Salient experiences are represented by unique transcriptional signatures in the mouse brain

  1. Diptendu Mukherjee
  2. Bogna Marta Ignatowska-Jankowska
  3. Eyal Itskovits
  4. Ben Jerry Gonzales
  5. Hagit Turm
  6. Liz Izakson
  7. Doron Haritan
  8. Noa Bleistein
  9. Chen Cohen
  10. Ido Amit
  11. Tal Shay
  12. Brad Grueter
  13. Alon Zaslaver
  14. Ami Citri  Is a corresponding author
  1. The Hebrew University of Jerusalem, Israel
  2. Weizmann Institute of Science, Israel
  3. Ben-Gurion University of the Negev, Israel
  4. Vanderbilt University School of Medicine, United States

Abstract

It is well established that inducible transcription is essential for the consolidation of salient experiences into long-term memory. However, whether inducible transcription relays information about the identity and affective attributes of the experience being encoded, has not been explored. To this end, we analyzed transcription induced by a variety of rewarding and aversive experiences, across multiple brain regions. Our results describe the existence of robust transcriptional signatures uniquely representing distinct experiences, enabling near-perfect decoding of recent experiences. Furthermore, experiences with shared attributes display commonalities in their transcriptional signatures, exemplified in the representation of valence, habituation and reinforcement. This study introduces the concept of a neural transcriptional code, which represents the encoding of experiences in the mouse brain. This code is comprised of distinct transcriptional signatures that correlate to attributes of the experiences that are being committed to long-term memory.

Article and author information

Author details

  1. Diptendu Mukherjee

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Bogna Marta Ignatowska-Jankowska

    The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Eyal Itskovits

    Department of Genetics, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Ben Jerry Gonzales

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Hagit Turm

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Liz Izakson

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Doron Haritan

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Noa Bleistein

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Chen Cohen

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Ido Amit

    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  11. Tal Shay

    Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Brad Grueter

    Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4224-3866
  13. Alon Zaslaver

    Department of Genetics, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Ami Citri

    Department of Biological Chemistry, Silberman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    For correspondence
    ami.citri@mail.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9914-0278

Funding

Israel Science Foundation (Personal Grant 393/12 & I-CORE 1796/12)

  • Ami Citri

The Lady Davis Postdoctoral Fellowship (Postdoctoral stipend)

  • Bogna Marta Ignatowska-Jankowska

German-Israeli Foundation for Scientific Research and Development (Young Investigator Award 2299-2291.1./2011)

  • Ami Citri

Brain and Behavior Research Foundation (Young Investigator Award #18795)

  • Ami Citri

Canadian Institute for Advanced Research (Research Support)

  • Ami Citri

Binational United-States Israel Research Foundation (Research Grant #2011266)

  • Ami Citri

Milton Rosenbaum Research Foundation (Research Grant)

  • Ami Citri

National Institutes for Psychobiology in Israel (Research Grant 109-15-16)

  • Ami Citri

Shimon Peres Postdoctoral Award (Postdoctoral stipend)

  • Bogna Marta Ignatowska-Jankowska

ELSC Postdoctoral Award (Postdoctoral stipend)

  • Bogna Marta Ignatowska-Jankowska

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

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#NS-13-13895-3 ; NS-15-14668-3 ; NS-14-14088-3 ; NS-15-14312-3 ; NS-15-14348-3) of the Hebrew University of Jerusalem. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Hebrew University. Every effort was made to minimize suffering.

Version history

  1. Received: September 4, 2017
  2. Accepted: February 5, 2018
  3. Accepted Manuscript published: February 7, 2018 (version 1)
  4. Accepted Manuscript updated: February 22, 2018 (version 2)
  5. Version of Record published: March 21, 2018 (version 3)

Copyright

© 2018, Mukherjee 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

  • 6,911
    views
  • 1,063
    downloads
  • 33
    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. Diptendu Mukherjee
  2. Bogna Marta Ignatowska-Jankowska
  3. Eyal Itskovits
  4. Ben Jerry Gonzales
  5. Hagit Turm
  6. Liz Izakson
  7. Doron Haritan
  8. Noa Bleistein
  9. Chen Cohen
  10. Ido Amit
  11. Tal Shay
  12. Brad Grueter
  13. Alon Zaslaver
  14. Ami Citri
(2018)
Salient experiences are represented by unique transcriptional signatures in the mouse brain
eLife 7:e31220.
https://doi.org/10.7554/eLife.31220

Share this article

https://doi.org/10.7554/eLife.31220

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

    1. Neuroscience
    Nicholas GW Kennedy, Jessica C Lee ... Nathan M Holmes
    Research Article

    How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.