A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

Nature, Год журнала: 2023, Номер 624(7991), С. 317 - 332

Опубликована: Дек. 13, 2023

The mammalian brain consists of millions to billions cells that are organized into many cell types with specific spatial distribution patterns and structural functional properties1-3. Here we report a comprehensive high-resolution transcriptomic cell-type atlas for the whole adult mouse brain. was created by combining single-cell RNA-sequencing (scRNA-seq) dataset around 7 million profiled (approximately 4.0 passing quality control), approximately 4.3 using multiplexed error-robust fluorescence in situ hybridization (MERFISH). is hierarchically 4 nested levels classification: 34 classes, 338 subclasses, 1,201 supertypes 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, visualize whole-brain along MERFISH datasets. systematically analysed neuronal non-neuronal across identified high degree correspondence between identity specificity each type. results reveal unique features organization different regions-in particular, dichotomy dorsal ventral parts part contains relatively fewer yet highly divergent types, whereas more numerous closely related other. Our study also uncovered extraordinary diversity heterogeneity neurotransmitter neuropeptide expression co-expression types. Finally, found transcription factors major determinants classification combinatorial factor code defines all establishes benchmark reference foundational resource integrative investigations cellular circuit function, development evolution

Язык: Английский

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Transforming the understanding of brain immunity

Science, Год журнала: 2023, Номер 380(6640)

Опубликована: Апрель 6, 2023

Contemporary studies have completely changed the view of brain immunity from envisioning as isolated and inaccessible to peripheral immune cells an organ in close physical functional communication with system for its maintenance, function, repair. Circulating reside special niches brain's borders, choroid plexus, meninges, perivascular spaces, which they patrol sense a remote manner. These niches, together meningeal lymphatic skull microchannels, provide multiple routes interaction between system, addition blood vasculature. In this Review, we describe current ideas about their implications aging, diseases, immune-based therapeutic approaches.

Язык: Английский

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Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Nature, Год журнала: 2023, Номер 622(7981), С. 120 - 129

Опубликована: Сен. 6, 2023

Abstract Multimodal astrocyte–neuron communications govern brain circuitry assembly and function 1 . For example, through rapid glutamate release, astrocytes can control excitability, plasticity synchronous activity 2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions 4–7 communicate fast focal they should possess an apparatus for Ca 2+ -dependent exocytosis similar neurons 8–10 However, the existence this mechanism has been questioned 11–13 owing inconsistent data 14–17 a lack direct supporting evidence. Here we revisited astrocyte hypothesis by considering emerging molecular heterogeneity 18–21 using molecular, bioinformatic imaging approaches, together with cell-specific genetic tools that interfere vivo. By analysing existing single-cell RNA-sequencing databases our patch-seq data, identified nine molecularly distinct clusters hippocampal astrocytes, among which found notable subpopulation selectively expressed synaptic-like glutamate-release machinery localized discrete sites. Using GluSnFR-based 22 situ vivo, corresponding subgroup responds reliably astrocyte-selective stimulations subsecond release events at spatially precise hotspots, were suppressed astrocyte-targeted deletion vesicular transporter (VGLUT1). Furthermore, or its isoform VGLUT2 revealed specific contributions glutamatergic cortico-hippocampal nigrostriatal circuits during normal behaviour pathological processes. uncovering atypical specialized adult brain, provide insights into complex roles central nervous system (CNS) physiology diseases, identify potential therapeutic target.

Язык: Английский

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Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration

Nature Metabolism, Год журнала: 2023, Номер 5(3), С. 445 - 465

Опубликована: Март 23, 2023

Язык: Английский

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Neuroinflammation: An astrocyte perspective

Science Translational Medicine, Год журнала: 2023, Номер 15(721)

Опубликована: Ноя. 8, 2023

Astrocytes are abundant glial cells in the central nervous system (CNS) that play active roles health and disease. Recent technologies have uncovered functional heterogeneity of astrocytes their extensive interactions with other cell types CNS. In this Review, we highlight intricate between astrocytes, CNS-resident cells, CNS-infiltrating as well potential therapeutic value context inflammation neurodegeneration.

Язык: Английский

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A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 6, 2023

The mammalian brain is composed of millions to billions cells that are organized into numerous cell types with specific spatial distribution patterns and structural functional properties. An essential step towards understanding function obtain a parts list, i.e., catalog types, the brain. Here, we report comprehensive high-resolution transcriptomic type atlas for whole adult mouse was created based on combination two single-cell-level, whole-brain-scale datasets: single-cell RNA-sequencing (scRNA-seq) dataset ~7 million profiled, spatially resolved ~4.3 using MERFISH. hierarchically five nested levels classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes 5,200 clusters. We systematically analyzed neuronal, non-neuronal, immature neuronal across identified high degree correspondence between identity specificity each type. results reveal unique features organization in different regions, particular, dichotomy dorsal ventral brain: part contains relatively fewer yet highly divergent whereas more closely related other. also characterized cell-type expression neurotransmitters, neuropeptides, transcription factors. study uncovered extraordinary diversity heterogeneity neurotransmitter neuropeptide co-expression brain, suggesting they mediate myriad modes intercellular communications. Finally, found factors major determinants classification combinatorial factor code defines all whole-mouse-brain establishes benchmark reference foundational resource deep integrative investigations circuit function, development, evolution

Язык: Английский

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Astrocyte–neuron subproteomes and obsessive–compulsive disorder mechanisms

Nature, Год журнала: 2023, Номер 616(7958), С. 764 - 773

Опубликована: Апрель 12, 2023

Astrocytes and neurons extensively interact in the brain. Identifying astrocyte neuron proteomes is essential for elucidating protein networks that dictate their respective contributions to physiology disease. Here we used cell-specific subcompartment-specific proximity-dependent biotinylation1 study of striatal astrocytes vivo. We evaluated cytosolic plasma membrane compartments discover how these cells differ at level signalling machinery. also assessed subcellular astrocytes, including end feet fine processes, reveal subproteomes molecular basis homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which associated with obsessive-compulsive disorder (OCD) repetitive behaviours2-8, was detected high levels enriched within specific subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined behavioural analyses assessments a mouse model OCD4 lacking revealed distinct astrocytic neuronal anxiety-related OCD-like phenotypes. Our data define major pathways. Moreover, they vary between physiological both mechanisms contribute OCD phenotypes mice. indicate therapeutic strategies target may be useful explore potentially other brain disorders.

Язык: Английский

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A concerted neuron–astrocyte program declines in ageing and schizophrenia

Nature, Год журнала: 2024, Номер 627(8004), С. 604 - 611

Опубликована: Март 6, 2024

Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions for synthesizing cholesterol, an astrocyte-supplied component membranes. call this neuron astrocyte program (SNAP). In schizophrenia ageing—two conditions that involve declines cognitive flexibility plasticity 1,2 —cells divested from SNAP: astrocytes, glutamatergic (excitatory) GABAergic (inhibitory) all showed reduced SNAP expression corresponding degrees. The astrocytic neuronal components both involved which genetic risk factors were concentrated. SNAP, varies quantitatively even among similar age, may underlie many aspects normal interindividual differences be important point convergence multiple kinds pathophysiology.

Язык: Английский

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Spatial transcriptomics reveal neuron–astrocyte synergy in long-term memory

Nature, Год журнала: 2024, Номер 627(8003), С. 374 - 381

Опубликована: Фев. 7, 2024

Abstract Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has key role in long-term fear memory formation 1 . Here we used spatial single-cell transcriptomics to illuminate the cellular molecular architecture memory. We identified transcriptional signatures subpopulations neurons astrocytes were memory-specific persisted for weeks. These implicate neuropeptide BDNF signalling, MAPK CREB activation, ubiquitination pathways, synaptic connectivity as components Notably, upon formation, neuronal subpopulation defined by increased Penk decreased Tac expression constituted most prominent component engram amygdala. changes observed both with RNA sequencing single-molecule intact slices, providing rich map engram. data enabled us determine this interacts adjacent astrocytes, functional experiments show require interactions encode

Язык: Английский

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Astrocyte morphology

Trends in Cell Biology, Год журнала: 2023, Номер 34(7), С. 547 - 565

Опубликована: Окт. 26, 2023

Astrocytes are predominant glial cells that tile the central nervous system (CNS). A cardinal feature of astrocytes is their complex and visually enchanting morphology, referred to as bushy, spongy, star-like. precept this review such morphological shapes evolved allow contact signal with diverse at a range distances in order sample, regulate, contribute extracellular milieu, thus participate widely cell–cell signaling during physiology disease. The recent use improved imaging methods cell-specific molecular evaluations has revealed new information on structural organization underpinnings astrocyte mechanisms morphogenesis, contributions disease states reduced morphology. These insights have reignited interest complexity cornerstone fundamental biology critical substrate for multicellular spatial physiological interactions CNS.

Язык: Английский

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