Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior

  1. Salvatore Lecca
  2. Frank Julius Meye
  3. Massimo Trusel
  4. Anna Tchenio
  5. Julia Harris
  6. Martin Karl Schwarz
  7. Denis Burdakov
  8. Francois Georges
  9. Manuel Mameli  Is a corresponding author
  1. Institut du Fer à Moulin, Inserm UMR-S 839, France
  2. The University of Lausanne, Switzerland
  3. The Francis Crick Institute, Kings Cross, United Kingdom
  4. University Clinic of Bonn, Germany
  5. Université de Bordeaux, Neurodegeneratives Diseases Institute, France

Abstract

A sudden aversive event produces escape behaviors, an innate response essential for survival in virtually all-animal species. Nuclei including the lateral habenula (LHb), the lateral hypothalamus (LH), and the midbrain are not only reciprocally connected, but also respond to negative events contributing to goal-directed behaviors. However, whether aversion encoding requires these neural circuits to ultimately prompt escape behaviors remains unclear. We observe that aversive stimuli, including foot-shocks, excite LHb neurons and promote escape behaviors in mice. The foot-shock-driven excitation within the LHb requires glutamatergic signaling from the LH, but not from the midbrain. This hypothalamic excitatory projection predominates over LHb neurons monosynaptically innervating aversion-encoding midbrain GABA cells. Finally, the selective chemogenetic silencing of the LH-to-LHb pathway impairs aversion-driven escape behaviors. These findings unveil a habenular neurocircuitry devoted to encode external threats and the consequent escape; a process that, if disrupted, may compromise the animal’s survival.

Article and author information

Author details

  1. Salvatore Lecca

    Institut du Fer à Moulin, Inserm UMR-S 839, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Frank Julius Meye

    Department of Fundamental Neuroscience, The University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Massimo Trusel

    Institut du Fer à Moulin, Inserm UMR-S 839, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna Tchenio

    Institut du Fer à Moulin, Inserm UMR-S 839, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Julia Harris

    The Francis Crick Institute, Kings Cross, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Martin Karl Schwarz

    Clinic for epilepsy life and Brain center, University Clinic of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Denis Burdakov

    The Francis Crick Institute, Kings Cross, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Francois Georges

    Université de Bordeaux, Neurodegeneratives Diseases Institute, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Manuel Mameli

    Institut du Fer à Moulin, Inserm UMR-S 839, Paris, France
    For correspondence
    manuel.mameli@unil.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0570-6964

Funding

This work was supported by INSERM Atip-Avenir, the City of Paris, the European Research Council (Starting grant SalienSy 335333) to M.M., the HFSP (Young Investigator Award RGY0076) to D.B.

Ethics

Animal experimentation: Mice were used in accordance with the guidelines of the Ministry of Agriculture and Forestry for animal handling and the ethic committee Charles Darwin #5 of the University Pierre et Marie Curie. Part of the current study was carried at the Department of Fundamental Neuroscience of the University of Lausanne (Lausanne, Switzerland) according to the regulations of the Cantonal Veterinary Offices of Vaud and Zurich (Switzerland; License VD3171).

Copyright

© 2017, Lecca 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

  • 5,417
    views
  • 1,126
    downloads
  • 125
    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. Salvatore Lecca
  2. Frank Julius Meye
  3. Massimo Trusel
  4. Anna Tchenio
  5. Julia Harris
  6. Martin Karl Schwarz
  7. Denis Burdakov
  8. Francois Georges
  9. Manuel Mameli
(2017)
Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior
eLife 6:e30697.
https://doi.org/10.7554/eLife.30697

Share this article

https://doi.org/10.7554/eLife.30697

Further reading

    1. Neuroscience
    Vincent Huson, Wade G Regehr
    Research Article

    Unipolar brush cells (UBCs) are excitatory interneurons in the cerebellar cortex that receive mossy fiber (MF) inputs and excite granule cells. The UBC population responds to brief burst activation of MFs with a continuum of temporal transformations, but it is not known how UBCs transform the diverse range of MF input patterns that occur in vivo. Here, we use cell-attached recordings from UBCs in acute cerebellar slices to examine responses to MF firing patterns that are based on in vivo recordings. We find that MFs evoke a continuum of responses in the UBC population, mediated by three different types of glutamate receptors that each convey a specialized component. AMPARs transmit timing information for single stimuli at up to 5 spikes/s, and for very brief bursts. A combination of mGluR2/3s (inhibitory) and mGluR1s (excitatory) mediates a continuum of delayed, and broadened responses to longer bursts, and to sustained high frequency activation. Variability in the mGluR2/3 component controls the time course of the onset of firing, and variability in the mGluR1 component controls the duration of prolonged firing. We conclude that the combination of glutamate receptor types allows each UBC to simultaneously convey different aspects of MF firing. These findings establish that UBCs are highly flexible circuit elements that provide diverse temporal transformations that are well suited to contribute to specialized processing in different regions of the cerebellar cortex.

    1. Neuroscience
    Eleni Hackwell, Sharon R Ladyman ... David R Grattan
    Research Article

    The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted in failure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation. GCaMP fibre photometry of arcuate kisspeptin neurons revealed that the normal episodic activity of these neurons is rapidly suppressed in pregnancy and this was maintained throughout early lactation. Deletion of Prlr from arcuate kisspeptin neurons resulted in early reactivation of episodic activity of kisspeptin neurons prior to a premature return of reproductive cycles in early lactation. These observations show dynamic variation in arcuate kisspeptin neuronal activity associated with the hormonal changes of pregnancy and lactation, and provide direct evidence that prolactin action on arcuate kisspeptin neurons is necessary for suppressing fertility during lactation in mice.