In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition DOI Creative Commons
Min Lin, Phillip Mackie,

Fatima Shaerzadeh

et al.

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: June 7, 2021

Abstract Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease (PD). Intracellular pathological inclusions protein α-synuclein within dopaminergic are a cardinal feature PD, but mechanisms by which contributes neuron vulnerability remain unknown. The inaccessibility diseased tissue has been limitation studying progression pathophysiology prior degeneration neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from PD patient carrying triplication mutation (AST) an unaffected first-degree relative (NAS) into In human-like overexpression reduced functional availability D2 receptors, resulting stark dysregulation firing activity, release, neuronal morphology. We back-translated findings primary mouse overexpressing found similar phenotype, supporting causal role for α-synuclein. Importantly, application receptor agonist, quinpirole, restored altered activity AST-derived normal levels. These results provide novel insights pre-degenerative pathophysiological neuro-phenotype introduce potential mechanism long-established clinical efficacy agonists treatment PD.

Language: Английский

A Unified Framework for Dopamine Signals across Timescales DOI Creative Commons
HyungGoo R. Kim, Athar N. Malik, John G. Mikhael

et al.

Cell, Journal Year: 2020, Volume and Issue: 183(6), P. 1600 - 1616.e25

Published: Nov. 27, 2020

Language: Английский

Citations

277
VTA dopamine neuron activity encodes social interaction and promotes reinforcement learning through social prediction error DOI
Clément Prévost-Solié, Benôıt Girard,

Beatrice Righetti

et al.

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 25(1), P. 86 - 97

Published: Dec. 2, 2021

Language: Английский

Citations

115
Mesolimbic dopamine adapts the rate of learning from action DOI Creative Commons
Luke T. Coddington, Sarah Lindo, Joshua T. Dudman

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7947), P. 294 - 302

Published: Jan. 18, 2023

Abstract Recent success in training artificial agents and robots derives from a combination of direct learning behavioural policies indirect through value functions 1–3 . Policy use distinct algorithms that optimize performance reward prediction, respectively. In animals, the role mesolimbic dopamine signalling have been extensively evaluated with respect to prediction 4 ; however, so far there has little consideration how policy might inform our understanding 5 Here we used comprehensive dataset orofacial body movements understand evolved as naive, head-restrained mice learned trace conditioning paradigm. Individual differences initial dopaminergic responses correlated emergence policy, but not putative encoding for predictive cue. Likewise, physiologically calibrated manipulations produced several effects inconsistent predicted by neural-network-based model signals set an adaptive rate, error signal, learning. This work provides strong evidence phasic activity can regulate policies, expanding explanatory power reinforcement models animal 6

Language: Английский

Citations

87
Unraveling the dynamics of dopamine release and its actions on target cells DOI Creative Commons
Tanya Sippy, Nicolas X. Tritsch

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(3), P. 228 - 239

Published: Jan. 10, 2023

Language: Английский

Citations

45
A feature-specific prediction error model explains dopaminergic heterogeneity DOI
Rachel S. Lee, Yotam Sagiv,

Ben Engelhard

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(8), P. 1574 - 1586

Published: July 3, 2024

Language: Английский

Citations

34
Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement DOI Creative Commons
Fabrice Chaudun,

Laurena Python,

Yu Liu

et al.

Nature, Journal Year: 2024, Volume and Issue: 630(8015), P. 141 - 148

Published: May 22, 2024

Abstract Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement 1 . also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative 2,3 (that is, individuals retake drug avoid withdrawal). Positive maintain opioid consumption, addiction in one-fourth of users, largest fraction for all addictive drugs 4 Among receptors, µ-opioid receptors have key role 5 , yet induction loci circuit adaptations eventually lead remain unknown. Here we injected mice with fentanyl acutely inhibit γ-aminobutyric acid-expressing neurons ventral tegmental area (VTA), causing disinhibition dopamine neurons, increased nucleus accumbens. Knockdown VTA abolished transients reinforcement, but remained unchanged. We identified expressing central amygdala (CeA) whose activity was enhanced during withdrawal. CeA eliminated symptoms, suggesting they mediate reinforcement. Thus, optogenetic stimulation caused place aversion, readily learned press lever pause express receptors. Our study parses neuronal populations trigger CeA, respectively. lay out organization develop interventions reducing facilitating rehabilitation.

Language: Английский

Citations

18
Lateral septum as a nexus for mood, motivation, and movement DOI Creative Commons
Hannah S. Wirtshafter,

Matthew A. Wilson

Neuroscience & Biobehavioral Reviews, Journal Year: 2021, Volume and Issue: 126, P. 544 - 559

Published: April 11, 2021

Language: Английский

Citations

92
Context-dependent representations of movement in Drosophila dopaminergic reinforcement pathways DOI
Aryeh Zolin, Raphael Cohn, Rich Pang

et al.

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(11), P. 1555 - 1566

Published: Oct. 25, 2021

Language: Английский

Citations

75
Mesoaccumbal Dopamine Heterogeneity: What Do Dopamine Firing and Release Have to Do with It? DOI
Johannes W. de Jong, Kurt M. Fraser, Stephan Lammel

et al.

Annual Review of Neuroscience, Journal Year: 2022, Volume and Issue: 45(1), P. 109 - 129

Published: Feb. 28, 2022

Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), prominent projection target of these neurons, has been implicated reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions versus a homogeneous role for neuron activity raises numerous questions regarding how VTA translates into NAc release. Further complicating this issue is increasing evidence that distinct projections defined subregions mediate diverse behavioral functions. Here, we evaluate heterogeneity within mesoaccumbal system argue frameworks function must incorporate precise topographic organization clarify their contribution health disease.

Language: Английский

Citations

66
Dopamine promotes head direction plasticity during orienting movements DOI Creative Commons
Yvette E. Fisher,

Michael Marquis,

Isabel D’Alessandro

et al.

Nature, Journal Year: 2022, Volume and Issue: 612(7939), P. 316 - 322

Published: Nov. 30, 2022

Abstract In neural networks that store information in their connection weights, there is a tradeoff between sensitivity and stability 1,2 . Connections must be plastic to incorporate new information, but if they are too plastic, stored can corrupted. A potential solution allow plasticity only during epochs when task-specific rich, on the basis of ‘when-to-learn’ signal 3 We reasoned dopamine provides when-to-learn allows brain’s spatial maps update available—that is, an animal moving. Here we show neurons innervating Drosophila head direction network specifically active fly turns change its direction. Moreover, activity scales with moment-to-moment fluctuations rotational speed. Pairing release visual cue persistently strengthens cue’s influence cells. Conversely, inhibiting these decreases cue. This mechanism should accelerate learning moments orienting movements providing rich stream allowing rates low at other times protect information. Our results how brain compressed into discrete which high matched intake.

Language: Английский

Citations

47