Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE312664 | GEO | 2026/01/15
REPOSITORIES: GEO
Similar Datasets
Project description:Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation
| PRJNA1375676 | ENA
Project description:Parkinson’s disease (PD) is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD, however the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. We aimed to study the impact of the A53T mutation on human microglia developed in a physiologically relevant context Here, we used 2-dimensional cultures of human iPSC-derived microglia and transplantation of these cells into the mouse brain to assess the effects of the A53T mutation on human microglia. We found that A53T-mutant human microglia had an intrinsically increased propensity towards pro-inflammatory activation upon inflammatory stimulus. Additionally, A53T mutant microglia showed increased oxidative stress, with a strong decrease in catalase expression in non-inflammatory conditions. Together, these results indicate that A53T mutant human microglia display cell-autonomous phenotypes that may worsen neuronal damage in early-onset PD.
2024-08-20 | GSE241437 | GEO
Project description:The rapid elimination of dying neurons and non-functional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene expression programs supporting clearance activity. We provide evidence that the Polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 led to the aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.
2018-07-13 | GSE108356 | GEO
Project description:To investigate the functional heterogeneity of astrocytes from a defined brain region, we performed single cell RNA-seq of striatal cells from adult mice (8-9 weeks old). From the analyses, we have identified context-specific changes of striatal astrocytes.
2020-10-01 | GSE156628 | GEO
Project description:To investigate the functional heterogeneity of astrocytes from a defined brain region, we designed 14 experimental manipulations including Huntington's disease models, pathological challenges, ionic and GPCR signaling alterations, and analyzed the transcriptomic profiles of striatal astrocytes. From the analyses, we have identified context-specific changes of striatal astrocytes.
2020-11-17 | GSE153791 | GEO
Project description:To investigate the functional heterogeneity of astrocytes from a defined brain region, we designed 12 experimental manipulations including Huntington's disease models, pathological challenges, ionic and GPCR signaling alterations, and analyzed the transcriptomic profiles of striatal astrocytes. From the analyses, we have identified context-specific changes of striatal astrocytes.
2020-11-17 | GSE143475 | GEO
Project description:Microglia are abundantly distributed throughout the central nervous system (CNS) to play critical roles in neural development and homeostasis, and act as immune sentinels to constantly monitor their surrounding neural environment. Given their high reactivity to brain insults, we hypothesised that the cerebral microenvironment altered by ischemic stroke would significantly impact microglial morphology and function in a spatially dependent manner. To investigate this, we examined regional changes in the expression of genes associated with microglial activation and neuroinflammation, microglial morphology using 3D image reconstruction and unbiased proteomics at 24 hours after transient middle cerebral artery occlusion (tMCAO). We found the microenvironment within the ischaemic infarct core has a distinct pro-inflammatory profile is very different to versus that of the sham-operated controls. , and more importantly this region of the brain displays dynamic and diverse inflammatory changes. Moreover, stroke induces region-specific changes to microglia morphology with those closer to the infarct displaying a more ameboid shape and less complex dendritic processes. Additionally, we identified 108 differentially expressed proteins in microglia that were isolated from the ipsilateral ischaemic hemisphere compared to those isolated from thethat of contralateral hemisphere. These differentially expressed proteins are predicted to influence signalling pathways that mediate TNF-α superfamily cytokine production, chemokine activities and leukocyte chemotaxis and migration. These findings support microglia as critical regulators of the inflammatory signalling after stroke. Mice Adult C57Bl/6J and Cx3cr1gfp/+ (both reporter strains are on C57Bl/6J background) male and female mice were obtained from the Monash Animal Research Platform and were housed at Monash Translational Health Precinct Animal Facility (MHTP-AF, Clayton, VIC, Australia) in specific pathogen-free (SPF) conditions with access to food and water ad libitum. Mice were housed in temperature-controlled rooms (22 °C) under a standard 12 h light-dark cycle. Prior to the start of experiments, mice were acclimatised for a minimum of 7 days before use. All procedures were approved by the Monash Medical Centre Animal Ethics Committee (MMCB/2018/002 and MMCB/2022/22, Monash Medical Centre, Clayton, Victoria, Australia). Middle cerebral artery occlusion (MCAO) surgery The mouse model of ischaemic stroke was performed as previously described (27), whereby infarct is induced in the right cerebral hemisphere. Briefly, mice were anaesthetised by intraperitoneal injection of ketamine (150 mg/kg) and xylazine (10 mg/kg). Once anaesthetised, an incision at the top of the head was made to expose the skull, and a laser Doppler holder (PeriFlux System 5000, Stroke model kit 407, Perimed, Järfälla-Stockholm, Sweden) was glued to the right side of the skull to monitor blood flow above the right hemisphere of the brain. The fur at the site of the neck incision was removed and the area was sterilised with 80 % ethanol. A 1–2-cm incision was made along the midline of the throat to expose the trachea. The right common carotid artery, external carotid artery, and internal carotid artery were dissected away from any connective tissue. A vessel clip was used on the right common carotid artery, and a slit was made in the external carotid artery. A silicone-coated monofilament with a diameter of 0.21–0.23 mm (Doccol Corporation) was immediately inserted into the external carotid artery and advanced into the internal carotid artery to occlude blood flow into the MCA. A successful occlusion was determined by >70% reduction in Doppler reading. The external carotid artery was tied off and the vessel clip removed. In this study, we utilised the reperfused model termed transient MCAO or tMCAO, whereby the monofilament was retracted to allow for reperfusion of blood flow into the MCA following 1 h of occlusion. After successful surgery, the neck incision was sutured closed, the doppler probe removed, and the head incision closed. As a control for surgical stress, sham operations were performed whereby similar surgical protocols were executed without the insertion of the monofilament. After surgery, all mice were allowed to recover overnight on a heat pad.
2025-12-22 | PXD055588 | Pride
Project description:Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences for which there are currently no FDA approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes related to protein folding, mRNA processing, immune signaling, and neurotransmission in striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analysis. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion did not alter methamphetamine-seeking behavior following 21 days of abstinence, highlighting the complexity of drug-seeking behaviors. Taken together, these results suggest that methamphetamine induces both short and long-term changes in striatal microglia that contribute to altered drug-taking behavior and may be leveraged for preclinical development of methamphetamine cessation therapeutics.
2024-06-11 | GSE245951 | GEO
Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.
2024-02-29 | GSE216999 | GEO
Project description:Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naïve microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.
2022-07-01 | GSE201807 | GEO