Dopaminergic Synapses Research Articles

Olfactory Dysfunction in a Novel Model of Prodromal Parkinson’s Disease in Adult Zebrafish

Olfactory dysfunction is a clinical marker of prodromal Parkinson’s disease (PD), yet the underlying mechanisms remain unclear. To explore this relationship, we developed a zebrafish model that recapitulates the olfactory impairment observed in prodromal PD without affecting motor function. We used zebrafish due to their olfactory system’s similarity to mammals and their unique nervous system regenerative capacity. By injecting 6-hydroxydopamine (6-OHDA) into the dorsal telencephalic ventricle, we observed a significant loss of dopaminergic (DA) periglomerular neurons in the olfactory bulb (OB) and retrograde degeneration of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE). These alterations impaired olfactory responses to cadaverine, an aversive odorant, while responses to alanine remained intact. 6-OHDA also triggered robust neuroinflammatory responses. By 7 days post-injection, dopaminergic synapses in the OB were remodeled, OSNs in the OE appeared recovered, and neuroinflammation subsided, leading to full recovery of olfactory responses to cadaverine. These findings highlight the remarkable neuroplasticity of zebrafish and suggest that this model of olfactory dysfunction associated with dopaminergic loss could provide valuable insights into some features of early PD pathology. Understanding the interplay between dopaminergic loss and olfactory dysfunction in a highly regenerative vertebrate may inform therapeutic strategies for individuals suffering from olfactory loss.

Unique and overlapping mechanisms of valbenazine, deutetrabenazine, and vitamin E for tardive dyskinesia

In 2017, the Food and Drug Administration (FDA) approved valbenazine and deutetrabenazine, two vesicular monoamine transporter 2 (VMAT2) inhibitors, as treatments for tardive dyskinesia (TD). Additionally, some trials have suggested that vitamin E may benefit TD patients. However, the mechanistic basis for these treatments remains unclear. The objective of this study was to analyze and compare the mechanisms of valbenazine, deutetrabenazine, and vitamin E in TD treatment utilizing network pharmacology and molecular docking approaches. Putative target genes associated with valbenazine, deutetrabenazine, and vitamin E were retrieved from the PharmMapper, CTD, GeneCards, SwissTargetPrediction, and DrugBank databases. TD-related targets were identified using the GeneCards, DisGeNET, OMIM, and TTD databases. A protein-protein interaction (PPI) network was created to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via DAVID, and Cytoscape was used to build a drug-pathway-target-disease network. Molecular docking evaluated drug-target interactions. A total of 32, 36, and 62 targets relevant to the treatment of TD were identified for valbenazine, deutetrabenazine, and vitamin E, respectively. PPI and KEGG pathway analyses suggested that valbenazine and deutetrabenazine may influence TD through the dopaminergic synapse signaling pathway via common core targets (e.g., Dopamine Receptor D1 (DRD1), DRD2, Monoamine Oxidase B (MAOB), Solute Carrier Family 6 Member 3 (SLC6A3), SLC18A2) and specific targets (DRD3 for valbenazine, MAOA for deutetrabenazine). Vitamin E may affect TD by targeting the PI3K-Akt pathway through AKT Serine/Threonine Kinase 1 (AKT1), Brain-Derived Neurotrophic Factor (BDNF), Insulin (INS), Nitric Oxide Synthase 3 (NOS3), and Toll-Like Receptor 4 (TLR4). This study provides insights into the common and unique molecular mechanisms by which valbenazine, deutetrabenazine, and vitamin E may treat TD. Pharmacological experiments should be conducted to verify and further explore these results. The findings offer a theoretical basis for further pharmacological investigation and a resource for TD drug screening.

Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons

Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2–6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.

Gene signatures and immune correlations in Parkinson’s disease Braak stages

BackgroundParkinson's disease (PD), a progressive neurodegenerative disease, still lacks disease-modifying treatment strategies. The formation of Lewy body is the typical pathological feature of PD. Pathological progression can be defined by Braak stages. However, the molecular mechanism for this ascending course of α-synuclein pathology remains unclear.MethodsIn this study, weighted gene co-expression network analysis (WGCNA) was used to screen Braak stage-related gene signatures, followed by the functional enrichment analysis, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). The hub genes were screened through CytoHubba and Least Absolute Shrinkage and Selection Operator (LASSO) analysis. The immune cell proportion was predicted by the ImmuCellAI. Furthermore, transcription factors (TFs) and miRNAs targeting the hub genes network were constructed. After verifying hub gene expression level through independent data sets. The validated hub gene was further analyzed to elucidate the potential molecular mechanism.ResultsTotal of 388 genes associated with Braak stages were screened out through WGCNA analysis. The KEGG analysis showed that these genes were involved in endocytosis, HIF-1 signaling pathway, synaptic vesicle cycle, dopaminergic synapse, oxytocin signaling pathway, etc. Immune infiltration analysis showed that CD4 + T cells, including nTreg, Th2, and Th17, were obviously different between different Braak stages in PD. Furthermore, eights Braak stages-related hub genes were identified, including CAMK2B, CPLX2, GAPDH, GRIN1, KCNA1, MAPK3, MAPT, and STXBP1 through the cytoHubba plugin and LASSO analysis. After verifying the expression level in three independent data sets, CPLX2 was finally identified as the most reliable Braak stages-associated hub genes in PD.ConclusionsThis study revealed the Braak stage-related gene signatures in PD and identified CPLX2 as a novel Braak stages-related hub gene in PD, which provided a novel target for future therapeutic interventions and disease markers. The specific molecular mechanism of CPLX2 in PD remained to be further clarified.

Substantia nigra and blood gene signatures and biomarkers for Parkinson's disease from integrated multicenter microarray-based transcriptomic analyses.

Parkinson's disease (PD) is a complex, common neurodegenerative disorder with unclear etiology. The pathogenic hallmark is the death of dopaminergic neurons in the substantia nigra. PD diagnosis depends on clinical manifestation of symptoms but is lack of effective biomarker. Available human microarray-based transcriptomic datasets of the substantia nigra and blood were acquired for PD cases and controls. Robust rank aggregation and Weighted Gene Co-expression Network analysis were performed to identify gene signatures in substantia nigra and blood of PD. An overlapping analysis and validation in an independent cohort were followed to identify PD blood biomarkers. Eight datasets of substantia nigra and 3 datasets of blood were retrieved, which comprised 150 substantia nigra and 571 blood samples. Integrated differentially expressed genes (DEG) and module analyses showed that the substantia nigra gene signature in PD comprised 170 key genes, mainly involved in dopaminergic synapse, neuroactive ligand-receptor interaction, calcium signaling pathway, and Parkinson disease. The blood gene signature had only 65 DEGs, but with no robust co-expression module identified. Two genes, LRRN3 and TUBB2A, were both downregulated in the substantia nigra and blood of PD. But only TUBB2A was validated in the blood of independent cohort and showed a capacity of PD prediction. The present study identified PD-associated gene signatures of the substantia nigra and blood, and demonstrated that the reduced expression of TUBB2A in the blood is promising to predict PD. Our findings provide novel insight into the mechanisms underlying PD pathophysiology and the development of PD biomarkers.

Exploring potential key genes and disease mechanisms in early-onset genetic epilepsy via integrated bioinformatics analysis.

Exploring potential key genes and disease mechanisms in early-onset genetic epilepsy via integrated bioinformatics analysis.

Dynamic proteomic and phosphoproteomic analysis reveals key pathways and targets in the early stages of high-altitude traumatic brain injury.

Dynamic proteomic and phosphoproteomic analysis reveals key pathways and targets in the early stages of high-altitude traumatic brain injury.

Gut Microbiome-Brain Crosstalk in the Early Life of Chicken Reveals the Circadian Regulation of Key Metabolic and Immune Signaling Processes.

Circadian rhythms are innate biological systems that control everyday behavior and physiology. Furthermore, bilateral interaction between the host's circadian rhythm and the gut microbes influences a variety of health ramifications, including metabolic diseases, obesity, and mental health including GALT physiology and the microbiome population. Therefore, we are studying the correlation between differential gene expression in the chicken brain and microbiota abundance during circadian rhythms. To understand this, we raised freshly hatched chicks under two photoperiod treatments: normal photoperiod (NP = 12/12 LD) and extended photoperiod (EP 23/1 LD). The chicks were randomly assigned to one of two treatments. After 21 days of circadian entrainment, the chicks were euthanized at nine time points spaced six hours apart over 48 h to characterize the brain transcriptomes. Each sample's RNA was extracted, and 36 mRNA libraries were generated and sequenced using Illumina technology, followed by data processing, count data generation, and differential gene expression analysis. We generated an average of 17.5 million reads per library for 237.9 M reads. When aligned to the Galgal6 reference genome, 11,867 genes had detectable expression levels, with a common dispersion value of 0.105. To identify the genes that follow 24 h rhythms, counts per million data were performed in DiscoRhythm. We discovered 577 genes with Cosinor and 417 with the JTK cycle algorithm that exhibit substantial rhythms. We used weighted gene co-expression network analysis (WGCNA) to analyze the correlation between differentially expressed genes and microbiota abundance. The most enriched pathways included aldosterone-regulated sodium reabsorption, endocrine and other factor-regulated calcium reabsorption, GABAergic synapse, oxidative phosphorylation, serotonergic synapse, dopaminergic synapse and circadian entrainment. This study builds on our previous study, and adds new findings about the specific interactions and co-regulation of the brain transcriptome and the gut microbiota. The interaction between gut microbiota and host gene expression highlights the potential benefits of microbiome-modulation approaches to improve gut health and performance in poultry.

Increased individual variability in functional connectivity of the default mode network and its genetic correlates in major depressive disorder

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder characterized with considerable individual variability in clinical manifestations which may correspond to brain alterations including the default mode network (DMN). This study analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from 796 MDD patients and 823 healthy controls (HC) to investigate individual variability in functional connectivity (IVFC) between the DMN and 108 non-DMN regions. We aimed to identify MDD-related IVFC abnormalities and their clinical relevance, alongside exploring gene expression correlations. The results revealed similar spatial patterns of IVFC within the DMN in both groups, yet significantly increased IVFC values in MDD patients were observed in regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, fusiform gyrus, and occipital cortex. Notably, the mean IVFC in the DMN and fusiform gyrus was positively correlated with Hamilton Rating Scale for Depression (HAMD) scores in MDD patients. Gene expression analyses explained 47.0% of the variance in MDD-related IVFC alterations, with the most associated genes enriched in processes including membrane potential regulation, head development, synaptic transmission, and dopaminergic synapse. These findings highlight the clinical importance of IVFC variability in the DMN and suggest its potential role as a biomarker in MDD.

MicroRNAs alteration and unique distribution in the soma and synapses of substantia nigra in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative condition after Alzheimer's. Abnormal accumulation of alpha-synuclein (α-syn) aggregates disrupts the balance of dopaminergic (DA-ergic) synapse components, interfering with dopamine transmission and leading to synaptic dysfunction and neuronal loss in PD. However exact molecular mechanism underlying DA-ergic neuronal cell loss in the SNpc in not known. MicroRNAs (miRNAs) are observed in various compartments of neural elements including cell bodies, nerve terminals, mitochondria, synaptic vesicles and synaptosomes. However, miRNAs expression and cellular distribution are unknown in the soma and synapse compartment in PD and healthy state. To address this void of information, we isolated synaptosomes and cytosolic fractions (soma) from post-mortem brains of PD-affected individuals and unaffected controls (UC) and processed for miRNA sequencing analysis. A group of miRNAs were significantly altered ( p < 0.05) with high fold changes (variance +/- > 2-fold) in their expressions in different comparisons: 1. UC synaptosome vs UC cytosol, 2. PD synaptosome vs PD cytosol, 3. PD synaptosome vs UC synaptosome, 4. PD cytosol vs UC cytosol. Our study unveiled some potential miRNAs in PD and their alteration and unique distribution in the soma and synapses of SNpc in PD and controls. Further, gene ontology enrichment analysis showed the involvement of deregulated miRNAs in several molecular function and cellular components: synapse assembly formation, cell junction organization, cell projections, mitochondria, Calcium ion binding and protein binding activities.

Multi-omics uncover acute stress vulnerability through gut-hypothalamic communication in ducks.

1. The avian gut hosts a complex and dynamic microbial ecosystem, which is essential for regulating host organ function. However, the relationship between the gut microbiota and the hypothalamic axis in acute stress vulnerability in ducks remains unclear.2. This study investigated how the gut microbiota affects microbial metabolism and the host stress response by comparing hypothalamic neurotransmitter availability, microbial composition and co-metabolites generated by both the microbiota and hypothalamus in ducks exhibiting the lowest active avoidance (LAA) and highest active avoidance (HAA) behaviour.3. The HAA group experienced a significant increase in the availability of arginine, histidine, glutamine, norepinephrine, L-tyrosine and melatonin during acute stress in the hypothalamus, compared to that in the LAA group. The 16S rRNA sequencing revealed significant differences in the gut microbiota composition based on acute stress vulnerabilities.4. Both caecal and hypothalamic metabolomic analyses identified 71 metabolites altered in caecal content and 95 in the hypothalamus. There was significant enrichment in pathways such as the cGMP-PKG signalling, dopaminergic synapse and endocrine resistance.5. Correlation analyses demonstrated that certain co-metabolites, including 1,3-dicyclohexylurea, 1-deoxyvaleric acid, 2-amino-2-methyl-1,3-propanediol, 3-chloroaniline, methenamine, N4-acetylcytidine-triphosphate and traumatin, may play a role in the gut microbiota-hypothalamic axis.6. The results suggested that the gut microbiome influenced acute stress responses. This provided a basis for understanding gut-hypothalamic communication and its impact on behaviour in ducks.

In Silico Analysis of miRNA-Regulated Pathways in Spinocerebellar Ataxia Type 7.

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, caused by an abnormal expansion of the CAG trinucleotide in the coding region of the ATXN7 gene. Currently, in silico analysis is used to explore mechanisms and biological processes through bioinformatics predictions in various neurodegenerative diseases. Therefore, the aim of this study was to identify candidate human gene targets of four miRNAs (hsa-miR-29a-3p, hsa-miR-132-3p, hsa-miR-25-3p, and hsa-miR-92a-3p) involved in pathways that could play an important role in SCA7 pathogenesis through comprehensive in silico analysis including the prediction of miRNA target genes, Gen Ontology enrichment, identification of core genes in KEGG pathways, transcription factors and validated miRNA target genes with the mouse SCA7 transcriptome data. Our results showed the participation of the following pathways: adherens junction, focal adhesion, neurotrophin signaling, endoplasmic reticulum processing, actin cytoskeleton regulation, RNA transport, and apoptosis and dopaminergic synapse. In conclusion, unlike previous studies, we highlight using a bioinformatics approach the core genes and transcription factors involved in the different biological pathways and which ones are targets for the four miRNAs, which, in addition to being associated with neurodegenerative diseases, are also de-regulated in the plasma of patients with SCA7.

Adolescent alcohol exposure disrupts episodic-like memory by impairing dopamine synapses in the mouse prelimbic cortex

Adolescent alcohol exposure disrupts episodic-like memory by impairing dopamine synapses in the mouse prelimbic cortex

Cucumaria frondosa intestines and ovum hydrolysates intervention ameliorates the symptoms of dextran sulfate sodium-induced colitis by modulating gut microbiota and its metabolites.

Colitis, a troublesome inflammatory disease that significantly impacts daily life, has garnered considerable attention in recent times. Protolysates play a crucial role in the treatment of colitis, and the intestines and ovum of Cucumaria frondosa represent a readily available source of these hydrolysates. However, the effects of C. frondosa intestines and ovum hydrolysates (CFHs) on colitis have not been thoroughly investigated. We initially examined the molecular weight distribution of CFHs and found that the fraction of molecules with a weight less than 1000Da accounted for 86.98%, indicating that the hydrolysis primarily produced oligopeptides. Subsequently, we employed a dextran sulfate sodium-induced experimental colitis model to assess the therapeutic potential of CFHs. The findings indicated that preventive administration of CFHs dramatically attenuated the pathological manifestations associated with colitis in mice, including weight loss, colon shortening, and tissue damage. Furthermore, CFHs suppressed the secretion of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, as well as MPO in colon tissue. Metagenomic sequencing demonstrated that CFHs could restore balance to the dysregulated gut microbiota by reinforcing Bacteroidota and suppressing Verrucomicrobia populations, impacting various microbial functions. Metabolomic analyses further revealed that CFHs exhibited a more efficacious modulatory effect on DSS-induced metabolic abnormalities, including amino acid biosynthesis, linoleic acid metabolism, and dopaminergic synapses. In conclusion, CFHs showed promise in alleviating colitis, laying the groundwork for the development and application of CFHs as functional food for colitis relief.

Sex reversal induced by 17β-estradiol may be achieved by regulating the neuroendocrine system of the Pacific white shrimp Penaeus vannamei

BackgroundDue to sexual dimorphism in growth of penaeid shrimp, all-female cultivation is desirable for the aquaculture industry. 17β-estradiol (E2) has the potential to induce the male-to-female sex reversal of decapod species. However, the mechanisms behind it remain poorly understood. This study aimed to investigate the effects of E2 immersion on the neuroendocrine system (the eyestalk ganglia, brain, thoracic ganglia, and ventral nerve cord) of the Pacific white shrimp Penaeus vannamei through comparative transcriptomic analyses of the control males (CM), E2-treated males without sex reversal (EM), and neo-females (NF).ResultsImmersion in E2 at 2 mg/l from post-larvae (PL) 5 to 85 results in a skewed female-to-male ratio of 2.56: 1. The survival rate remains unaffected by E2 exposure, while a notable inhibition in growth is exclusively observed in the EM compared to the CM group. The transcriptome analysis result indicates that the observed retardation in growth of the EM may be attributed to the potential neuronal damage caused by the excessive neurotransmission, which in turn disrupts the PI3K-Akt signaling and cell cycle pathways. In contrast, the negatively regulated pathways of neuroactive ligand-receptor interaction and the dopaminergic synapse in the NF group suggest a potential impact of E2 on neuroplasticity through the modulation of neuroregulator binding and signaling, which affects the establishment of morphological differences and gender identity. Moreover, the activation of steroidogenesis and the inhibition of the insulin signaling may be associated with the success of E2-induced sex reversal. With these findings, a proposed mechanism of neuroendocrine system in decapods in response to E2 exposure is presented.ConclusionsThe present study represents a first step in understanding the effects of E2 on the neuroendocrine system at the molecular level. The observed retardation in growth in the EM group may be attributed to the potential for neuronal damage and disruptions in the cell cycle and PI3K-Akt signaling pathways. Furthermore, the success of E2-induced sex reversal may be associated with the downregulation of neuroactive ligand-receptor interaction, dopaminergic synapse, and insulin signaling pathways, as well as the activation of steroidogenesis. These findings provide new insights into the mode of action of E2, and underscore the potential for large-scale production of all-female stocks in P. vannamei.

Network pharmacology combined with experimental verification for exploring the potential mechanism of phellodendrine against depression

The anti-inflammatory effect of phellodendrine (PHE), derived from Phellodendri Chinensis Cortex, has been verified in previous studies. Major depressive disorder (MDD) is associated with immune dysregulation and inflammatory processes. This study aimed to explore the therapeutic effects of PHE on MDD through network pharmacology and experimental validation. Multiple databases were used to predict the targets of PHE and MDD. The intersection targets between PHE and MDD were obtained to identify as targets for PHE against MDD, followed by protein–protein interaction network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Molecular docking was applied to further confirm the anti-MDD effects of PHE. The mitochondrial DNA (mtDNA) copy number, inflammatory cytokines and pathway-related mRNA expressions in PC12 cell were determined via quantitative PCR (qPCR) and enzyme-linked immunosorbent assay to verify our finding. Thirty-eight intersection targets were obtained between PHE and MDD. PHE exerted an anti-MDD effect by regulating SLC6A4, SLC6A3, SLC6A2, MAOA and other targets through serotonergic synapse, salivary secretion, dopaminergic synapse, and cAMP signalling pathway. In vitro, PHE induced an increment in mtDNA copy number compared with the CORT group. PHE affected the levels of IL6 and IL1β with different concentrations. The mRNA levels of CHRM1, HTR1A and key targets of the PI3K/Akt signalling pathway were also influenced. Our research reveals novel mechanisms underlying the anti-MDD effects of PHE through network pharmacology and experiments, which provides a new direction for the development of antidepressants.

Specific plasma metabolite profile in intestinal Behçet’s syndrome

BackgroundIntestinal Behçet’s syndrome (IBS) has high morbidity and mortality rates with serious complications. However, there are few specific biomarkers for IBS. The purposes of this study were to investigate the distinctive metabolic changes in plasma samples between IBS patients and healthy people, active IBS and inactive IBS patients, and to identify candidate metabolic biomarkers which would be useful for diagnosing and predicting IBS.MethodsIn this study, we performed a global untargeted metabolomics approach in plasma samples from 30 IBS patients and 20 healthy subjects. P value < 0.05 and variable importance projection (VIP) values > 1 were considered to be statistically significant metabolites. Univariate receiver operating characteristic (ROC) curve analysis was plotted as a measure for assessing the clinical performance of metabolites, and area under curve (AUC) were assessed.ResultsA total of 147 differentially abundant metabolites (DAMs) were identified between IBS patients and normal control (NC) group. The potential pathways involved in the pathogenesis of IBS include linoleic acid metabolism; GABAergic synapse; biosynthesis of unsaturated fatty acids; valine, leucine and isoleucine biosynthesis; ovarian steroidogenesis; and others. In addition, a total of 103 significant metabolites were selected to distinguish active IBS from inactive IBS patients. Tyrosine metabolism, dopaminergic synapse and neuroactive ligand-receptor interaction were found to be closely related to the disease activity of IBS. Furthermore, three potential metabolites including quinate, stearidonic acid (SDA) and capric acid (CA) could significantly differ IBS patients from NC group. On the other hand, 1-methyladenosine (m1A), genipin, methylmalonic acid (MMA) and ascorbate could significantly differentiated active IBS from inactive IBS patients.ConclusionIn conclusion, this study demonstrated the characteristic plasma metabolic profiles between IBS group and NC group, as well as between active and inactive IBS patients by using an untargeted LC/MS metabolomics profiling approach. In this study, quinate, SDA and CA were identified as potential diagnostic biomarkers for IBS. Additionally, m1A, genipin, MMA and ascorbate could serve as potential biomarkers for evaluating IBS activity. These findings might provide potential valuable insights for developing therapeutic strategies to manage IBS in the future.

Genome-Wide Insights into Internalizing Symptoms in Admixed Latin American Children.

Internalizing disorders, including depression and anxiety, are major contributors to the global burden of disease. While the genetic architecture of these disorders in adults has been extensively studied, their early-life genetic mechanisms remain underexplored, especially in non-European populations. This study investigated the genetic mechanisms underlying internalizing symptoms in a cohort of Latin American children. This study included 1244 Brazilian children whose legal guardians completed the Child Behavior Checklist (CBCL) questionnaire. Genotyping was performed using the Illumina HumanOmni 2.5-8v1 BeadChip. The genome-wide association analysis revealed a significant association of rs7196970 (p = 4.5 × 10-8, OR = 0.61), in the ABCC1 gene, with internalizing symptoms. Functional annotation highlighted variants in epigenetically active regulatory regions, with multiple variants linked to differential expression of ABCC1 across several human tissues. Pathway enrichment analysis identified 42 significant pathways, with notable involvement in neurobiological processes such as glutamatergic, GABAergic, and dopaminergic synapses. This study identifies ABCC1 variants as novel genetic factors potentially associated with early-life internalizing symptoms. These results may contribute to future research on targeted interventions for childhood internalizing conditions.

Identification of Critical Signature in Post-Traumatic Stress Disorder Using Bioinformatics Analysis and in Vitro Analyses.

Post-traumatic stress disorder (PTSD) is a complex psychiatric condition that emerges following exposure to trauma and significantly affects daily functioning. Current research is focused on identifying effective treatments for PTSD. Advances in bioinformatics provide opportunities to elucidate the underlying mechanisms of PTSD. RNA sequencing (RNA-seq) datasets were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using GEO2R. Weighted gene co-expression network analysis (WGCNA) was employed to examine gene correlation patterns. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for functional annotation and enrichment analysis, respectively. The MCODE plugin in Cytoscape software was utilized to analyze the protein-protein interaction (PPI) network. Anxiety and depression in a mice stress model were assessed using the open-field test (OFT), elevated plus maze test (EPMT), and forced swimming test (FST). Real-time quantitative PCR (qRT-PCR) was conducted to validate key genes in stress-exposed models. A total of 157 common upregulated DEGs and 53 common downregulated DEGs were identified in the amygdala (AMY) and the hippocampus (HIP). Notably enriched pathways included neuroactive ligand-receptor interaction, mechanistic target of rapamycin (mTOR) signaling pathway, nicotine addiction, and dopaminergic synapse. The PPI network identified four hub genes, with key pathways associated with nicotine addiction and dopaminergic synapse. qRT-PCR validation confirmed that the expression trends of these four genes were consistent with microarray data. Behavioral tests (OFT, EMPT, and FST) revealed significant changes. This study utilized bioinformatics and in vitro experiments to identify genes and pathways potentially crucial for PTSD development. Key genes were validated in a mouse model, providing insights into potential target genes for PTSD treatment.

ITRAQ proteomic analysis of the anterior insula in morphine-induced conditioned place preference rats with high-frequency deep brain stimulation intervention.

Morphine dependence or addiction is a serious global public health and social problem, and traditional treatments are very limited. Deep brain stimulation (DBS) has emerged as a new potential treatment for drug addiction. Repeated use of morphine leads to neuroadaptive and molecular changes in the addiction-related brain regions. We have previously performed isobaric tags for relative and absolute quantitation (iTRAQ) labelling coupled with 2D-LC MS/MS in anterior insular samples from rats treated with saline control, morphine or morphine plus DBS, and the identified expression of eight proteins are altered by morphine and reversed by high-frequency DBS (HF-DBS). In this study, we analysed the proteomic data in more details. A total of 5575 proteins were identified. Relative to the saline group, the morphine group showed 14 down-regulated and three up-regulated proteins. There were 118 proteins increased and 87 proteins decreased between DBS implanted animals and morphine group. Several differentially expressed proteins were verified with parallel reaction monitoring (PRM) assay. Based on Gene Ontology enrichment an KEGG pathway analyses, the majority of these differentially expressed proteins (DEPs) were involved in protein metabolic process, G-protein coupled receptor signalling pathway, calcium-mediated signalling, neurotransmitter transport, dopaminergic synapse and mTOR signalling pathway. These data offer a comprehensive understanding of the proteomic changes associated with morphine addiction and DBS therapy in addicted animal models, which is important for the development of DBS interventions for drug addiction.