Hierarchical architecture of dopaminergic circuits enables second-order conditioning in Drosophila

  1. Daichi Yamada
  2. Daniel Bushey
  3. Feng Li
  4. Karen L Hibbard
  5. Megan Sammons
  6. Jan Funke
  7. Ashok Litwin-Kumar
  8. Toshihide Hige  Is a corresponding author
  9. Yoshinori Aso  Is a corresponding author
  1. University of North Carolina at Chapel Hill, United States
  2. Janelia Research Campus, United States
  3. Columbia University, United States

Abstract

Dopaminergic neurons with distinct projection patterns and physiological properties compose memory subsystems in a brain. However, it is poorly understood whether or how they interact during complex learning. Here, we identify a feedforward circuit formed between dopamine subsystems and show that it is essential for second-order conditioning, an ethologically important form of higher-order associative learning. The Drosophila mushroom body comprises a series of dopaminergic compartments, each of which exhibits distinct memory dynamics. We find that a slow and stable memory compartment can serve as an effective 'teacher' by instructing other faster and transient memory compartments via a single key interneuron, which we identify by connectome analysis and neurotransmitter prediction. This excitatory interneuron acquires enhanced response to reward-predicting odor after first-order conditioning and, upon activation, evokes dopamine release in the 'student' compartments. These hierarchical connections between dopamine subsystems explain distinct properties of first- and second-order memory long known by behavioral psychologists.

Data availability

The confocal images of expression patterns are available online (http://www.janelia.org/split-gal4). The source data for each figure are included in the manuscript.

Article and author information

Author details

  1. Daichi Yamada

    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel Bushey

    Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9258-6579
  3. Feng Li

    Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6658-9175
  4. Karen L Hibbard

    Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2001-6099
  5. Megan Sammons

    Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4516-5928
  6. Jan Funke

    Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4388-7783
  7. Ashok Litwin-Kumar

    Department of Neuroscience, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2422-6576
  8. Toshihide Hige

    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    hige@email.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0007-3192
  9. Yoshinori Aso

    Janelia Research Campus, Ashburn, United States
    For correspondence
    asoy@janelia.hhmi.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2939-1688

Funding

NIH (R01DC018874)

  • Toshihide Hige

NSF (DBI-1707398)

  • Ashok Litwin-Kumar

Toyobo Biotechnology Foundation Postdoctoral Fellowship

  • Daichi Yamada

Japan Society for the Promotion of Science Overseas Research Fellowship

  • Daichi Yamada

HHMI

  • Daniel Bushey
  • Feng Li
  • Karen L Hibbard
  • Megan Sammons
  • Jan Funke
  • Yoshinori Aso

NSF (2034783)

  • Toshihide Hige

BSF (2019026)

  • Toshihide Hige

UNC Junior Faculty Development Award

  • Toshihide Hige

Burroughs Wellcome Foundation

  • Ashok Litwin-Kumar

Gatsby Charitable Foundation

  • Ashok Litwin-Kumar

McKnight Endowment Fund

  • Ashok Litwin-Kumar

Simons Collaboration on the Global Brain

  • Ashok Litwin-Kumar
  • Yoshinori Aso

NIH (R01EB029858)

  • Ashok Litwin-Kumar

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

Copyright

© 2023, Yamada 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

  • 2,751
    views
  • 402
    downloads
  • 27
    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. Daichi Yamada
  2. Daniel Bushey
  3. Feng Li
  4. Karen L Hibbard
  5. Megan Sammons
  6. Jan Funke
  7. Ashok Litwin-Kumar
  8. Toshihide Hige
  9. Yoshinori Aso
(2023)
Hierarchical architecture of dopaminergic circuits enables second-order conditioning in Drosophila
eLife 12:e79042.
https://doi.org/10.7554/eLife.79042

Share this article

https://doi.org/10.7554/eLife.79042

Further reading

    1. Neuroscience
    Selene Seoyun Lee, Livia Civitelli, Laura Parkkinen
    Research Article

    The alpha-synuclein (αSyn) seeding amplification assay (SAA) that allows the generation of disease-specific in vitro seeded fibrils (SAA fibrils) is used as a research tool to study the connection between the structure of αSyn fibrils, cellular seeding/spreading, and the clinicopathological manifestations of different synucleinopathies. However, structural differences between human brain-derived and SAA αSyn fibrils have been recently highlighted. Here, we characterize the biophysical properties of the human brain-derived αSyn fibrils from the brains of patients with Parkinson’s disease with and without dementia (PD, PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and compare them to the ‘model’ SAA fibrils. We report that the brain-derived αSyn fibrils show distinct biochemical profiles, which were not replicated in the corresponding SAA fibrils. Furthermore, the brain-derived αSyn fibrils from all synucleinopathies displayed a mixture of ‘straight’ and ‘twisted’ microscopic structures. However, the PD, PDD, and DLB SAA fibrils had a ’straight’ structure, whereas MSA SAA fibrils showed a ‘twisted’ structure. Finally, the brain-derived αSyn fibrils from all four synucleinopathies were phosphorylated (S129). Interestingly, phosphorylated αSyn were carried over to the PDD and DLB SAA fibrils. Our findings demonstrate the limitation of the SAA fibrils modeling the brain-derived αSyn fibrils and pay attention to the necessity of deepening the understanding of the SAA fibrillation methodology.

    1. Neuroscience
    Mazen Makke, Alejandro Pastor-Ruiz ... Dieter Bruns
    Research Article

    Complexin determines magnitude and kinetics of synchronized secretion, but the underlying molecular mechanisms remained unclear. Here, we show that the hydrophobic face of the amphipathic helix at the C-terminus of Complexin II (CpxII, amino acids 115–134) binds to fusion-promoting SNARE proteins, prevents premature secretion, and allows vesicles to accumulate in a release-ready state in mouse chromaffin cells. Specifically, we demonstrate that an unrelated amphipathic helix functionally substitutes for the C-terminal domain (CTD) of CpxII and that amino acid substitutions on the hydrophobic side compromise the arrest of the pre-fusion intermediate. To facilitate synchronous vesicle fusion, the N-terminal domain (NTD) of CpxII (amino acids 1–27) specifically cooperates with synaptotagmin I (SytI), but not with synaptotagmin VII. Expression of CpxII rescues the slow release kinetics of the Ca2+-binding mutant Syt I R233Q, whereas the N-terminally truncated variant of CpxII further delays it. These results indicate that the CpxII NTD regulates mechanisms which are governed by the forward rate of Ca2+ binding to Syt I. Overall, our results shed new light on key molecular properties of CpxII that hinder premature exocytosis and accelerate synchronous exocytosis.