Simultaneous CRISPR screening and spatial transcriptomics reveal intracellular, intercellular, and functional transcriptional circuits

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

Published: March 1, 2025

Highlights•Perturb-FISH combines spatial transcriptomics and readout of CRISPR perturbation•We recover the effects genetic perturbation on transcriptome single cells•We find specific networks related to cell neighbors in tissue•We connect time-resolved imaging phenotypes after perturbationSummaryPooled optical screens have enabled study cellular interactions, morphology, or dynamics at massive scale, but they not yet leveraged power highly plexed single-cell resolved transcriptomic readouts inform molecular pathways. Here, we present a combination with parallel detection situ amplified guide RNAs (Perturb-FISH). Perturb-FISH recovers intracellular that are consistent RNA-sequencing-based (Perturb-seq) screen lipopolysaccharide response cultured monocytes, it uncovers intercellular density-dependent regulation innate immune response. Similarly, three-dimensional xenograft models, identifies tumor-immune interactions altered by knockout. When paired functional separate autism spectrum disorder risk genes human-induced pluripotent stem (hIPSC) astrocytes, shows common calcium activity their associated dysregulated is thus general method for studying associations biology resolution.Graphical abstract

Language: Английский

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Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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Functional neurogenomics in autism spectrum disorders: A decade of progress

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 86, P. 102858 - 102858

Published: March 27, 2024

Language: Английский

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Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 11, 2024

Oligodendrocytes play a crucial role in our central nervous system (CNS) by myelinating axons for faster action potential conduction, protecting from degeneration, structuring the position of ion channels, and providing nutrients to neurons. Oligodendrocyte dysfunction and/or dysmyelination can contribute range neurodegenerative diseases neuropsychiatric disorders such as Multiple Sclerosis (MS), Leukodystrophy (LD), Schizophrenia (SCZ), Autism Spectrum Disorder (ASD). Common characteristics identified across these were either an inability oligodendrocytes remyelinate after degeneration or defects oligodendrocyte development maturation. Unfortunately, causal mechanisms are still uncertain, therapeutic targets remain elusive. Many studies rely on use animal models identify molecular cellular behind disorders, however, face species-specific challenges therefore lack translatability. The human induced pluripotent stem cells (hiPSCs) model neurological is becoming powerful new tool, improving understanding pathophysiology capacity explore targets. Here, we focus application hiPSC-derived systems caused dysregulation.

Language: Английский

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Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons are embedded in distinct information processing pathways. Their morphology, connectivity, electrophysiological properties, role behavior have been extensively analyzed. However, the molecular composition of their synapses remains largely uncharacterized. Here, we dissect protein excitatory postsynaptic compartment mouse L5 intact somatosensory circuits, using an optimized proximity biotinylation workflow with high spatial accuracy. We find synaptic signatures IT PT that defined by proteins regulating organization transmission, including cell-surface (CSPs), neurotransmitter receptors ion channels. In addition, a differential vulnerability to disease, marked enrichment autism risk genes signature compared neurons. These results align human studies suggest is susceptible autism. Our approach versatile can be broadly applied other neuron types create protein-based, atlas cortical circuits. Authors use proteomics reporting disease vulnerabilities.

Language: Английский

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Astrocytic-supplied cholesterol drives synaptic gene expression programs in developing neurons and downstream astrocytic transcriptional programs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Astrocytes participate in neuronal synaptic programs that are enriched for genetic associations schizophrenia and autism spectrum disorders (ASD). To better understand how these co-regulated cellular induced during early development, we studied astrocytes iPSC-derived neurons co-cultures mono-cultures at 16 time points spanning 0.5 hours to 8 days. We found upregulation of genes involved cholesterol biosynthesis preceded the activation gene astrocytic Nrxn1 . Neuronal knockdown key receptors led downregulation a robust transcriptional response astrocytes, including further This suggests astrocyte-supplied drives changes bi-directional signalling is occuring. The upregulated were deleterious variants neurodevelopmental disorders, suggesting their pathogenic effect may be, part, mediated by reduced buffering capacity astrocyte supply neurons. These findings highlight critical role astrocyte-neuron interactions psychiatric particularly relation lipid metabolism plasticity.

Language: Английский

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Single-cell technology grows up: Leveraging high-resolution omics approaches to understand neurodevelopmental disorders

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 102990 - 102990

Published: March 3, 2025

Language: Английский

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A practical guide for single-cell transcriptome data analysis in neuroscience

Neuroscience Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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The single-cell opioid responses in the context of HIV (SCORCH) consortium

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(12), P. 3950 - 3961

Published: June 15, 2024

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families communities. One seminal challenges in treating studying human populations is high prevalence co-morbid conditions, including an increased risk contracting a immunodeficiency virus (HIV) infection. Of ~15 million people who inject drugs globally, 17% persons HIV. Conversely, HIV factor for SUD because chronic pain syndromes, often encountered HIV, can lead opioid medications that turn increase addiction. We hypothesize exert shared effects on brain cell types, adaptations related neuroplasticity, neurodegeneration, neuroinflammation. Basic research needed refine our understanding these affected types adaptations. Studying context at single-cell level represents compelling strategy understand reciprocal interactions among both made feasible by availability large, extensively-phenotyped tissue collections have been amassed Neuro-HIV community. In addition, sophisticated animal models developed conditions provide means precisely evaluate specific exposures stages disease. propose genomics uniquely powerful technology characterize brain, integrating data from cohorts models. formed Single-Cell Opioid Responses Context (SCORCH) consortium carry out this strategy.

Language: Английский

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The gut microbiota–oligodendrocyte axis: A promising pathway for modulating oligodendrocyte homeostasis and demyelination-associated disorders

Life Sciences, Journal Year: 2024, Volume and Issue: 354, P. 122952 - 122952

Published: Aug. 9, 2024

The bidirectional regulation between the gut microbiota and brain, known as gut-brain axis, has received significant attention. myelin sheath, produced by oligodendrocytes or Schwann cells, is essential for efficient nervous signal transmission maintenance of brain function. Growing evidence shows that both oligodendrogenesis myelination are modulated its metabolites, when dysbiosis occurs, changes in composition and/or associated metabolites may impact developmental occurrence neurodevelopmental disabilities. Although link demyelinating disease such multiple sclerosis been extensively studied, our knowledge about role other myelin-related disorders, neurodegenerative diseases, limited. Mechanistically, microbiota-oligodendrocyte axis primarily mediated factors inflammation, vagus nerve, endocrine hormones, evidenced metagenomics, metabolomics, vagotomy, morphological molecular approaches. Treatments targeting this include probiotics, prebiotics, microbial herbal bioactive compounds, specific dietary management. In addition to commonly used approaches, viral vector-mediated tracing gene manipulation, integrated multiomics multicenter clinical trials will greatly promote mechanistic interventional studies ultimately, development new preventive therapeutic strategies against gut-oligodendrocyte axis-mediated impairments. Interestingly, recent findings showed can be induced hippocampal damage reversible myelin-targeted drugs, which provides insights into understanding how hippocampus-based functional impairment (such Alzheimer's disease) regulates peripheral homeostasis systemic disorders.

Language: Английский

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