Slowly evolving dopaminergic activity modulates the moment-to-moment probability of reward-related self-timed movements

  1. Allison E Hamilos  Is a corresponding author
  2. Giulia Spedicato
  3. Ye Hong
  4. Fangmiao Sun
  5. Yulong Li
  6. John Assad
  1. Harvard Medical School, United States
  2. Peking University School of Life Science, China
  3. Peiking University School of Life Sciences, China

Abstract

Clues from human movement disorders have long suggested that the neurotransmitter dopamine plays a role in motor control, but how the endogenous dopaminergic system influences movement is unknown. Here we examined the relationship between dopaminergic signaling and the timing of reward-related movements in mice. Animals were trained to initiate licking after a self-timed interval following a start-timing cue; reward was delivered in response to movements initiated after a criterion time. The movement time was variable from trial-to-trial, as expected from previous studies. Surprisingly, dopaminergic signals ramped-up over seconds between the start-timing cue and the self-timed movement, with variable dynamics that predicted the movement/reward time on single trials. Steeply rising signals preceded early lick-initiation, whereas slowly rising signals preceded later initiation. Higher baseline signals also predicted earlier self-timed movements. Optogenetic activation of dopamine neurons during self-timing did not trigger immediate movements, but rather caused systematic early-shifting of movement initiation, whereas inhibition caused late-shifting, as if modulating the probability of movement. Consistent with this view, the dynamics of the endogenous dopaminergic signals quantitatively predicted the moment-by-moment probability of movement initiation on single trials. We propose that ramping dopaminergic signals, likely encoding dynamic reward expectation, can modulate the decision of when to move.

Data availability

All datasets supporting the findings of this study are publicly available (DOI: 10.5281/zenodo.4062749). Source data files have been provided for all figures.

The following data sets were generated

Article and author information

Author details

  1. Allison E Hamilos

    Department of Neurobiology, Harvard Medical School, Boston, United States
    For correspondence
    allisonhamilos@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9486-0017
  2. Giulia Spedicato

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Ye Hong

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Fangmiao Sun

    State Key Laboratory of Membrane Biology, Peking University School of Life Science, Beijing, China
    Competing interests
    No competing interests declared.
  5. Yulong Li

    State Key Laboratory of Membrane Biology, Peiking University School of Life Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  6. John Assad

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    John Assad, co-founder of OptogeniX, which produces the tapered optical fibers used in some experiments..

Funding

National Institutes of Health (UF-NS108177)

  • John Assad

National Institutes of Health (U19 NS113201)

  • John Assad

National Institutes of Health (EY-12196)

  • John Assad

Lefler Predoctoral Fellowship (n/a)

  • Allison E Hamilos

Stuart H.Q. and Victoria Quan Predoctoral Fellowship (n/a)

  • Allison E Hamilos

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments and protocols were approved by the Harvard Institutional Animal Care and Use Committee (IACUC protocol #05098, Animal Welfare Assurance Number #A3431-01) and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Surgeries were conducted under aseptic conditions with isoflurane anesthesia, and every effort was taken to minimize suffering.

Copyright

© 2021, Hamilos et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,639
    views
  • 800
    downloads
  • 48
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Allison E Hamilos
  2. Giulia Spedicato
  3. Ye Hong
  4. Fangmiao Sun
  5. Yulong Li
  6. John Assad
(2021)
Slowly evolving dopaminergic activity modulates the moment-to-moment probability of reward-related self-timed movements
eLife 10:e62583.
https://doi.org/10.7554/eLife.62583

Share this article

https://doi.org/10.7554/eLife.62583

Further reading

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.