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Brain Structure and Function

, Volume 221, Issue 8, pp 4007–4025 | Cite as

Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain

  • Sebastian Pablo Fernandez
  • Bruno Cauli
  • Carolina Cabezas
  • Aude Muzerelle
  • Jean-Christophe Poncer
  • Patricia Gaspar
Original Article

Abstract

Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice. Our results show that 5-HT neurons projecting to the dHP and the mPFC and the BLA form largely non-overlapping populations and that BLA-projecting neurons have characteristic excitability and membrane properties. In addition, using an unbiased clustering method that correlates anatomical, molecular and electrophysiological phenotypes, we find that 5-HT neurons with projections to the mPFC and the dHP segregate from those projecting to the BLA. Single-cell gene profiling showed a restricted expression of the peptide galanin in the population of 5-HT neurons projecting to the mPFC. Finally, cluster analysis allowed identifying an atypical subtype of 5-HT neuron with low excitability, long firing delays and preferential expression of the vesicular glutamate transporter type 3. Overall, these findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system.

Keywords

Serotonin Raphe Galanin Amygdala Hippocampus Prefrontal cortex Single-cell PCR Patch-clamp 

Notes

Acknowledgments

This work was funded by INSERM, the University Pierre et Marie Curie, the European Commission (FP7-health-2007-A-201714), The Fondation pour la Recherche Medicale (equipe FRM to PG) and the Agence Nationale pour la recherche (ANR605-neur-046 and ANR 2011 MALZ 003 01). SPF received a Fellowship from the Fondation pour la Recherche Medicale. The teams of PG and JCP are part of the Ecole de Neuroscience de Paris (ENP) training network and Labex Bio-Psy (Investissement d’Avenir, ANR). We thank Evan Deneris and Gord Fishell for providing the founders of ePet1-Cre and RCE:LoxP mouse lines. Sophie Scotto-Lomassese is acknowledged for help with confocal microscopy and Emma Martinelli and Mariano Soiza-Reilly for their helpful comments on the manuscript. The authors declare no competing financial interests.

Supplementary material

429_2015_1142_MOESM1_ESM.tif (518 kb)
Figure S1. A mixture of red and green retrobeads was injected into the mPFC. Both tracer solutions have a similar diffusion pattern, and therefore target a similar tissue volume, as shown in the injection site photos taken in the mPFC. All retrogradely filled cells were found to contain both tracers, suggesting that individual axons are capable of incorporating multiple tracers, and indicating that the small number of co-labelled cells found in the study is not the result of an experimental artifact. (TIFF 518 kb)
429_2015_1142_MOESM2_ESM.tif (986 kb)
Figure S2. Co-localization of 5-HT and GFP in the raphe of Pet1-EGFP mice. A) Strong expression of GFP was detected across all subfield of the raphe nuclei, and co-localized with 5-HT immunoreactivity. B) high magnification confocal images showing co-localization between GFP and 5-HT in Pet1-EGFP mice raphe. Scale bar = 15 µm. (TIFF 985 kb)
429_2015_1142_MOESM3_ESM.docx (15 kb)
Supplementary material 3 (DOCX 14 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Sebastian Pablo Fernandez
    • 1
    • 2
    • 3
  • Bruno Cauli
    • 2
    • 4
    • 5
  • Carolina Cabezas
    • 1
    • 2
    • 3
  • Aude Muzerelle
    • 1
    • 2
    • 3
  • Jean-Christophe Poncer
    • 1
    • 2
    • 3
  • Patricia Gaspar
    • 1
    • 2
    • 3
  1. 1.Institut du Fer à Moulin, INSERM U839ParisFrance
  2. 2.Université Pierre et Marie CurieParisFrance
  3. 3.Institut du Fer a MoulinParisFrance
  4. 4.CNRS, UMR 8246, Neuroscience Paris SeineParisFrance
  5. 5.Inserm UMR-S 1130, Neuroscience Paris SeineParisFrance

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