Reward prediction error does not explain movement selectivity in DMS-projecting dopamine neurons
Abstract
Although midbrain dopamine (DA) neurons have been thought to primarily encode reward prediction error (RPE), recent studies have also found movement-related DAergic signals. For example, we recently reported that DA neurons in mice projecting to dorsomedial striatum are modulated by choices contralateral to the recording side. Here, we introduce, and ultimately reject, a candidate resolution for the puzzling RPE vs movement dichotomy, by showing how seemingly movement-related activity might be explained by an action-specific RPE. By considering both choice and RPE on a trial-by-trial basis, we find that DA signals are modulated by contralateral choice in a manner that is distinct from RPE, implying that choice encoding is better explained by movement direction. This fundamental separation between RPE and movement encoding may help shed light on the diversity of functions and dysfunctions of the DA system.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute for Health Research (5R01MH106689-02)
- Ilana B Witten
New York Stem Cell Foundation (Robertson Investigator)
- Ilana B Witten
Army Research Office (W911NF-16-1-0474)
- Nathaniel D Daw
Army Research Office (W911NF-17-1-0554)
- Ilana B Witten
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Geoffrey Schoenbaum, National Institute on Drug Abuse, National Institutes of Health, United States
Version history
- Received: October 19, 2018
- Accepted: April 3, 2019
- Accepted Manuscript published: April 4, 2019 (version 1)
- Version of Record published: April 15, 2019 (version 2)
Copyright
© 2019, Lee 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
-
- 6,378
- views
-
- 716
- downloads
-
- 45
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Genetics and Genomics
- Neuroscience
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
-
- Cell Biology
- Neuroscience
Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.