The HPA Axis as Target for Depression

Current Neuropharmacology, Journal Year: 2023, Volume and Issue: 22(5), P. 904 - 915

Published: Aug. 15, 2023

Abstract: Major depressive disorder (MDD) is a stress-related mental with lifetime prevalence of 20% and, thus, one the most prevalent health disorders worldwide. Many studies large number patients support notion that abnormalities hypothalamus-pituitaryadrenal (HPA) axis are crucial for development MDD. Therefore, strategies and drugs have been investigated to target different components HPA axis: 1) corticotrophinreleasing hormone (CRH) 1 receptor antagonists; 2) vasopressin V1B antagonists, 3) glucocorticoid 4) FKBP5 antagonists. Until now, antagonists GR provided promising results. Preclinical data also FKBP5, which seem be partly responsible effects exerted by ketamine. However, as alterations occur only in subset patients, specific treatment approaches single will effective this patients. Companion tests measure function identify an impaired axis, such dexamethasone-corticotrophin-releasing (dex-CRH) test or molecular dexamethasonesuppression (mDST) test, may match patient enable patient-tailored treatments terms precision medicine approach.

Language: Английский

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New Research Perspectives on the Interplay Between Genes and Environment on Executive Function Development

Biological Psychiatry, Journal Year: 2023, Volume and Issue: 94(2), P. 131 - 141

Published: Jan. 17, 2023

Language: Английский

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Examining the biological mechanisms of human mental disorders resulting from gene-environment interdependence using novel functional genomic approaches

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 178, P. 106008 - 106008

Published: Jan. 20, 2023

We explore how functional genomics approaches that integrate datasets from human and non-human model systems can improve our understanding of the effect gene-environment interplay on risk for mental disorders. start by briefly defining G-E paradigm its challenges then discuss different levels regulation gene expression corresponding data existing in humans (genome wide genotyping, transcriptomics, DNA methylation, chromatin modifications, chromosome conformational changes, non-coding RNAs, proteomics metabolomics), discussing novel to application these study origins health. Finally, we multilevel integration diverse types data. Advance use context a perspective improves detection vulnerabilities, informing development preventive therapeutic interventions.

Language: Английский

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DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(5), P. 1510 - 1520

Published: Feb. 5, 2024

Abstract Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of REs, also the context x environment interactions, have not yet been explored humanized models. We applied high-accuracy measurement DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) investigate DNAm three tissues/brain regions (blood, prefrontal cortex hippocampus) mice carrying FK506-binding protein 5 ( FKBP5 ) gene, an important candidate associated with stress-related psychiatric disorders. functional intronic glucocorticoid-responsive (at introns 2, 5, 7) at baseline, cases differing genotype (rs1360780 single nucleotide polymorphism), following application synthetic glucocorticoid dexamethasone. compared patterns N = 58) those peripheral blood 447 89) postmortem brain 86). Overall, model seem recapitulate observed tissue. At this was a higher extent The animal recapitulated effects dexamethasone on DNAm, especially lesser DNAm. could thus assist reverse translation findings psychiatry that involve genetic epigenetic regulation elements.

Language: Английский

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The evolving neurobiology of early-life stress

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Taking stock to move forward: Where the field of developmental psychopathology might be heading

Development and Psychopathology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 10

Published: Feb. 23, 2024

Abstract In this paper, dedicated to Dante Cicchetti’s contributions and enduring influence, we explore the prospective directions of developmental psychopathology. Our focus centers on key domains where significant achievements have continually shaped our evolving thinking about psychological development. These include (a) concepts equifinality multifinality, along with challenges in predicting trajectories, (b) imperative integrate wider sociocultural viewpoints into psychopathology frameworks, (c) interplay genetic environmental influences courses, (d) significance mental state language, (e) progress, or its absence, development prevention intervention tactics for children, adolescents, their caregivers. While many forecasts regarding future may not materialize, maintain optimistic that essential ideas presented will influence research agenda field contribute growth over next fifty years.

Language: Английский

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Support to caregivers who have received genetic information about neurodevelopmental and psychiatric vulnerability in their young children: A narrative review

Clinical Genetics, Journal Year: 2023, Volume and Issue: 104(2), P. 163 - 173

Published: April 25, 2023

Abstract Diagnosis of pathogenic genetic variants associated with neurodevelopmental and psychiatric disorders (NPDs) is increasingly made early in life. This narrative review focuses on the need for, provision of, psychological supports following diagnosis. We conducted a literature search publications how caregivers are informed about NPD vulnerability variants, challenges unmet needs when receiving this information, whether provided. Given its recognition, 22q11.2 deletion has been studied thoroughly for two decades, providing generalizable insights. indicates complex caregivers' related to learning potential vulnerabilities variant, include communicate diagnosis, identify signs NPDs, deal stigma lack medical expertise outside specialized genetics clinics. With one exception, no describe psychotherapeutic support provided parents. In absence support, struggle several regarding longer‐term implications The field go beyond explaining diagnoses vulnerabilities, develop approaches communicating managing across child's lifespan.

Language: Английский

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Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high‐accuracy DNA methylation measurement via targeted bisulfite sequencing

European Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 58(3), P. 2662 - 2676

Published: July 6, 2023

FKBP5 is an important stress-regulatory gene implicated in stress-related psychiatric diseases. Single nucleotide polymorphisms of the were shown to interact with early life stress alter glucocorticoid-related response and moderate disease risk. Demethylation cytosine-phosphate-guanine-dinucleotides (CpGs) regulatory glucocorticoid-responsive elements was suggested be mediating epigenetic mechanism for long-term effects, but studies on Fkbp5 DNA methylation (DNAm) rodents are so far limited. We evaluated applicability high-accuracy measurement via targeted bisulfite sequencing (HAM-TBS), a next-generation sequencing-based technology, allow more in-depth characterisation murine locus three different tissues (blood, frontal cortex hippocampus). In this study, we not only increased number sites previously described regions (in introns 1 5), also extended evaluation novel, possibly relevant intron 8, transcriptional start site, proximal enhancer CTCF-binding within 5'UTR). here describe assessment HAM-TBS assays panel 157 CpGs possible functional relevance gene. DNAm profiles tissue-specific, lesser differences between two brain than blood. Moreover, identified changes after exposure Our findings indicate that valuable tool broader exploration its involvement response.

Language: Английский

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Greater maltreatment severity is associated with smaller brain volume with implication for intellectual ability in young children

Neurobiology of Stress, Journal Year: 2023, Volume and Issue: 27, P. 100576 - 100576

Published: Sept. 23, 2023

Childhood maltreatment profoundly alters trajectories of brain development, promoting markedly increased long-term health risks and impaired intellectual development. However, the immediate impact on development in children extent to which altered global volume contributes with experience is currently unknown. We here utilized MRI data obtained from within 6 months after exposure assess association severity changes. further assessed between tested for mediating effect this association. used structural (3T) a sample 49 aged 3–5 years exposure, i.e. emotional physical abuse and/or neglect months, characterize intracranial tissue-specific volumes. Maltreatment was coded using Maternal Interview Classification Maltreatment. IQ at study entry one year Snijders Oomen Nonverbal Test. Higher significantly correlated smaller (r = -.393, p .008), mainly driven by lower total turn primarily due gray matter -.454, .002). Furthermore, associated -.548, < .001) predicted later -.493, .004.). The observed associations were independent potential confounding variables, including height, socioeconomic status, age sex. provide evidence that greater early childhood related size very young significant consequences ability, likely setting path far-reaching disadvantages. Insights into molecular neural processes underlie structure function are urgently needed derive mechanism-driven targets intervention.

Language: Английский

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Interaction between childhood trauma experience and TPH2 rs7305115 gene polymorphism in brain gray matter volume

Behavioral and Brain Functions, Journal Year: 2023, Volume and Issue: 19(1)

Published: Dec. 13, 2023

Abstract Background Childhood trauma is one of the most extensively studied and well-supported environmental risk factors for development mental health problems. The human tryptophan hydroxylase 2 (TPH2) gene promising candidate genes in numerous psychiatric disorders. However, it now widely acknowledged that neither genetic variation nor exposure alone can fully explain all phenotypic variance observed Therefore, necessary to consider interaction between two research. Methods We enrolled a sizable nonclinical cohort 786 young, healthy adults who underwent structural MRI scans completed genotyping, Trauma Questionnaire (CTQ) behavioural scores. identified childhood TPH2 rs7305115 polymorphism gray matter volume (GMV) specific brain subregions behaviour our sample using multiple linear regression framework. utilized mediation effect analysis identify environment /gene-brain-behaviour relationships. Results found interacted both GMV subregions. Our findings indicated right posterior parietal thalamus served as significant mediator supporting relationship (measured by CTQ score) anxiety scores study population, process was partly modulated polymorphism. Moreover, we only main parahippocampal gyrus area, mediator. Conclusions suggest early-life may have long-term on GMV, potentially leading altered cognitive emotional processes involving also be This finding highlights importance considering when examining impact experiences structure function. Gene‒environment studies regarded powerful objective supplement targeted therapy, early diagnosis treatment evaluation future.

Language: Английский

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