deprivation on socioemotional behaviors in adult mice

The lactation period is an important period for individual development and a sensitive period for the behavioral phenotypes and plasticity of individual offspring. Early life experiences (e.g., maternal deprivation (MD) and neglect) have significant long-lasting and dual effects on individual stress reactivities during adulthood. Theoretically, stress inoculation can improve the adaptive capacity of the body, but overstress can lead to dysfunction when adaptive mechanisms fail.To date, the potential effects of late lactational MD on the socioemotional behaviors of mouse offspring during adulthood are still not fully understood. In the present study, mice were subjected to early deprivation by individually separating pups from their dam for 0 min, 15 min, and 3 h per day from PND 13–25. The social dominance test (SDT), social interaction test (SI), open field test (OFT), and forced swim test (FST) were carried out during adulthood. The results showed that the social dominance of male mice in the 15 min/d MD group significantly increased, especially in low-rank mice. In the 3 h/d MD group, the social dominance of female mice was decreased, especially in the lower-rank mice. The anxiolytic and antidepressant-like effects of the 15 min/d MD group were significantly increased in male mice. Our study provides direct evidence that MD during late lactation period results in long-lasting effects on social dominance as well as on anxiety and depression phenotypes in a sex-dependent manner.

Abstract WMP109: Aged Maternal Biome Impairs Offspring Health

Background: The gut and its microbiome have become highlighted because of their holistic effect on the body in health and disease. The bi-directional communication of the gut-brain axis is highly involved in, among others, the immune response. Additionally, the maternal gut microbiome affects offspring brain, immune system, and gut microbiome formation and development. Therefore, an aged and unhealthy maternal biome that is may increase both stroke risk factors among offspring. Method: Young female C57B6 mice 3-month (M) of age had their host gut bacteria cleared via antibiotic treatment prior to recolonization via fecal microbiome transplants from 3M control, and 18M reproductively senescent female mice. The subsequent offspring was aged to 18 months, followed by behavioral tests, glucose tolerance, and blood pressure measurement, prior to a transient 90-minute middle cerebral artery occlusion (MCAO). Results: Compared to control females with 3M biome, females with an aged biome had decreased fecundity from 26.4 days to 54.75 days at the onset of breeding to birth of pups (p=0.0018). There was no change in estrus cycle between the groups. The offspring gut microbiome had been affected in a sex specific manner. Female pups from dysbiotic, aged, biome mothers differed significantly in terms of b-diversity compared to those from control mothers (p=0.009) with pathogenic increases to firmicutes shifting the F:B ratio. There was a less pronounced trend in male offspring (p=0.241). Interestingly, no weight differences were observed in offspring depending on the maternal biome. At 2M of age, a depressive phenotype in tail suspension test was noted for male(p=0.0001) and female (p=0.0059). However, at 6M and older, the depressive phenotype subsided. Male offspring at 18M demonstrated a significant change (p=0.0001) in Glucose tolerance test compared to age matched females. Conclusion: The maternal microbiome has a significant impact on offspring biome composition and health. Mice from mothers with aged microbiome exhibited early life depressive phenotypes, slower glucose metabolism, and a pathogenic gut microbiome composition. Therefore, maternal gut has transgenerational health effects which may be exacerbating stroke risk and potentially outcome.

Deep gray matter substructure volumes and depressive symptoms in a large multiple sclerosis cohort

Background Consistent findings on underlying brain features or specific structural atrophy patterns contributing to depression in multiple sclerosis (MS) are limited. Objective To investigate how deep gray matter (DGM) features predict depressive symptom trajectories in MS patients. Methods We used data from the MS Partners Advancing Technology and Health Solutions (MS PATHS) network in which standardized patient information and outcomes are collected. We performed whole-brain segmentation using SLANT-CRUISE. We assessed if DGM structures were associated with elevated depressive symptoms over follow-up and with depressive symptom phenotypes. Results We included 3844 participants (average age: 46.05 ± 11.83 years; 72.7% female) of whom 1905 (49.5%) experienced ⩾1 periods of elevated depressive symptoms over 2.6 ± 0.9 years mean follow-up. Higher caudate, putamen, accumbens, ventral diencephalon, thalamus, and amygdala volumes were associated with lower odds of elevated depressive symptoms over follow-up (odds ratio (OR) range per 1 SD (standard deviation) increase in volume: 0.88–0.94). For example, a 1 SD increase in accumbens or caudate volume was associated with 12% or 10% respective lower odds of having a period of elevated depressive symptoms over follow-up (for accumbens: OR: 0.88; 95% confidence interval (CI): 0.83–0.93; p < 0.001; for caudate: OR: 0.90; 95% CI: 0.85–0.96; p = 0.003). Conclusion Lower DGM volumes were associated with depressive symptom trajectories in MS.

Pre-pregnancy BMI was associated with gestational depressive phenotypes in a population of 12,099 women in Chongqing, China.

To investigate the association between pre-pregnancy body mass index (BMI) and gestational depressive phenotypes. The pregnant women receiving the first prenatal examination (4th -13th week of gestation) in Chongqing Health Center for Women and Children were recruited between February 2020 and September 2021. Depressive phenotypes was assessed by the Patient Health Questionnaire (PHQ-9) and the Symptom Checklist 90 (SCL-90) scale at recruitment. Pre-pregnancy weight and height were self-reported by the participants. Demographic and obstetric characteristics were obtained from the hospital information system. The association between pre-pregnancy BMI and the scores of PHQ-9 or SCL-90 scale was investigated by uni-variate analysis with Kruskal-Wallis test and by multi-variate analysis with linear regression model with adjustment of age, parity, smoking, alcohol consumption, and assisted reproduction. The association between pre-pregnancy BMI and PHQ-9 or SCL-90 diagnosed depressive phenotypes was analyzed by Chi-square test and logistic regression respectively. A total of 12,099 pregnant women were included, where 100% of them filled out the PHQ-9 scale and 99.6% filled out the SCL-90 scale, and 47.26% and 4.62% of the pregnant women had depressive phenotypes, respectively. Women with higher pre-pregnancy BMI had lower depressive phenotypes scores during pregnancy. Multivariable analysis of the PHQ-9 scale showed that overweight/obese subjects had a higher incidence of depressive phenotypes compared with subjects with normal BMI (OR=0.803, 95% CI [0.723, 0.892]). In a stratified analysis assessed by the PHQ-9, women who were overweight/obese prior to pregnancy were less likely to develop depressive phenotypes during pregnancy than women who were normal weight prior to pregnancy, regardless of whether they were nulliparous (OR=0.795, 95%CI[0.696,0.908]) or multiparous (OR=0.809, 95%CI[0.0.681,0.962]), while in the three age groups of 25-29 years, 30-34 years and ≥35 years, pre-pregnancy overweight/obesity were associated with lower risk of gestational depressive phenotypes. However, analysis of the SCL-90 scale showed no statistical association between depressive symptom and BMI. No substantial interaction was observed between BMI and parity or age. Increased pre-pregnancy BMI may be associated with reduced risk of gestational depressive phenotypes in Chinese women. Independent studies are warranted to validate the findings of the present study.

Tunicamycin induces depression-like behaviors in male rats, accompanied by initiated chaperon-mediated autophagy and decreased synaptic protein expression in the hippocampus

Background and aimEndoplasmic reticulum (ER) stress participates in the occurrence and development of depression, but the underlying mechanism is not fully understood. This study aimed to investigate the behavioral performance and intracerebral molecular changes in an ER stress model of male rats. MethodsIntrahippocampal injection of tunicamycin (TM) was performed on male rats as a model of ER stress. The body weight was determined, and behavioral tests, including sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST), were performed to evaluate depressive and anxiety-like phenotypes within 8 days after injection. The levels of chaperone-mediated autophagy (CMA), synaptic proteins, and neuroinflammation related factors in this model were measured via real-time quantitative PCR and Western blot analysis. ResultsIntrahippocampal injection of TM (2 or 1 μg) induced depression-like behaviors in rats, as indicated by the reduced body weight, sucrose preference in SPT, central time in OFT, and increased immobility time in FST. The mRNA and protein levels of GRP78, ATF4, CHOP, LAMP2A, IL-1β, IL-6, and TNF-α were significantly increased, while the expressions of MEF2D, PSD95, SYN, p-CREB (Ser133), and BDNF were significantly decreased in the hippocampus in the model group compared with the sham group. ConclusionsThese results confirmed that intrahippocampal injection of TM was a valid method to induce an ER stress rat model with depression-like behaviors accompanied by decreased synaptic protein expression and neuroinflammation. The alteration in CMA-related proteins in this ER stress depression model indicated the involvement of CMA in the development of depression.

Methylation in MAD1L1 is associated with the severity of suicide attempt and phenotypes of depression

Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD14+ cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.

Association of depression and anxiety with somatic diseases: negative lifestyle factors impact

To assess the associations of various depression and anxiety phenotypes with manifestations of different somatic disorders and negative lifestyle factors. The study involved 5116 people. In the online questionnaire, participants provided information about age, sex, height and weight, as well as a history of smoking, alcohol use, physical activity and diagnoses/symptoms of various physical diseases. Self-questions based on the DSM-5 criteria and the online version of the HADS were used to screen for phenotypes of affective and anxiety disorders in a population sample. An association of both subclinical and clinical depressive symptoms on HADS-D was noted for respondents with weight gain (OR 1.43; CI: 1.29-1.58, p<0.05 and OR 1,CI: 1.05-1.52, p<0.05, respectively), increased BMI (OR 1.36; CI: 1.24-1.48, p<0.05 OR 1.27; CI: 1.09-1.47, p<0.05 respectively), and decreased physical activity (OR 1.67; CI: 1.35-2.07, p<0.05 and OR 2.35; CI: 1.59-3.57, p<0.05, respectively) at the time of testing. The phenotypes of depression, anxiety disorders, and bipolar disorder by DSM criteria were associated with a history of smoking. (OR 1.37; CI: 1.18-1.62, p<0.001; OR 1.36; CI: 1.24-1.48, p<0.05 and OR 1.59; CI: 1.26-2.01, p<0.001, respectively). For higher BMI the association was reported only for the bipolar depression phenotype (OR 1.16; CI: 1.04-1.29, p<0.05), and with a decrease in physical activity - for the phenotypes of major depression and anxiety disorders (OR 1.27; CI: 1.07-1.52, p<0.05 and OR 1.61; CI: 1.31-1.99, p<0.001, respectively). A significant association with various somatic disorders was noted for all phenotype variants, but to the greatest extent for those based on DSM criteria. The study confirmed the association of negative external factors and various somatic disorders with depression. These associations were noted for various phenotypes of anxiety and depression, both in severity and structure, and may be due to complex mechanisms that have shared biological and environmental mechanisms.

Deep learning-based activity recognition and fine motor identification using 2D skeletons of cynomolgus monkeys.

Video-based action recognition is becoming a vital tool in clinical research and neuroscientific study for disorder detection and prediction. However, action recognition currently used in non-human primate (NHP) research relies heavily on intense manual labor and lacks standardized assessment. In this work, we established two standard benchmark datasets of NHPs in the laboratory: MonkeyinLab (MiL), which includes 13 categories of actions and postures, and MiL2D, which includes sequences of two-dimensional (2D) skeleton features. Furthermore, based on recent methodological advances in deep learning and skeleton visualization, we introduced the MonkeyMonitorKit (MonKit) toolbox for automatic action recognition, posture estimation, and identification of fine motor activity in monkeys. Using the datasets and MonKit, we evaluated the daily behaviors of wild-type cynomolgus monkeys within their home cages and experimental environments and compared these observations with the behaviors exhibited by cynomolgus monkeys possessing mutations in the MECP2 gene as a disease model of Rett syndrome (RTT). MonKit was used to assess motor function, stereotyped behaviors, and depressive phenotypes, with the outcomes compared with human manual detection. MonKit established consistent criteria for identifying behavior in NHPs with high accuracy and efficiency, thus providing a novel and comprehensive tool for assessing phenotypic behavior in monkeys.

Anhedonia in mood disorders and somatic diseases: results of exploratory Mendelian randomization analysis

To conduct an exploratory Mendelian randomization analysis of the causal relationships of anhedonia with a wide range of psychiatric and somatic phenotypes based on the genetic data of participants in a population study. This cross-sectional study included 4520 participants, of which 50.4% (n=2280) were female. The mean age was 36.8 (S.D.=9.8) years. Participants were pheno-nailed based on the DSM-5 criteria for anhedonia in the framework of depression. An episode of anhedonia exceeding 2 weeks during life was reported by 57.6% (n=2604) of participants. A genome-wide association study (GWAS) of the anhedonia phenotype was performed, as well as a Mendelian randomization analysis using summary statistics of large-scale GWASs on psychiatric and somatic phenotypes. The GWAS on anhedonia did not reveal the variants with genome-wide significant association (p<10-8). The most significant (p=9.71×10-7) was the variant rs296009 (chr5:168513184) in an intron of the slit guidance ligand 3 (SLIT3) gene. Using Mendelian randomization, nominally significant (p<0.05) causal associations of anhedonia with 24 phenotypes were identified, which can be divided into 5 main groups: psychiatric/neurological diseases, inflammatory diseases of the digestive system, respiratory diseases, oncological diseases and metabolic disorders. The most significant causal effects of anhedonia were found for breast cancer (p=0.0004, OR=0.9986, 95% confidence interval (CI) (0.9978-0.999)), minimal depression phenotype (p=0.009, OR=1.004, 95% CI (1.001-1.007)), as well as for apolipoprotein A (p=0.01, OR=0.973, 95% CI (0.952-0.993)) and respiratory diseases (p=0.01, OR=0.9988, 95% CI (0.9980-0.9997)). The polygenic nature of anhedonia may cause the risks of comorbidity of this phenotype with a wide range of somatic diseases, as well as may be associated with mood disorders.

Psilocybin rescues depressive phenotype and modulates serotonin-2A and glucocorticoid receptor mRNA expression in brain cortex of a stress animal model

Psilocybin rescues depressive phenotype and modulates serotonin-2A and glucocorticoid receptor mRNA expression in brain cortex of a stress animal model

Ameliorative Effect of Rutin Supplement on Chronic Unpredictable Mild Stress-Induced Depressive Phenotypes in Mice

Depression is a severe disorder that results in poor quality of life and affects hundreds of millions worldwide. Research on the relationship between depression and oxidative stress has shown important biochemical aspects in disease development. Flavonoids are a class of natural products that exhibit several pharmacological properties, including antidepressant-like activity and hence, suggested by studies to be exciting prototypes for new antidepressant drugs. Rutin is a flavonoid glycoside abundantly found in plants. The study evaluated the effect of rutin supplementation on depression using the chronic unpredictable mild stress depression mice models. Twenty-five mice were grouped into 5 (n = 5) and subjected to chronic unpredictable mild stressors. Groups 1-5 were orally served distilled water (no treatment), Rutin 30 mg/kg, 60 mg/kg, 120 mg/kg, and fluoxetine 20 mg/kg respectively. The study was conducted in the span of 30 days. Administration of rutin produced a reduction in immobility time at a dose of 120 mg/kg, a significant (p&lt;0.05) decrease in the concentration of serum superoxide dismutase at doses of 30 and 60 mg/kg, and showed no significant difference on catalase and malondialdehyde levels. Rutin supplementation showed the potential of positively reversing behavioural despair. Thus, may be considered a possible treatment option for depressive symptoms in view of it attaining lesser side effects compared to orthodox treatments

Normalization of HPA Axis, Cholinergic Neurotransmission, and Inhibiting Brain Oxidative and Inflammatory Dynamics Are Associated with The Adaptogenic-like Effect of Rutin Against Psychosocial Defeat Stress.

Social defeat stress (SDS) due to changes in biochemical functions has been implicated in the pathogenesis of affective and cognitive disorders. Employing pharmacological approach with adaptogens in the management and treatment of psychosocial stress is increasingly receiving scientific attention. In this study, we investigated the neuroprotective effect of rutin, a bioflavonoid with neuroprotective and anti-inflammatory functions on neurobehavioral and neuro-biochemical changes in mice exposed to SDS. Groups of mice named the intruder mice received normal saline(10 mL/kg), rutin (5, 10, and 20mg/kg, i.p.), and ginseng (50mg/kg, i.p.) daily for 14days, and then followed by 10min daily SDS (physical/psychological) exposures to aggressor micefrom days 7-14. Investigations consisting of neurobehavioral (locomotion, memory, anxiety, and depression)phenotypes, neuro-biochemical (oxidative, nitrergic, cholinergic, and pro-inflammatory cytokines) levelsin discrete brain regions, and hypothalamic-pituitary-adrenal(HPA) axis consistingadrenalweight, corticosterone, and glucoseconcentrations were assessed. Rutin restored the neurobehavioral deficits and reduced the activity of acetylcholinesterase in the brains. Adrenal hypertrophy, increased serum glucose and corticosterone levels were significantly attenuated by rutin. SDS-induced release of tumor necrosis factor-alpha and interleukin-6 in the striatum, prefrontal cortex, and hippocampus were also suppressed by rutin in a brain-region-dependent manner. Moreover, SDS-induced oxidative stress characterized by low antioxidants (glutathione, superoxide-dismutase, catalase) and lipid peroxidation and nitrergic stress were reversed by rutin in discrete brain regions. Collectively, our data suggest that rutin possesses an adoptogenic potential in mice exposed to SDS via normalization of HPA, oxidative/nitrergic, and neuroinflammatory inhibitions. Thus, may be adopted in the management of neuropsychiatric syndrome due to psychosocial stress.

Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice.

In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (NEGR1) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1-/- mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1-/- mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1-/- mice, and escitalopram rescued reduced weight of hippocampi in Negr1-/- mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene.

Latent Class Analysis of Depressive Symptom Phenotypes Among Black/African American Mothers.

Depression is a growing global problem with significant individual and societal costs. Despite their consequences, depressive symptoms are poorly recognized and undertreated because wide variation in symptom presentation limits clinical identification-particularly among African American (AA) women-an understudied population at an increased risk of health inequity. The aims of this study were to explore depressive symptom phenotypes among AA women and examine associations with epigenetic, cardiometabolic, and psychosocial factors. This cross-sectional, retrospective analysis included self-reported Black/AA mothers from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure study (data collected in 2015-2020). Clinical phenotypes were identified using latent class analysis. Bivariate logistic regression examined epigenetic age, cardiometabolic traits (i.e., body mass index ≥ 30 kg/m 2 , hypertension, or diabetes), and psychosocial variables as predictors of class membership. All participants were Black/AA and predominantly non-Hispanic. Over half of the sample had one or more cardiometabolic traits. Two latent classes were identified (low vs. moderate depressive symptoms). Somatic and self-critical symptoms characterized the moderate symptom class. Higher stress overload scores significantly predicted moderate-symptom class membership. In this sample of AA women with increased cardiometabolic burden, increased stress was associated with depressive symptoms that standard screening tools may not capture. Research examining the effect of specific stressors and the efficacy of tools to identify at-risk AA women are urgently needed to address disparities and mental health burdens.

The role of the Locus Coeruleus in depression in Alzheimer’s disease

AbstractBackgroundDepression, one of many common neuropsychiatric symptoms (NPS) seen in Alzheimer’s disease (AD), frequently predisposes the onset of cognitive deficits. NPS are often reported to cause the most suffering in patients and their loved ones so understanding their cause could lead to treatments that afford a better quality of life. The Locus coeruleus (LC) has strong links to depression and, being one of the first areas to show AD pathology, could be integral to understanding this NPS‐AD link. Alongside a natural LC neuron loss with age, AD causes its neurodegeneration reducing the LC’s neuroprotective capabilities and control of inflammatory pathways. Examination of the LC, inflammation and depressive phenotype could offer insights into future treatments.MethodBehavioural testing was done using a novel, knock‐in mouse model, AppNL‐G‐F , to assess depressive phenotype at an early and old time point. This included tests for anxiety (open field, elevated plus maze), social deficits (social preference test) and anhedonia (lick cluster analysis) all common NPS symptoms. Brains extracted from these animals were used to stain for LC neurons, plaques and microglia as well as assess astrocytes and inflammatory markers using western blotting technique.ResultAn anxiolytic phenotype was prominent but no social deficits or anhedonia suggesting a lack of depressive phenotype. There was also no loss of LC neurons with age or genotype. Western blotting revealed a large increase in astrocytes within the AppNL‐G‐F but no differences in inflammatory markers.ConclusionOverall, without the loss of LC neurons, it is difficult to draw firm conclusions on its role in NPS onset. Hence, the AppNL‐G‐F mice are insufficient at modelling affective deficits seen in human AD due to the lack of neurodegeneration of the LC. It may be concluded that, as this is a model of amyloid beta pathology, that plaques and inflammation play a minimal role in NPS without LC loss. Future testing could lesion the LC to better understand its role.

Associations Between Mild Behavioral Impairment (MBI‐C) Affective Domains and Alzheimer’s Disease Neuroimaging Biomarkers in Older Adults

AbstractBackgroundPrevious work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease (AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.Method21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.ResultGDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p&lt;0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.ConclusionPreliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.