1. Neuroscience

Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area

  1. Elina Nagaeva
  2. Ivan Zubarev
  3. Carolina Bengtsson Gonzales
  4. Mikko Forss
  5. Kasra Nikouei
  6. Elena de Miguel
  7. Lauri Elsilä
  8. Anni-Maija Linden
  9. Jens Hjerling-Leffler
  10. George J Augustine
  11. Esa R Korpi  Is a corresponding author
  1. University of Helsinki, Finland
  2. Aalto University, Finland
  3. Karolinska Insitutet, Sweden
  4. Karolinska Institutet, Sweden
  5. Nanyang Technological University, Singapore
https://doi.org/10.7554/eLife.59328
Share this article
Cite this article
  1. Elina Nagaeva
  2. Ivan Zubarev
  3. Carolina Bengtsson Gonzales
  4. Mikko Forss
  5. Kasra Nikouei
  6. Elena de Miguel
  7. Lauri Elsilä
  8. Anni-Maija Linden
  9. Jens Hjerling-Leffler
  10. George J Augustine
  11. Esa R Korpi
(2020)
Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area
eLife 9:e59328.
https://doi.org/10.7554/eLife.59328
  2. Download BibTeX
  3. Download .RIS

Abstract

The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.

Data availability

scRNA-seq raw and expression data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-8780.The following previously published data sets were used:•https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115746 (Tasic et al., 2018)•https://storage.googleapis.com/dropviz-downloads/static/regions/F_GRCm38.81.P60SubstantiaNigra.raw.dge.txt.gz (Saunders et al., 2018)Custom written software for automated firing pattern analysis is available for downloading from here: https://github.com/zubara/fffpa.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Elina Nagaeva

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2828-6234

  2. Ivan Zubarev

    Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1620-8485

  3. Carolina Bengtsson Gonzales

    Department of Medical Biochemistry and Biophysics, Karolinska Insitutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  4. Mikko Forss

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.

  5. Kasra Nikouei

    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  6. Elena de Miguel

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.

  7. Lauri Elsilä

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9744-4753

  8. Anni-Maija Linden

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.

  9. Jens Hjerling-Leffler

    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  10. George J Augustine

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.

  11. Esa R Korpi

    Department of Pharmacology, University of Helsinki, University of Helsinki, Finland
    For correspondence
    esa.korpi@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0683-4009

Funding

The project was funded by the Academy of Finland (1278174 and 1317399), The Finnish National Agency for Education EDUFI, the Sigrid Juselius Foundation, and research grants MOE2015-T2-2-095 and MOE2017-T3-1-002 from the Singapore Ministry of Education. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Olivier J Manzoni, Aix-Marseille University, INSERM, INMED, France

Ethics

Animal experimentation: Animal experiments were authorized by the National Animal Experiment Board in Finland (Eläinkoelautakunta, ELLA; Permit Number: ESAVI/1172/04.10.07/2018) and Institutional Animal Care and Use Committee in Singapore (NTU-IACUC).

Version history

  1. Received: May 26, 2020
  2. Accepted: August 1, 2020
  3. Accepted Manuscript published: August 4, 2020 (version 1)
  4. Version of Record published: August 20, 2020 (version 2)

Copyright

© 2020, Nagaeva 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

  • 3,671
    views
  • 428
    downloads
  • 10
    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. Elina Nagaeva
  2. Ivan Zubarev
  3. Carolina Bengtsson Gonzales
  4. Mikko Forss
  5. Kasra Nikouei
  6. Elena de Miguel
  7. Lauri Elsilä
  8. Anni-Maija Linden
  9. Jens Hjerling-Leffler
  10. George J Augustine
  11. Esa R Korpi
(2020)
Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area
eLife 9:e59328.
https://doi.org/10.7554/eLife.59328

Share this article

https://doi.org/10.7554/eLife.59328

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Aberrant hippocampal Ca2+ microwaves following synapsin-dependent adeno-associated viral expression of Ca2+ indicators

    Nicola Masala, Manuel Mittag ... Tony Kelly
    Research Article

    Genetically encoded calcium indicators (GECIs) such as GCaMP are invaluable tools in neuroscience to monitor neuronal activity using optical imaging. The viral transduction of GECIs is commonly used to target expression to specific brain regions, can be conveniently used with any mouse strain of interest without the need for prior crossing with a GECI mouse line, and avoids potential hazards due to the chronic expression of GECIs during development. A key requirement for monitoring neuronal activity with an indicator is that the indicator itself minimally affects activity. Here, using common adeno-associated viral (AAV) transduction procedures, we describe spatially confined aberrant Ca2+ microwaves slowly travelling through the hippocampus following expression of GCaMP6, GCaMP7, or R-CaMP1.07 driven by the synapsin promoter with AAV-dependent gene transfer in a titre-dependent fashion. Ca2+ microwaves developed in hippocampal CA1 and CA3, but not dentate gyrus nor neocortex, were typically first observed at 4 wk after viral transduction, and persisted up to at least 8 wk. The phenomenon was robust and observed across laboratories with various experimenters and setups. Our results indicate that aberrant hippocampal Ca2+ microwaves depend on the promoter and viral titre of the GECI, density of expression, as well as the targeted brain region. We used an alternative viral transduction method of GCaMP which avoids this artefact. The results show that commonly used Ca2+-indicator AAV transduction procedures can produce artefactual Ca2+ responses. Our aim is to raise awareness in the field of these artefactual transduction-induced Ca2+ microwaves, and we provide a potential solution.

    1. Neuroscience

    Using synchronized brain rhythms to bias memory-guided decisions

    John J Stout, Allison E George ... Amy L Griffin
    Research Article

    Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6–11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain-machine interface that initiated task trials based on the magnitude of prefrontal-hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain-machine interfacing.

    1. Neuroscience

    Firing rate adaptation affords place cell theta sweeps, phase precession, and procession

    Tianhao Chu, Zilong Ji ... Si Wu
    Research Article

    Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here, we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between ‘bimodal cells’ showing interleaved phase precession and procession, and ‘unimodal cells’ in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells’ firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.