Gut microbiota mediates anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice

Gut Microbes, Год журнала: 2024, Номер 16(1)

Опубликована: Авг. 25, 2024

Background Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, potential role of induced by remains unclear.

Язык: Английский

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Depressive patient‐derived GABA interneurons reveal abnormal neural activity associated with HTR2C

EMBO Molecular Medicine, Год журнала: 2022, Номер 15(1)

Опубликована: Ноя. 14, 2022

Article14 November 2022Open Access Source DataTransparent process Depressive patient-derived GABA interneurons reveal abnormal neural activity associated with HTR2C Kaiqin Lu Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School Pharmacy, Nanjing Medical University, Nanjing, China Contribution: Data curation, Formal analysis, Funding acquisition, ​Investigation, Writing - original draft, Project administration, review & editing Search more papers by this author Yuan Hong orcid.org/0000-0002-4390-7353 Software, ​Investigation Mengdan Tao Luping Shen Zhilong Zheng Department Neurobiology, Human Functional Genomics Jiangsu Province, Methodology Kaiheng Fang Min Xu Resources, Methodology, administration Chun Wang Brain Hospital Affiliated to Dongya Zhu Xing Guo Corresponding Author [email protected] orcid.org/0000-0002-0216-0310 Co-innovation Center Neuroregeneration, Nantong Jiangsu, Yan Liu orcid.org/0000-0003-2918-5398 Supervision, Information Lu1,†, Hong1,†, Tao1,†, Shen1,†, Zheng2, Fang1, Yuan1, Xu1, Wang3, Zhu1, *,2,4 *,1 1Institute 2Department 3Nanjing 4Co-innovation † These authors contributed equally work *Corresponding author. Tel: +86 25 86869345; E-mail: 86868467; EMBO Mol Med (2023)15:e16364https://doi.org/10.15252/emmm.202216364 PDFDownload PDF article text main figures.PDF PLUSDownload text, figures, expanded view figures appendix. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Major depressive disorder suicide behavior (sMDD) is severe mood disorder, bringing tremendous burden family society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues sMDD patients, molecular mechanism which levels are altered remains elusive. In study, we generated induced pluripotent stem cells (iPSC) from five patients differentiated iPSCs GABAergic (GINs) ventral forebrain organoids. GINs exhibited neuronal morphology increased firing, as well weakened calcium signaling propagation, compared controls. Transcriptomic sequencing revealed that decreased expression serotoninergic receptor 2C (5-HT2C) may cause defected sMDD. Furthermore, targeting 5-HT2C receptor, using small molecule agonist or genetic approach, restored deficits GINs. Our findings provide human cellular model studying mechanisms drug discoveries Synopsis iPSC-derived major disorders exhibit expression. Trazodone hydrochloride (Trzd) targets restores deficits, indicating could be therapeutic target sMDD-derived display GIN subtypes. show electrophysiological hyperexcitability signaling. Transcriptional analysis reveals low sMDD-associated defects can overexpression 5-HT2CR Trzd. Introduction (MDD) leading disability, global prevalence 4.4–5.0% (WHO, 2017). Individuals MDD often loss pleasure, sleep disorders, mental disturbances (First et al, 2015). So far, pathogenesis elusive, at least partly due highly heterogeneity symptoms etiology. Thus, one subgroup MDD, such (sMDD), shares common symptom, open window revealing MDD. Severe who have committed pose serious families communities (Ferrari 2013). Neuroimaging studies reported subcortical brain structures (Krishnan Nestler, 2008; Murrough 2016; Belleau 2019) sMDD, volume dentate gyrus (DG) (MacQueen 2008) nerve growth factor (Wohleb 2016). Immunohistochemical evidence slices showed GABAB receptor-mediated inhibition dysregulated, suggesting were involved regulation glutamate-glutamine-GABA cycle suicidal individuals (Bernstein 2013; Lewis 2018). An integrative genomics study GABAA 2 (GABRG2), lower (Yin Also, female veterans behavior, ratio over creatine+ phosphocreatine anterior cingulate cortex was significantly (Prescot Some these biochemical changes, reduction transmission GABA-synthesizing enzyme 67 (GAD67) protein levels, GABAA/B animal models (Luscher 2011; Banasr 2017; Jacobson 2018; Duman 2019), hypothesis disrupted structural functional integrity prefrontal networks pathophysiological basis Clinically, elevating Brexanolone (SAGE-547) transcranial stimulation, developed antidepressant treatments (Kanes Heimrath 2020). However, whether system still unclear. it big challenge etiology potential drugs (Preti, Locci Pinna, 2019). Induced (iPSCs) derived neurological offer (Fujimori Differentiation iPSCs-derived bipolar (BD) into hippocampal gyrus-like neurons mitochondrial abnormalities excitation BD (Mertens two disease pathophysiology organoids psychiatric Fragile X syndrome (Wen 2014; Kang 2021). Two recent longer neurites serotonin-induced hyperactivity downstream upregulated excitatory serotonergic receptors respectively SSRI-resistant default (Vadodaria 2019a,b). provided discoveries. iPSC not reported. Here, attempted once patient-specific included We found subtype GINs, reversed an FDA-approved targeted receptors. Taken together, our current important phenotypes organoids, offering tool identifying approaches. Results neurite branches subtypes reprogrammed peripheral blood (SA004, SA005-1, SA005-3, SA006, SA007, SA008. Notably, SA005-1 SA005-3 same subject). parallel, used NC3-1, IMR90-4, RC01001-A, ihtc-03, RC01001-C lines controls (CTRLs, Figs 1A EV1A, Table EV1). The established expressed pluripotency markers, alkaline phosphatase (AP), SOX2, NANOG (Fig EV1B). Following differentiation (Stefansson 2003) protocol (Liu 2020) EV1C), both CTRL > 80% GABA+ among TUJ1+ day 35 1B C). proportion MAP2+ mature (ranging 69.91 81.54%) HO+ total 49.63 72.43%) EV1D–G). There no significant difference between different cell lines. Figure 1. Scheme illustrating generation (five CTRLs six patients). Representative images cultures showing TUJ1 Scale bar = 100 μm. 35. (CTRL, n 120 fields counted lines; 134 6 lines). Mean ± SEM. schematic morphometric Sholl 50 intersection number (Each red box lines, independently differentiations each point represents mean value independent experiments, 226 groups. Each blue 30 260 groups). Two-way ANOVA distance soma, ****P < 0.0001 10, center line shows median SEM whiskers represent maximum minimum. 65. Quantification primary branch numbers shown 65, ≥ 11, Nested t-test, **P 0.0016 versus median. longest length 0.0075 calretinin (CR) CR+ days 35, 40 50, respectively. (Red 5 line. timepoints, ns: 50. somatostatin (SST) co-staining neuron marker MAP2 SST+ 43 groups 37 T-test, 0.0001. data available online figure. 1 [emmm202216364-sup-0006-SDataFig1.zip] Download figure PowerPoint Click here expand EV1. Generation patients. Related Fig patients' mononuclear (PBMC). 250 (MEF, Mouse Embryonic Fibroblast). Alkaline staining immunostaining undifferentiated images. Schematic diagram left three pannels: scale right pannel: 15. HO 13.Mean intersections groups, sum ***P 0.0006 83 *P 0.0118 0.0027 stress-induced defect dendritic density (Qiao Zhao then examined 1D). increase concentric circles 30, μm soma 1E), interactions elevated, EV1H I), complexity next analyzed similar results 1F), intersections, EV1J K). measured 1G H). Previous suggested subtypes, (SST), related (Smiley Song To further analyze assessed CR 40, group (11.8 0.4%) fewer than (17.4 0.7%). population obtained (sMDD: 16.0 0.7%; CTRL: 28.3 1.2%) 1I J). At 1K L). Altogether, indicated One hypothesized impaired circuits (Duman performed whole-cell patch-clamp recording on 6-week-old measure intrinsic membrane properties 2A). Under voltage clamp, APs evoked injection range 10 60 pA readily CTRLs. AP amplitude frequency higher 2B–E). half-width ~56% narrower 2F), excessive channel activation (Bean, 2007; Paşca 2011). sodium potassium currents correlate APs. larger inward 2G), activated response depolarization CTRL. fast 30–80 mV markedly elevated 2H). Collectively, determine characteristics later stage, 70. Consistent 45, amplitudes EV2A–D), along EV2E–G). demonstrated 2. 45–60 A. representative recording. B. traces holding −70 (blue) (red) C. Average during 500 ms stepwise 55 0.01. D–F. Amplitude half width first 10-pA 0.01; 0.001. G. Traces Na+/K+ recorded average peak values Na+ 46 38 H. 36 ANOVA, 0.001; [emmm202216364-sup-0007-SDataFig2.zip] EV2. 70–80. method 23 0.05. D. Half P 0.0872. E, F. Sample 24 Calcium imaging reliable (de Melo Reis rodent studies, disturbance Ca2+ homeostasis signals (Ma 2019; investigate coupled changes depolarization, via fluorescence indicator dye Fluo-4 AM time-series microscopy 3A). After loaded onto cells, intracellular fluctuations monitored fluorescent intensity time mM KCL stimulation 3B). Then decrease [Ca2+]i rise following after 1-min continuous 3C). Next, statistical curve. Peak Ca2+(Fmax–F0)/F0, 2013), 3D). 3. Defects dyes. timepoint. 20 trajectory (red line) (blue KCL. CTRL, neurons; neurons. experiment (the whole quantification result D). [Ca2+] (Fmax–F0)/F0 per (n 155 198 0.0022 hiPS cells. Immunostaining interneuron GAD67, progenitor SOX2 prosencephalic NKX2.1 states. 156 four 88 0.0005 3

Язык: Английский

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Prelimbic cortex is involved in the regulation of morphine-induced conditioned place preference in both resistant and sensitive mice

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 15, 2025

Abstract A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control desire obtain drugs, which shows some variation between different individuals. Here, using a morphine-induced conditioned place preference (CPP) model with footshock, we found that mice exhibited significant individual differences addiction. Despite consequences of small percentage (24%) still showed stable morphine preference, demonstrating resistant punishment. The majority (76%) were relatively sensitive punishment termination preference. As region advanced cognitive function mammalian brain, medial prefrontal cortex (mPFC) involved regulating drug-induced addictive behaviors. We activating pyramidal neurons prelimbic (PrL) could effectively reverse CPP mice, inhibiting PrL promote mice. To further explore analyzed gene expression their regions through RNA-seq analysis. results compared significantly downregulated differentially expressed genes (DEGs), such as Panx2 , Tcf7l2 Htr2c Htr5a Orai3 Slc24a4 Cacnb2 mainly synaptic formation neurodevelopment. speculated there may be defects neuronal system caused they are more prone CPP. These findings likely contribute research therapy, also serve potential therapeutic targets for

Язык: Английский

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Synergistic neuroprotective effects of two natural medicinal plants against CORT-induced nerve cell injury by correcting neurotransmitter deficits and inflammation imbalance

Phytomedicine, Год журнала: 2023, Номер 121, С. 155102 - 155102

Опубликована: Сен. 18, 2023

Язык: Английский

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Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2680 - 2680

Опубликована: Фев. 26, 2024

Since its inception, induced pluripotent stem cell (iPSC) technology has been hailed as a powerful tool for comprehending disease etiology and advancing drug screening across various domains. While earlier iPSC-based modeling assessment primarily operated at the cellular level, recent years have witnessed significant shift towards organoid-based investigations. Organoids derived from iPSCs offer distinct advantages, particularly in enabling observation of progression metabolism an vivo-like environment, surpassing capabilities iPSC-derived cells. Furthermore, therapy emerged focal point clinical interest. In this review, we provide extensive overview non-integrative reprogramming methods that evolved since inception iPSC technology. We also deliver comprehensive examination organoids, spanning realms nervous system, cardiovascular oncology, well systematically elucidate advancements iPSC-related therapies.

Язык: Английский

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circFKBP8(5S,6)-encoded protein as a novel endogenous regulator in major depressive disorder by inhibiting glucocorticoid receptor nucleus translocation

Science Bulletin, Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Язык: Английский

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Advances and Applications of Brain Organoids

Neuroscience Bulletin, Год журнала: 2023, Номер 39(11), С. 1703 - 1716

Опубликована: Май 24, 2023

Abstract Understanding the fundamental processes of human brain development and diseases is great importance for our health. However, existing research models such as non-human primate mouse remain limited due to their developmental discrepancies compared with humans. Over past years, an emerging model, “brain organoid” integrated from pluripotent stem cells, has been developed mimic disease-associated phenotypes some extent, making it possible better understand complex structures functions brain. In this review, we summarize recent advances in organoid technologies applications diseases, including neurodevelopmental, neurodegenerative, psychiatric tumors. Finally, also discuss current limitations potential organoids.

Язык: Английский

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Divergent suicidal symptomatic activations converge on somato-cognitive action network in depression

Molecular Psychiatry, Год журнала: 2024, Номер 29(7), С. 1980 - 1989

Опубликована: Фев. 14, 2024

Individuals with depression have the highest lifetime prevalence of suicide attempts (SA) among mental illnesses. Numerous neuroimaging studies developed biomarkers from task-related neural activation in depressive patients SA, but findings are inconsistent. Empowered by contemporary interconnected view as a system disorder, we sought to identify specific brain circuit utilizing published heterogeneous activations. We systematically reviewed all cognitive and emotional functional MRI that investigated differences location activations between without SA. subsequently mapped an underlying functionally connecting each experimental using large normative connectome database (n = 1000). The identified SA-related network was compared derived disease control group. Finally, decoded this convergent connectivity microscale transcriptomic chemo-architectures, macroscale psychological processes. enrolled 11 tasks eight studies, including SA 147) 196). localized somato-cognitive action (SCAN), exhibiting robustness little perturbations specificity for depression. Furthermore, colocalized brain-wide gene expression involved inflammatory immunity-related biological processes aligned distribution GABA noradrenaline neurotransmitter systems. demonstrate is predominantly located at SCAN, which essential implication understanding

Язык: Английский

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Artificial Meshed Vessel-Induced Dimensional Breaking Growth of Human Brain Organoids and Multiregional Assembloids

ACS Nano, Год журнала: 2024, Номер unknown

Опубликована: Сен. 13, 2024

Brain organoids are widely used to model brain development and diseases. However, a major challenge in their application is the insufficient supply of oxygen nutrients core region, restricting size maturation organoids. In order vascularize enhance nutritional areas, two-photon polymerization (TPP) 3D printing employed fabricate high-resolution meshed vessels this study. These made photoresist with densely distributed micropores diameter 20 μm on sidewall, cocultured facilitate diffusion culture medium into The vascularized exhibit dimensional breaking growth enhanced proliferation, reduced hypoxia apoptosis, suggesting that 3D-printed partially mimic vascular function promote Furthermore, cortical, striatal medial ganglionic eminence (MGE) respectively differentiated generate Cortico-Striatal-MGE assembloids by vessels. migration, projection excitatory signaling transduction observed between different regional assembloids. This study presents an approach using TPP construct for enhancing assembly, offering research platform neurological

Язык: Английский

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Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3620 - 3620

Опубликована: Март 23, 2024

A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development function oligodendrocytes (OLs) interneurons. OLs are myelin-forming cells in central nervous system (CNS), while interneurons important neural types gating excitatory neurons. These two great significance for establishment circuits, they share similar developmental origins transcriptional architectures, interact each other multiple ways during development. In this review, we compare similarities differences these cell types, providing an reference further revealing pathogenesis related brain disorders.

Язык: Английский

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