Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease DOI Open Access
Zachary Gaertner,

Cameron Oram,

Amanda Schneeweis

et al.

Published: Nov. 21, 2024

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, using cell profiling techniques begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown molecularly defined the substantia nigra (SNc) distinctive anatomic and functional properties, differential vulnerability in Parkinson’s disease (PD). Based these provocative results, granular understanding of putative alterations PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) generated high-resolution hierarchically organized map revealing 20 distinct neuron belonging three main families. integrated this data with spatial MERFISH technology map, high definition, location mouse midbrain, heterogeneity sub-structures. Finally, we demonstrate preclinical LRRK2 G2019S knock-in model PD, subtype organization proportions are preserved. Transcriptional occur many including those localized ventral tier SNc, where expression observed synaptic pathways, which might account previously described release deficits model. Our provides advancement current taxonomic schemes subtypes, view locations, prodromal PD.

Language: Английский

Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model DOI Creative Commons
Behzad Yaghmaeian Salmani, Laura Lahti,

Linda Gillberg

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: April 8, 2024

Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA substantia nigra compacta (SNc) in patients Parkinson’s disease, while those ventral tegmental area (VTA) are relatively spared. Here, we used single nuclei RNA sequencing (snRNA-seq) approximately 70,000 mouse midbrain to build a high-resolution atlas neuron diversity at molecular level. The results showed that differences between groups could best be understood as continuum without sharp subtypes. Thus, assigned several ‘territories’ ‘neighborhoods’ within shifting gene expression landscape where boundaries gradual rather than discrete. Based on enriched patterns these territories neighborhoods, were able localize them adult midbrain. Moreover, because underlying mechanisms for variable sensitivities pathological insults not well understood, analyzed surviving after partial 6-hydroxydopamine (6-OHDA) lesions unravel correlate vulnerability resilience. Together, this provides basis further studies neurophysiological role health disease.

Language: Английский

Citations

4
Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson’s disease model DOI Creative Commons

Natalia López‐González del Rey,

Nagore Hernández-Pinedo, Maria Christina Carrillo

et al.

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 2, 2024

The differential vulnerability of dopaminergic neurons the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies mice show diverse susceptibility subpopulations nigral to various toxic agents. In primate midbrain, molecular phenotypes their are poorly characterized. We performed detailed histological study determine anatomical distribution different within identified midbrain selective control MPTP-treated monkeys. ventral tier SNc (nigrosome), rich Aldh1a1 Girk2 intermingled, whereas calbindin marker that best identifies most resilient located dorsal tegmental area, recapitulating well-defined dorsoventral axis degeneration neurons. particular, loss Aldh1a1+ was observed parallel progressive development parkinsonism. were main population vulnerable nigrostriatal-projecting neurons, while Aldh1a1- giving rise nigropallidal projections remained relatively preserved. Moreover, bundles entwined dendrites with long trajectories extending towards reticulata emerged from clusters colocalized dense cannabinoid receptor 1 afferent fibers likely representing part striatonigral projection affected human disorders, including conclusion, can be by using Girk2. Further studies needed define afferent/efferent patterns these

Language: Английский

Citations

4
MAPPING THE CEREBROSPINAL FLUID PROTEOME IN BIPOLAR DISORDER DOI Creative Commons
Andreas Göteson,

Jessica Holmén‐Larsson,

Hakan Hamdi Çelik

et al.

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Establishing functionally segregated dopaminergic circuits DOI
Akiko Terauchi, Erin Johnson‐Venkatesh, Hisashi Umemori

et al.

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Cross-species dissection of the modular role of the ventral tegmental area in depressive disorders DOI
Laurel S. Morris,

Jacqueline Beltran,

James W. Murrough

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Genetically encoded dopamine sensors: principles, applications, and future directions DOI
Hui Dong, Zhenghua Wang,

Yulong Li

et al.

Current Opinion in Behavioral Sciences, Journal Year: 2025, Volume and Issue: 62, P. 101489 - 101489

Published: Feb. 21, 2025

Language: Английский

Citations

0
Human Midbrain Organoids Enriched With Dopaminergic Neurons for Long‐Term Functional Evaluation DOI Creative Commons
Xinyue Wang,

Gaoying Sun,

Mingming Tang

et al.

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

ABSTRACT Human midbrain organoids with functional dopaminergic (DA) neurons are invaluable for the therapeutic development of Parkinson's disease (PD). However, current methods face significant limitations, including challenges in generating pint‐sized enriched DA and lack robust assays efficiently evaluating neural networks over extended periods. Here we present an innovative approach that combines developmental patterning mechanical cutting to produce small organoids, diameters less than 300 μm, suitable long‐term evaluation, along a comprehensive assay system consisting calcium transient assay, neurite extension multielectrode array (MEA) assay. Radial into four eight portions according their sizes at appropriate stage significantly increases yield viable while reducing necrotic cell regions. Using system, demonstrate within extend long projections, respond dopamine stimulation, form characterised by giant depolarising potential‐like events. Our supports generation PD models can be used testing.

Language: Английский

Citations

0
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease DOI Open Access
Zachary Gaertner,

Cameron Oram,

Amanda Schneeweis

et al.

Published: March 5, 2025

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, using cell profiling techniques begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown molecularly defined the substantia nigra (SNc) distinctive anatomic and functional properties, differential vulnerability in Parkinson’s disease (PD). Based these provocative results, granular understanding of putative alterations PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) generated high-resolution hierarchically organized map revealing 20 distinct neuron belonging three main families. integrated this data with spatial MERFISH technology map, high definition, location mouse midbrain, heterogeneity sub-structures. Finally, we demonstrate preclinical LRRK2 G2019S knock-in model PD, subtype organization proportions are preserved. Transcriptional occur many including those localized ventral tier SNc, where expression observed synaptic pathways, which might account previously described release deficits model. Our provides advancement current taxonomic schemes subtypes, view locations, prodromal PD.Teaser: Using snRNASeq identified mapped location,

Language: Английский

Citations

0
Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus–reward associations DOI Creative Commons
Guofeng Yan, Hidetoshi Amita, Satoshi Nonomura

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 13, 2025

Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, dynamics of DA remain unknown since conventional methods are not necessarily appropriate terms spatiotemporal resolution or chemical specificity sufficient for detecting signals. our study, fiber photometry with a fluorescent sensor was employed identify reward-related transients monkey striatum. This technique, which directly monitors local release, reveals reward prediction error signal anterior putamen originating from midbrain neurons. Further, head caudate nucleus exhibit value-based response reward-predicting stimuli. These have been found arise two separate groups neurons substantia nigra pars compacta. The present results demonstrate that fluorescence monitoring is applicable detect primate investigating their roles.

Language: Английский

Citations

0
Reelin marks cocaine-activated striatal neurons, promotes neuronal excitability, and regulates cocaine reward DOI
Kasey L. Brida, Emily T. Jorgensen, Robert A. Phillips

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(13)

Published: March 26, 2025

Drugs of abuse activate defined neuronal populations in reward structures such as the nucleus accumbens (NAc), which promote enduring synaptic, circuit, and behavioral consequences drug exposure. While molecular cellular effects arising from experience with drugs like cocaine are increasingly well understood, mechanisms that dictate NAc recruitment remain unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling targeted situ detection to identify Reln (encoding secreted glycoprotein, Reelin) a marker cocaine-activated within rat NAc. A CRISPR interference approach enabling selective knockdown adult altered expression calcium signaling genes, promoted trajectory consistent loss sensitivity, decreased MSN excitability. Behaviorally, prevented locomotor sensitization, abolished place preference memory, self-administration behavior. These results Reelin critical mechanistic link between activation cocaine-induced adaptations.

Language: Английский

Citations

0