Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 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

Language: Английский

---

Striosomes and Matrisomes: Scaffolds for Dynamic Coupling of Volition and Action

Annual Review of Neuroscience, Journal Year: 2023, Volume and Issue: 46(1), P. 359 - 380

Published: April 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.

Language: Английский

---

Interneuron diversity in the human dorsal striatum

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 22, 2024

Abstract Deciphering the striatal interneuron diversity is key to understanding basal ganglia circuit and untangling complex neurological psychiatric diseases affecting this brain structure. We performed snRNA-seq spatial transcriptomics of postmortem human caudate nucleus putamen samples elucidate abundance populations their inherent transcriptional structure in dorsal striatum. propose a comprehensive taxonomy interneurons with eight main classes fourteen subclasses, providing full transcriptomic identity expression profile as well additional quantitative FISH validation for specific populations. have also delineated correspondence our previous standardized classifications shown class differences between putamen. Notably, based on functional genes such ion channels synaptic receptors, we found matching known mouse most abundant populations, recently described PTHLH TAC3 interneurons. Finally, were able integrate other published datasets ours, supporting generalizability harmonized taxonomy.

Language: Английский

---

Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3733 - 3733

Published: March 27, 2024

-methyl-d-aspartate receptors (NMDARs) are the main class of ionotropic for excitatory neurotransmitter glutamate. They play a crucial role in permeability Ca

Language: Английский

---

Compensation between FOXP transcription factors maintains proper striatal function

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114257 - 114257

Published: May 1, 2024

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations regulatory transcription factors expressed SPNs can result neurodevelopmental disorders (NDDs). Paralogous Foxp1 Foxp2, which both dopamine receptor 1 (D1) expressing SPNs, known have variants implicated NDDs. Utilizing mice with a D1-SPN-specific loss Foxp1, or combination behavior, electrophysiology, cell-type-specific genomic analysis, genes results impaired social behavior as well increased firing D1-SPNs. Differential gene expression analysis implicates involved autism risk, electrophysiological properties, neuronal development function. Viral-mediated re-expression into double knockouts is sufficient restore behavioral deficits. These data indicate complementary roles between Foxp2

Language: Английский

---

Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 1, 2023

Abstract Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether associations are due to changes in cell numbers and/or per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) examine proportions transcriptomes four regions, each from 12 donors aged 20-30 years (young) or 60-85 (old). We sampled 155,192 nuclei two cortical regions (entorhinal cortex middle temporal gyrus) subcortical (putamen subventricular zone) relevant diseases the proliferative niche. found no cellular composition of healthy aging. Surprisingly, did find region has distinct aging signature, only minor overlap differentially associated genes Moreover, type shows age-associated changes, loss protein synthesis inhibitory neurons, axonogenesis excitatory neurons oligodendrocyte precursor cells, enhanced gliosis markers astrocytes disease-associated microglia, critical for neuron-glia communication. Importantly, type-specific enrichments nominated by disease genome-wide association (GWAS), such as apolipoprotein E ( APOE ), leucine-rich repeat kinase 2 LRRK2 ) microglia independent overall levels types. present data new resource which highlights, first, region- transcriptomic may contribute selective vulnerability and, second, provide context testing GWAS-nominated subtypes developing more targeted therapeutic strategies. The readily accessible without requirement extensive computational support public website, https://brainexp-hykyffa56a-uc.a.run.app/ Graphical *Created using Biorender.com Highlights Establishment atlas human Each exhibits unique aging-associated transcriptome signature Gene occur absence overt categorically types Neurological patterns specific

Language: Английский

---

Postmortem neuropathology in early Huntington disease

Journal of Neuropathology & Experimental Neurology, Journal Year: 2024, Volume and Issue: 83(5), P. 294 - 306

Published: March 29, 2024

Abstract Two aspects of the neuropathology early Huntington disease (HD) are examined. Neurons neostriatum counted to determine relative loss in striosomes versus matrix at stages, including for first time preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes HD from mimic disorders postmortem brains. Counts striatal projection neurons (SPNs) defined by calbindin immunohistochemistry counts surrounding reported 8 Vonsattel grade 0 (including 5 premanifest), 1, 2 HD, and control Mean striosome SPNs were significantly lower premanifest controls, with than matrix. In 1 brains, no higher SPN observed. Comparing dorsal ventral neostriatum, declined more ventral, making clear importance dorsoventral site tissue selection research studies. A characteristic pattern expanded polyglutamine-immunopositive inclusions was seen all Inclusions always present some pontine nucleus absent Purkinje cells, which showed obvious cell loss.

Language: Английский

---

Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits

Current Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

---

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Brain, Journal Year: 2023, Volume and Issue: 146(11), P. 4532 - 4546

Published: Aug. 17, 2023

Abstract Cortical cell loss is a core feature of Huntington’s disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it unclear how genetic topography relates to cortical loss. Here, we explore biological processes and types underlying this relationship validate these using cell-specific post-mortem data. Eighty participants on average 15 from onset 71 controls were included. Using volumetric diffusion MRI extracted HD-specific whole brain maps where lower grey matter volume higher mean diffusivity, relative controls, used as proxies These combined with gene expression data Allen Human Brain Atlas (AHBA) investigate relating was positively correlated developmental genes (i.e. greater atrophy increased diffusivity) negatively synaptic metabolic that have been implicated in neurodegeneration. findings consistent for maps. As wild-type huntingtin known play role neurodevelopment, explored association between (HTT) across AHBA. Co-expression network analyses 134 human brains free neurodegenerative disorders also performed. HTT involved neurodevelopment while co-expression revealed associated processes. Expression weighted cell-type enrichment (EWCE) which specific HD associations validated single nucleus RNAseq (snRNAseq) brains. The transcriptomic profile preHD enriched astrocytes endothelial cells, neuronal microglial cells. Astrocyte-specific differentially expressed snRNAseq profile, microglial-specific profile. Our suggest may arise dual pathological processes, emerging consequence neurodevelopmental changes, at life, followed by neurodegeneration adulthood, targeting areas reduced genes. events result age-related death multiple types.

Language: Английский

---

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

---