Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019Smodel of Parkinson’s disease DOI Creative Commons
Zachary Gaertner,

Cameron Oram,

Amanda Schneeweis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 8, 2024

Abstract 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

Mechanisms of neuromodulatory volume transmission DOI Creative Commons
Özge Demet Özçete, Aditi Banerjee, Pascal S. Kaeser

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(11), P. 3680 - 3693

Published: May 24, 2024

Abstract A wealth of neuromodulatory transmitters regulate synaptic circuits in the brain. Their mode signaling, often called volume transmission, differs from classical transmission important ways. In vesicles rapidly fuse response to action potentials and release their transmitter content. The are then sensed by nearby receptors on select target cells with minimal delay. Signal is restricted contacts typically occurs within ~1 ms. Volume doesn’t rely contact sites main monoamines neuropeptides, neuromodulators It less precise than underlying molecular mechanisms spatiotemporal scales not well understood. Here, we review literature raise scientific questions that should be addressed years ahead. We define five domains which systems can differ one another. These (1) innervation patterns firing properties, (2) synthesis loading into different types vesicles, (3) architecture distribution sites, (4) diffusion, degradation, reuptake, (5) receptor positioning cells. discuss these for dopamine, a well-studied monoamine, compare dopamine norepinephrine serotonin. include assessments neuropeptide signaling central acetylcholine transmission. Through this review, provide cellular framework This mechanistic knowledge essential how control behavior health disease understand they modulated medical treatments drugs abuse.

Language: Английский

Citations

22
Synaptic and circuit functions of multitransmitter neurons in the mammalian brain DOI Creative Commons
Michael L. Wallace, Bernardo L. Sabatini

Neuron, Journal Year: 2023, Volume and Issue: 111(19), P. 2969 - 2983

Published: July 17, 2023

Language: Английский

Citations

42
The Formation and Function of the VTA Dopamine System DOI Open Access
Guoqiang Hou,

Hao Mei,

Jiawen Duan

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3875 - 3875

Published: March 30, 2024

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well maternal and reproductive behaviors. Dopamine neurotransmitter binds G-protein-coupled receptors. also works together with other neurotransmitters various neuropeptides maintain the balance of synaptic functions. dysfunction leads several conditions, Parkinson’s disease, Huntington’s major depression, schizophrenia, drug addiction. ventral tegmental area (VTA) has been identified an important relay nucleus modulates homeostatic plasticity in system. Due complexity transmissions input–output connections VTA, structure function this crucial brain region are still not fully understood. In review article, we mainly focus on cell types, neurotransmitters, neuropeptides, ion channels, receptors, neural circuits VTA system, hope obtaining new insight into formation vital region.

Language: Английский

Citations

17
Distributional coding of associative learning in discrete populations of midbrain dopamine neurons DOI Creative Commons
Riccardo Avvisati, Anna-Kristin Kaufmann, Callum J. Young

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114080 - 114080

Published: April 1, 2024

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity signaling, yet it remains poorly understood how heterogeneous signals might be organized facilitate role of downstream circuits mediating distinct aspects behavior. Here, we investigated organizational logic dopaminergic signaling recording labeling individual midbrain during associative Our findings show that reward information behavioral parameters not only heterogeneously encoded but also differentially distributed across populations neurons. Retrograde tracing fiber photometry suggest projecting different striatal regions convey signals. These data, supported computational modeling, indicate such distributional coding can maximize dynamic range tailor specialized regions.

Language: Английский

Citations

14
Humanized brain organoids-on-chip integrated with sensors for screening neuronal activity and neurotoxicity DOI
Pelin Sağlam-Metiner, Ender Yıldırım, Can Dincer

et al.

Microchimica Acta, Journal Year: 2024, Volume and Issue: 191(1)

Published: Jan. 1, 2024

Language: Английский

Citations

12
Inflammation-free electrochemical in vivo sensing of dopamine with atomic-level engineered antioxidative single-atom catalyst DOI Creative Commons
Xiaolong Gao, Huan Wei, Wenjie Ma

et al.

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

Published: Sept. 10, 2024

Language: Английский

Citations

10
Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging DOI Creative Commons
Anna Rappe, Helena Vihinen, Fumi Suomi

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Abstract Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated age-related neurodegenerative disorders such as Parkinson’s Alzheimer’s disease. While decreases throughout the lifespan of short-lived model organisms, it remains unknown whether a decline occurs aging mammalian brain—a question fundamental importance for understanding cell type- region-specific susceptibility to neurodegeneration. Here, we define longitudinal dynamics basal macroautophagy across neuronal non-neuronal types within intact mouse brain vivo. Quantitative profiling reporter cohorts from young geriatric ages reveals cell- tissue-specific alterations between distinct subregions populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia interneurons. We also find that healthy is hallmarked by dynamic accumulation differentially acidified lysosomes several neural subsets. Our findings argue against any widespread mitophagic activity, instead demonstrating fluctuations trajectory, with strong implications ongoing theragnostic development.

Language: Английский

Citations

9
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

1
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

1
Dopaminergic neuron metabolism: relevance for understanding Parkinson’s disease DOI Creative Commons

Xóchitl Flores-Ponce,

Iván Velasco

Metabolomics, Journal Year: 2024, Volume and Issue: 20(6)

Published: Oct. 13, 2024

Abstract Background Dopaminergic neurons from the substantia nigra pars compacta (SNc) have a higher susceptibility to aging-related degeneration, compared midbrain dopaminergic cells present in ventral tegmental area (VTA); death of dopamine SNc results Parkinson´s disease (PD). In addition increased loss by aging, are more prone cell when exposed genetic or environmental factors, that either interfere with mitochondrial function, cause an increase oxidative stress. The oxidation is contributing source reactive oxygen species (ROS), but this production not enough explain differences degeneration between and VTA neurons. Aim review we aim highlight intrinsic neurons, terms gene expression, calcium oscillations, bioenergetics, ROS responses. Also, describe changes pentose phosphate pathway induction apoptosis during as related development PD. Key scientific concepts Recent work showed possess characteristics result metabolic differences, their intricate morphology, render them susceptible degeneration. particular, these elevated basal energy metabolism, required fulfill demands constant firing action potentials, at same time, associated production, cells. Finally, discuss how mutations PD affect pathways, mechanisms, revealed metabolomics.

Language: Английский

Citations

9