Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions DOI Creative Commons
Junchen Yang, Kriti Agrawal, Jay S. Stanley

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 8, 2025

Abstract HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map transcriptomic epigenetic landscapes of postmortem human brains from 13 healthy individuals 20 with who have a history treatment ART. Our study spanned three distinct regions—the prefrontal cortex, insular ventral striatum—enabling comprehensive exploration region-specific cross-regional perturbations. We found widespread persistent HIV-associated transcriptional alterations across multiple cell types. Detailed analyses microglia revealed state changes marked by immune activation metabolic dysregulation, while integrative multiomic profiling astrocytes identified subpopulations, including reactive subpopulation unique HIV-infected brains. These findings suggest cells people exhibit molecular shifts may underlie ongoing neuroinflammation CNS dysfunction. Furthermore, cell–cell communication uncovered dysregulated pro-inflammatory interactions among glial populations, underscoring multifaceted enduring impact brain milieu. Collectively, our atlas reveals states signatures signaling providing framework for developing targeted therapies neurological

Язык: Английский

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need DOI
Bowen Tan, Caleb J. Browne, Tobias Nöbauer

и другие.

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

Процитировано

30
Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder DOI Creative Commons
BaDoi N. Phan, Madelyn H. Ray, Xiangning Xue

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 31, 2024

Abstract In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction linked to psychiatric disorders, including opioid use disorder (OUD). subregions are divided based on neuroanatomy, each with unique roles OUD. OUD, dorsal altered processing, formation of habits, development negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) less abundant cell populations interneurons) human striatum. Pathways related neurodegeneration, interferon response, DNA damage were significantly enriched striatal neurons individuals markers also elevated opioid-exposed rhesus macaques. Sex-specific molecular differences glial subtypes associated chronic stress found particularly female individuals. Together, describe different types identify type-specific alterations

Язык: Английский

Процитировано

18
Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits DOI Creative Commons
Avery C. Hunker, Morgan Wirthlin,

Gursajan Gill

и другие.

Neuron, Год журнала: 2025, Номер 113(10), С. 1507 - 1524.e17

Опубликована: Май 1, 2025

We present an enhancer-AAV toolbox for accessing and perturbing striatal cell types circuits. Best-in-class vectors were curated major neuron populations including medium spiny neurons (MSNs), direct- indirect-pathway MSNs, Sst-Chodl, Pvalb-Pthlh, cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes virus delivery, with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell-type-specific labeling under experimental contexts. demonstrate direct pathway circuit-selective optogenetic perturbation behavior multiplex interneuron targeted analysis cellular features. Lastly, show conserved in vivo activity exemplary MSN enhancers rats macaques. This collection enhancer AAVs offers greater versatility compared available transgenic lines can readily be applied type circuit studies mammalian species beyond the mouse model.

Язык: Английский

Процитировано

3
Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease DOI Creative Commons
A. Matsushima, S. Sebastian Pineda, Jill R. Crittenden

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 17, 2023

Abstract Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and striosome-matrix compartmentation. It is well established that indirect-pathway SPNs susceptible to neurodegeneration transcriptomic disturbances, but less known about how axis compromised HD relation axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 patient post-mortem brain samples zQ175 R6/2 mouse models, axes multiplexed differentially HD. In HD, striosomal most depleted SPN population. distinctiveness of diminished more than SPNs. Furthermore, loss distinction prominent within These results open possibility compartments late early stages progression, respectively, contributing symptoms, thus calling for distinct therapeutic strategies.

Язык: Английский

Процитировано

41
Distinct subpopulations of D1 medium spiny neurons exhibit unique transcriptional responsiveness to cocaine DOI Creative Commons
Robert A. Phillips, Jennifer J. Tuscher, N. Dalton Fitzgerald

и другие.

Molecular and Cellular Neuroscience, Год журнала: 2023, Номер 125, С. 103849 - 103849

Опубликована: Март 24, 2023

Drugs of abuse increase extracellular concentrations dopamine in the nucleus accumbens (NAc), resulting transcriptional alterations that drive long-lasting cellular and behavioral adaptations. While decades research have focused on mechanisms by which drugs influence neuronal physiology function, few studies comprehensively defined NAc cell type heterogeneity responses to abuse. Here, we used single RNA-seq (snRNA-seq) characterize transcriptome over 39,000 cells from male female adult Sprague-Dawley rats following acute or repeated cocaine experience. This dataset identified 16 transcriptionally distinct populations, including two populations medium spiny neurons (MSNs) express Drd1 receptor (D1-MSNs). Critically, while both expressed classic marker genes D1-MSNs, only one population exhibited a robust response cocaine. Validation population-selective transcripts using RNA situ hybridization revealed spatial compartmentalization these D1-MSN within NAc. Finally, analysis published snRNA-seq datasets non-human primates humans demonstrated conservation MSN subtypes across rat higher order mammals, further highlighted type-specific differences broader striatum. These results highlight utility provides useful resource for cross-species comparisons composition.

Язык: Английский

Процитировано

41
Striosomes and Matrisomes: Scaffolds for Dynamic Coupling of Volition and Action DOI Creative Commons
Ann M. Graybiel, A. Matsushima

Annual Review of Neuroscience, Год журнала: 2023, Номер 46(1), С. 359 - 380

Опубликована: Апрель 18, 2023

Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up modules called matrisomes. Striosome-matrix architecture is multiplexed with canonical direct-indirect organization striatum. Striosomal functions remain to be fully clarified, but key information emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, following rebound excitation. Second, receive limbic cognition-related corticostriatal afferents are dynamically modulated relation value-based actions. Third, spatially interspersed among matrisomes interneurons influenced by local global neuromodulatory oscillatory activities. Fourth, tune engagement motivation perform reinforcement learning, manifest stereotypical behaviors, navigate valence conflicts discriminations. We suggest that, at an algorithmic level, could serve as distributed scaffolds provide formats striatal computations generated through development refined learning. propose that affect subjective states. By transforming corticothalamic other inputs functional striatum, they implement state transitions nigro-striato-nigral circuits bodily cognitive actions according internal motives whose compromised neuropsychiatric conditions.

Язык: Английский

Процитировано

28
Human striatal glia differentially contribute to AD- and PD-specific neurodegeneration DOI
Jinbin Xu,

Huifangjie L. Farsad,

Yiran Hou

и другие.

Nature Aging, Год журнала: 2023, Номер unknown

Опубликована: Фев. 9, 2023

Язык: Английский

Процитировано

25
Vocal learning–associated convergent evolution in mammalian proteins and regulatory elements DOI
Morgan Wirthlin, Tobias A. Schmid, Julie E. Elie

и другие.

Science, Год журнала: 2024, Номер 383(6690)

Опубликована: Фев. 29, 2024

Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (

Язык: Английский

Процитировано

14
Transcriptomic characterization of human lateral septum neurons reveals conserved and divergent marker genes across species DOI Creative Commons
Robert A. Phillips, Seyun Oh, Svitlana V. Bach

и другие.

iScience, Год журнала: 2025, Номер 28(2), С. 111820 - 111820

Опубликована: Янв. 18, 2025

The lateral septum (LS) is a midline, subcortical structure that critical regulator of social behaviors. Mouse studies have identified molecularly distinct neuronal populations within the LS, which control specific facets behavior. Despite its known molecular heterogeneity in mouse and role regulating behavior, comprehensive profiling human LS has not been performed. Here, we conducted single-nucleus RNA sequencing (snRNA-seq) to generate transcriptomic profiles compared recently collected snRNA-seq datasets. Our analyses TRPC4 as conserved marker while FREM2 enriched only LS. We also identify cell type marked by OPRM1, gene encoding μ-opioid receptor. Together, these results highlight transcriptional robust genes for

Язык: Английский

Процитировано

2
Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition DOI Creative Commons
Jessica Zhou, Giordano de Guglielmo,

Aaron J. Ho

и другие.

Nature Neuroscience, Год журнала: 2023, Номер 26(11), С. 1868 - 1879

Опубликована: Окт. 5, 2023

Abstract The amygdala processes positive and negative valence contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus expression chromatin accessibility in outbred rats with high low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between groups were enriched for energy metabolism across cell types. Rats addiction index (AI) showed increased relapse-like GABAergic transmission amygdala. Both phenotypes reversed by pharmacological inhibition glyoxalase 1 enzyme, which metabolizes methylglyoxal—a GABA A receptor agonist produced glycolysis. Differences AI implicated pioneer transcription factors basic helix-loop-helix, FOX, SOX activator protein families. observed opposite regulation many Most notably, excitatory neurons had greater inhibitory rats.

Язык: Английский

Процитировано

18