Integrating genetics and transcriptomics to study major depressive disorder: a conceptual framework, bioinformatic approaches, and recent findings DOI Creative Commons
Emily M. Hicks, Carina Seah, Alanna C. Cote

et al.

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: April 19, 2023

Abstract Major depressive disorder (MDD) is a complex and heterogeneous psychiatric syndrome with genetic environmental influences. In addition to neuroanatomical circuit-level disturbances, dysregulation of the brain transcriptome key phenotypic signature MDD. Postmortem gene expression data are uniquely valuable resources for identifying this genomic drivers in human depression; however, scarcity tissue limits our capacity observe dynamic transcriptional landscape It therefore crucial explore integrate depression stress transcriptomic from numerous, complementary perspectives construct richer understanding pathophysiology depression. review, we discuss multiple approaches exploring reflecting stages MDD: predisposition, onset, illness. We next highlight bioinformatic hypothesis-free, genome-wide analyses their integration. Last, summarize findings recent studies within conceptual framework.

Language: Английский

The cortisol switch between vulnerability and resilience DOI
E. R. de Kloet, Marian Joëls

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 29(1), P. 20 - 34

Published: Jan. 4, 2023

Language: Английский

Citations

91
Patient-derived organoids in translational oncology and drug screening DOI Creative Commons
Ruixin Yang, Yingyan Yu

Cancer Letters, Journal Year: 2023, Volume and Issue: 562, P. 216180 - 216180

Published: April 13, 2023

Patient-derived organoids (PDO) are a new biomedical research model that can reconstruct phenotypic and genetic characteristics of the original tissue useful for on pathogenesis drug screening. To introduce progression in this field, we review key factors constructing derived from epithelial tissues cancers, covering culture medium matrix, morphological characteristics, profiles, high-throughput screening, application potential. We also discuss co-culture system cancer with tumor microenvironment (TME) associated cells. The is widely used evaluating crosstalk cells TME components, such as fibroblasts, endothelial cells, immune microorganisms. article provides prospective standardized cultivation mode, automatic evaluation, sensitivity screening using methods.

Language: Английский

Citations

60
Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity DOI Open Access
Simone Battaglia, Chiara Di Fazio,

Matteo Mazzà

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 864 - 864

Published: Jan. 10, 2024

Fear extinction is a phenomenon that involves gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how regions communicate during these processes. Stress, ubiquitous aspect of life, influences learning and by changing the activity amygdala, prefrontal cortex, hippocampus, leading enhanced and/or impaired extinction. Glucocorticoid receptors (GRs) are key stress response show dual function regulation: while they enhance consolidation memories, also facilitate Accordingly, GR dysregulation associated with anxiety mood disorders. Recent advancements cognitive neuroscience underscore need for comprehensive understanding integrates perspectives from molecular, cellular, systems levels. In particular, neuropharmacology provides neurotransmitter receptor systems, aiding investigation mechanisms underlying regulation potential therapeutic targets. A notable player this context cortisol, hormone, which significantly both memory reconsolidation Gaining thorough intricate interactions has implications terms addressing psychiatric disorders related stress. This review sheds light on complex between processes, emotions, their neural bases. endeavor, our aim reshape comprehension fear, stress, emotional well-being, ultimately development interventions.

Language: Английский

Citations

37
Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood DOI
Nikolaos P. Daskalakis, Artemis Iatrou, Chris Chatzinakos

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study posttraumatic stress disorder (PTSD) and major depressive (MDD) included the central nucleus amygdala, hippocampal dentate gyrus, medial prefrontal cortex (mPFC). Genes exons within mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal synaptic regulation, hormones. Multiomic factor gene network analyses provided underlying genomic structure. Single RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) non-neuronal cell types. Analyses brain-blood intersections >50,000 UK Biobank participants were conducted along with fine-mapping results PTSD MDD genome-wide association studies distinguish risk from processes. data suggest shared distinct both propose potential therapeutic targets biomarkers.

Language: Английский

Citations

27
Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression DOI Creative Commons
Carina Seah, Michael S. Breen,

Tom Rusielewicz

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(11), P. 1434 - 1445

Published: Oct. 20, 2022

Abstract Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute individual clinical outcomes is unknown. Here, we compared transcriptional responses hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD ( n = 19 hiPSC 20 PBMC donors) controls donors). In only, observed diagnosis-specific glucocorticoid-induced changes gene expression corresponding PTSD-specific transcriptomic patterns found postmortem brains. We glucocorticoid hypersensitivity neurons, identified genes that this PTSD-dependent response. find evidence of a coregulated network transcription mediates hyper-responsivity PTSD. These findings suggest represent platform for examining molecular mechanisms underlying PTSD, identifying biomarkers response, conducting drug screening identify new therapeutics.

Language: Английский

Citations

41
Ethical Implications in Making Use of Human Cerebral Organoids for Investigating Stress—Related Mechanisms and Disorders DOI Creative Commons
Katherine Bassil, Dorothee Horstkötter

Cambridge Quarterly of Healthcare Ethics, Journal Year: 2023, Volume and Issue: 32(4), P. 529 - 541

Published: Feb. 17, 2023

Abstract The generation of three-dimensional cerebral organoids from human-induced pluripotent stem cells (hPSC) has facilitated the investigation mechanisms underlying several neuropsychiatric disorders, including stress-related namely major depressive disorder and post-traumatic stress disorder. Generating hPSC-derived neurons, organoids, even assembloids (or multi-organoid complexes) can facilitate research into biomarkers for susceptibility or resilience may bring about advances in personalized medicine biomarker psychiatric disorders. Nevertheless, organoid does not come without its own set ethical considerations. With increased complexity resemblance to vivo conditions, discussions moral status these models are ongoing, questions sentience, consciousness, status, donor protection, chimeras. There are, however, unique considerations that arise worth looking context disorders using organoids. This paper provides research-specific use purposes. as a case study here help inform other practices vitro studies brain with high

Language: Английский

Citations

35
Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response DOI

Chris Chatzinakos,

Cameron D. Pernia,

Filomene G. Morrison

et al.

American Journal of Psychiatry, Journal Year: 2023, Volume and Issue: 180(10), P. 739 - 754

Published: July 26, 2023

Objective: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk pathophysiology. Postmortem brain have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted first single-nucleus postmortem study PTSD elucidate transcriptomic pathology with resolution. Method: Profiling 32 DLPFC samples from 11 individuals PTSD, 10 MDD, control subjects was (∼415K nuclei; >13K cells per sample). A replication sample included 15 (∼160K >11K Results: Differential gene expression analyses identified significant differentially expressed genes (snDEGs) excitatory (EX) inhibitory (IN) neurons astrocytes, not other cell types or bulk tissue. MDD had more false discovery rate–corrected snDEGs, a greater rate. In EX IN neurons, biological pathways that were enriched compared glucocorticoid signaling. Furthermore, signaling induced pluripotent stem (iPSC)–derived cortical demonstrated relevance opposite direction regulation especially neurons. Many snDEGs 17q21.31 locus are particularly interesting given causal roles pathogenesis DLPFC-based neuroimaging (PTSD: ARL17B, LINC02210-CRHR1, LRRC37A2; MDD: LRRC37A LRP4), while others regulated by glucocorticoids iPSC-derived SLC16A6, TAF1C; CDH3). Conclusions: findings point mechanisms response highlighting importance examining indicating promising novel biomarkers therapeutic targets.

Language: Английский

Citations

31
Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression DOI Creative Commons
Anthi C. Krontira, Cristiana Cruceanu, Leander Dony

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(9), P. 1426 - 1443.e11

Published: March 4, 2024

Glucocorticoids are important for proper organ maturation, and their levels tightly regulated during development. Here, we use human cerebral organoids mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that increase a specific type basal progenitors (co-expressing PAX6 EOMES) has been shown contribute cortical expansion in gyrified species. This effect is mediated via transcription factor ZBTB16 leads increased production neurons. A phenome-wide Mendelian randomization analysis an enhancer variant moderates glucocorticoid-induced reveals causal relationships with higher educational attainment altered brain structure. The relationship postnatal cognition also supported by data from prospective pregnancy cohort study. work provides cellular molecular pathway neurogenesis relates lasting phenotypes.

Language: Английский

Citations

14
In vitro modeling of the neurobiological effects of glucocorticoids: A review DOI Creative Commons
Katherine Bassil, Anthi C. Krontira,

Thomas Leroy

et al.

Neurobiology of Stress, Journal Year: 2023, Volume and Issue: 23, P. 100530 - 100530

Published: Feb. 23, 2023

Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the glands a result of HPA-axis activation. The release GCs is with several neurobiological changes that associated negative consequences chronic onset course psychiatric disorders. Investigating underlying effects may help to better understand pathophysiology impact plethora neuronal processes at genetic, epigenetic, cellular, molecular levels. Given scarcity difficulty accessing human brain samples, 2D 3D vitro cultures becoming increasingly useful studying GC effects. In this review, we provide an overview studies investigating on key proliferation survival progenitor cells, neurogenesis, synaptic plasticity, activity, inflammation, genetic vulnerability, epigenetic alterations. Finally, discuss challenges field offer suggestions for improving use models investigate

Language: Английский

Citations

21
Extracellular vesicle-mediated trafficking of molecular cues during human brain development DOI Creative Commons
Andrea Carolina Pérez Forero, Fabrizia Pipicelli, Sylvain Moser

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(10), P. 114755 - 114755

Published: Sept. 19, 2024

Language: Английский

Citations

8