Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain

Neuron, Год журнала: 2021, Номер 109(19), С. 3088 - 3103.e5

Опубликована: Сен. 27, 2021

Язык: Английский

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Quantifying the effect of experimental perturbations at single-cell resolution

Nature Biotechnology, Год журнала: 2021, Номер 39(5), С. 619 - 629

Опубликована: Фев. 8, 2021

Язык: Английский

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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

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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

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Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens

Neuropsychopharmacology, Год журнала: 2020, Номер 45(9), С. 1423 - 1430

Опубликована: Март 20, 2020

Oxytocin is currently being considered as a novel therapeutic for anxiety disorders due to its ability promote affiliative behaviors. In the nucleus accumbens (NAc) activation of oxytocin receptors (OTR) promotes social approach (time spent near an unfamiliar individual). Here, we show that stressful experiences reduce expression NAc OTR mRNA, coinciding with decreases in approach. Social stressors also increase vigilance, characterized orienting individual without approaching. Vigilance key component behavioral inhibition, personality trait risk factor disorders. To understand whether can modulate both and use pharmacological approaches assess impact or inhibition downstream pathways on these First, unstressed male female California mice, by unbiased antagonist (L-368,899) reduces but does not induce vigilance. Next, infusion Atosiban, OTR-Gq antagonist/OTR-Gi agonist, has same effect females. Finally, Carbetocin, biased increases stressed females while simultaneously inhibiting Taken together data suggest differentially primarily through mechanism. Importantly, alone insufficient vigilance suggesting mechanisms modulating may be distinct from

Язык: Английский

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Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens

Molecular Psychiatry, Год журнала: 2021, Номер 27(1), С. 687 - 709

Опубликована: Июнь 2, 2021

Язык: Английский

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Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum

Current Biology, Год журнала: 2021, Номер 31(24), С. 5473 - 5486.e6

Опубликована: Ноя. 1, 2021

Язык: Английский

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Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine

Neuropsychopharmacology, Год журнала: 2021, Номер 46(13), С. 2358 - 2370

Опубликована: Авг. 16, 2021

Язык: Английский

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The Signaling and Pharmacology of the Dopamine D1 Receptor

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Янв. 17, 2022

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, cognitive processes. Although D1R was initially identified as promising drug target almost 40 years ago, development of clinically useful ligands has until recently been hampered by lack suitable candidate molecules. emergence new non-catechol agonists, biased allosteric modulators renewed clinical interest drugs targeting this receptor, specifically for treatment impairment Parkinson's Disease, neuropsychiatric disorders. To develop better therapeutics, advances ligand chemistry must be matched an expanded understanding signaling across cell populations brain, disease states. Depending on brain region, couples primarily to either Gαs or Gαolf through which it activates cAMP/PKA-dependent cascade can regulate neuronal excitability, stimulate gene expression, facilitate synaptic plasticity. However, like many GPCRs, signal multiple downstream pathways, specific signatures may differ between types altered disease. guide improved ligands, important understand how unfolds cells, affects circuit function behavior. In review, we provide summary D1R-directed various describe pathways have linked physiological behavioral outcomes. addition, address current state development, including pharmacology newly developed non-catecholamine discuss potential utility D1R-agonists Disease impairment.

Язык: Английский

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Cell-type specific changes in PKC-delta neurons of the central amygdala during alcohol withdrawal

Translational Psychiatry, Год журнала: 2022, Номер 12(1)

Опубликована: Июль 20, 2022

The central amygdala (CeA) contains a diverse population of cells, including multiple subtypes GABAergic neurons, along with glia and epithelial cells. Specific CeA cell types have been shown to affect alcohol consumption in animal models dependence may be involved negative during withdrawal. We used single-nuclei RNA sequencing determine cell-type specificity differential gene expression the induced by Cells within were classified using unbiased clustering analyses identified based on known marker genes. Differential analysis was performed each cell-type. It revealed astrocytes neurons associated further subclassified into 13 clusters Analyzing transcriptomic responses these subclusters that exposure differentially expressed genes one subtype protein kinase C delta (PKCδ) expressing neurons. These results suggest PKCδ uniquely sensitive effects identify novel cells

Язык: Английский

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