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

---

Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans

Neuron, Год журнала: 2021, Номер 109(13), С. 2091 - 2105.e6

Опубликована: Май 28, 2021

Язык: Английский

---

Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder

Biological Psychiatry, Год журнала: 2021, Номер 90(8), С. 550 - 562

Опубликована: Июнь 12, 2021

BackgroundPrevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge overdose deaths. While dependence has been extensively studied in preclinical models, an understanding the biological alterations that occur brains people who chronically opioids and are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on dorsolateral prefrontal cortex nucleus accumbens, regions heavily implicated OUD, from postmortem subjects OUD.MethodsWe performed accumbens unaffected comparison (n = 20) 20). Our transcriptomic analyses identified differentially expressed transcripts investigated transcriptional coherence between brain using rank-rank hypergeometric orderlap. Weighted gene coexpression OUD-specific modules networks. Integrative genome-wide association study datasets linkage disequilibrium scores assessed genetic liability psychiatric-related phenotypes OUD.ResultsRank-rank overlap revealed extensive related to synaptic remodeling neuroinflammation. Identified were enriched for factors control proinflammatory cytokine, chondroitin sulfate, extracellular matrix signaling. Cell-type deconvolution role microglia as potential driver opioid-induced neuroplasticity. Linkage score analysis suggested liabilities risky behavior, attention-deficit/hyperactivity disorder, depression OUD.ConclusionsOverall, our findings suggest connections brain's immune system human brain.

Язык: Английский

---

An atlas of transcriptionally defined cell populations in the rat ventral tegmental area

Cell Reports, Год журнала: 2022, Номер 39(1), С. 110616 - 110616

Опубликована: Апрель 1, 2022

The ventral tegmental area (VTA) is a complex brain region that essential for reward function and frequently implicated in neuropsychiatric disease. While decades of research on VTA have focused dopamine neurons, recent evidence has identified critical roles GABAergic glutamatergic neurons processes. Additionally, although subsets express genes involved the synthesis transport multiple neurotransmitters, characterization these combinatorial populations largely relied low-throughput methods. To comprehensively define molecular architecture VTA, we performed single-nucleus RNA sequencing 21,600 cells from rat VTA. Analysis neuronal subclusters identifies selective markers reveals expression profiles receptors targeted by drugs abuse, demonstrates population-specific enrichment gene sets linked to disorders. These results highlight heterogeneity provide resource further exploration expression.

Язык: Английский

---

Automatic cell-type harmonization and integration across Human Cell Atlas datasets

Cell, Год журнала: 2023, Номер 186(26), С. 5876 - 5891.e20

Опубликована: Дек. 1, 2023

Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building standardized Human Cell Atlas. Here, we present CellHint, predictive clustering tree-based tool resolve cell-type differences in annotation resolution technical biases datasets. CellHint accurately quantifies cell-cell transcriptomic similarities places relationship graph that hierarchically defines shared unique subtypes. Application multiple immune datasets recapitulates expert-curated annotations. also reveals underexplored relationships between healthy diseased lung states eight diseases. Furthermore, workflow for fast cross-dataset integration guided by harmonized hierarchy, which uncovers underappreciated adult human hippocampus. Finally, apply 12 tissues from 38 datasets, providing deeply curated cross-tissue database with ∼3.7 million cells various machine learning models automatic tissues.

Язык: Английский

---

Neuronal ambient RNA contamination causes misinterpreted and masked cell types in brain single-nuclei datasets

Neuron, Год журнала: 2022, Номер 110(24), С. 4043 - 4056.e5

Опубликована: Окт. 13, 2022

Язык: Английский

---

The gut microbiome modulates the transformation of microglial subtypes

Molecular Psychiatry, Год журнала: 2023, Номер 28(4), С. 1611 - 1621

Опубликована: Март 13, 2023

Abstract Clinical and animal studies have shown that gut microbiome disturbances can affect neural function behaviors via the microbiota–gut–brain axis, may be implicated in pathogenesis of several brain diseases. However, exactly how modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize cell type–specific transcriptomic changes prefrontal cortex hippocampus derived from germ-free (GF), specific pathogen free, colonized-GF mice. We found absence microbiota resulted cell-specific changes. Furthermore, microglia transcriptomes were preferentially influenced, which could effectively reversed by microbial colonization. Significantly, modulated mutual transformation microglial subpopulations two regions. Cross-species analysis showed transcriptome these mainly associated with Alzheimer’s disease (AD) major depressive disorder (MDD), further supported behavioral tests. Our findings demonstrate modulate subtypes, lead new insights into AD MDD.

Язык: Английский

---

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Science Advances, Год журнала: 2023, Номер 9(6)

Опубликована: Фев. 10, 2023

Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal financial costs on patients society. Sharp increases in cocaine drive the urgent need for better mechanistic insight into this chronic relapsing brain currently lacks effective treatment options. To investigate transcriptomic changes involved, we conducted RNA sequencing two striatal regions are heavily implicated CUD, nucleus accumbens caudate nucleus, from men suffering CUD matched controls. Weighted gene coexpression analyses identified CUD-specific networks enriched ionotropic receptors linked to lowered neuroinflammation, contrasting proinflammatory responses found opioid disorder. Integration of comprehensive datasets mouse self-administration models revealed evolutionarily conserved implicate especially D1 medium spiny neurons as drivers cocaine-induced plasticity.

Язык: Английский

---

Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate?

Neuron, Год журнала: 2023, Номер 111(11), С. 1714 - 1731.e3

Опубликована: Апрель 3, 2023

The notion of exploiting the regenerative potential human brain in physiological aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing restoring function. However, major first question address is whether does possess ability regenerate. existence adult hippocampal neurogenesis (AHN) has been at center fierce scientific debate many years. advent single-cell transcriptomic technologies was initially viewed as panacea resolving this controversy. recent RNA sequencing studies hippocampus yielded conflicting results. Here, we critically discuss and re-analyze previously published AHN-related datasets. We argue that, although promising, profiling AHN can be confounded by methodological, conceptual, biological factors that need consistently addressed across openly discussed within community.

Язык: Английский

---

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

Science, Год журнала: 2024, Номер 384(6693)

Опубликована: Апрель 18, 2024

Drugs of abuse are thought to promote addiction in part by “hijacking” brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and vivo single-neuron calcium imaging, we found that drugs augment dopaminoceptive ensemble activity nucleus accumbens (NAc) disorganize overlapping responses natural rewards a cell type–specific manner. Combining FOS-Seq, CRISPR-perturbation, single-nucleus RNA sequencing, identified Rheb as molecular substrate regulates signal transduction NAc while enabling suppress consumption. Mapping NAc-projecting regions activated revealed input-specific effects on These findings characterize dynamic, circuit basis common pathway, wherein interfere with fulfillment innate needs.

Язык: Английский

---