Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

  1. Antoine Cherix  Is a corresponding author
  2. Thomas Larrieu
  3. Jocelyn Grosse
  4. João Rodrigues
  5. Bruce McEwen
  6. Carla Nasca
  7. Rolf Gruetter
  8. Carmen Sandi  Is a corresponding author
  1. École Polytechnique Fédérale de Lausanne (EPFL), Switzerland
  2. Lausanne University Hospital (CHUV), Switzerland
  3. The Rockefeller University, United States

Abstract

Emerging evidence suggests that hierarchical status provide vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using 1H-magnetic resonance spectroscopy (1H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Antoine Cherix

    Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    For correspondence
    ant.cherix@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4168-8273
  2. Thomas Larrieu

    Center for Psychiatric Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Jocelyn Grosse

    Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. João Rodrigues

    Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Bruce McEwen

    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Carla Nasca

    Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rolf Gruetter

    Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Carmen Sandi

    Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    For correspondence
    carmen.sandi@epfl.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7713-8321

Funding

Swiss National Science Foundation (31003A-152614)

  • Carmen Sandi

Swiss National Science Foundation (31003A-176206)

  • Carmen Sandi

Swiss National Science Foundation - NCCR Synapsy (51NF40-158776)

  • Carmen Sandi

Swiss National Science Foundation - NCCR Synapsy (51NF40-185897)

  • Carmen Sandi

European Union's Seventh Framework Program for Research (603016)

  • Carmen Sandi

EPFL-Jebsen Research Program

  • Carmen Sandi

Center for Biomedical Imaging - EPFL

  • Rolf Gruetter

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

Ethics

Animal experimentation: All experiments were performed with the approval of the Cantonal Veterinary Authorities (Vaud, Switzerland) and carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609EEC).

Copyright

© 2020, Cherix 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

  • 5,023
    views
  • 429
    downloads
  • 51
    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. Antoine Cherix
  2. Thomas Larrieu
  3. Jocelyn Grosse
  4. João Rodrigues
  5. Bruce McEwen
  6. Carla Nasca
  7. Rolf Gruetter
  8. Carmen Sandi
(2020)
Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine
eLife 9:e50631.
https://doi.org/10.7554/eLife.50631

Share this article

https://doi.org/10.7554/eLife.50631

Further reading

    1. Neuroscience
    Jean-François Brunet
    Review Article

    Historically, the creation of the parasympathetic division of the autonomic nervous system of the vertebrates is inextricably linked to the unification of the cranial and sacral autonomic outflows. There is an intriguing disproportion between the entrenchment of the notion of a ‘cranio-sacral’ pathway, which informs every textbook schematic of the autonomic nervous system since the early XXth century, and the wobbliness of its two roots: an anatomical detail overinterpreted by Walter Holbrook Gaskell (the ‘gap’ between the lumbar and sacral outflows), on which John Newport Langley grafted a piece of physiology (a supposed antagonism of these two outflows on external genitals), repeatedly questioned since, to little avail. I retrace the birth of a flawed scientific concept (the cranio-sacral outflow) and the way in which it ossified instead of dissipated. Then, I suggest that the critique of the ‘cranio-sacral outflow’ invites, in turn, a radical deconstruction of the very notion of a ‘parasympathetic’ outflow, and a more realistic description of the autonomic nervous system.

    1. Developmental Biology
    2. Neuroscience
    Mahima Bose, Ishita Talwar ... Shubha Tole
    Research Article

    In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss of Foxg1 in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway component Fgfr3, which is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons. Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated in Foxg1 null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.