1. Neuroscience
Download icon

Neuronal Plasticity: Genetic signatures of memories

  1. Vivek Sagar  Is a corresponding author
  2. Thorsten Kahnt  Is a corresponding author
  1. Northwestern University, Feinberg School of Medicine, United States
  2. Northwestern University, Weinberg College of Arts and Sciences, United States
Insight
  • Cited 2
  • Views 2,663
  • Annotations
Cite this article as: eLife 2018;7:e36064 doi: 10.7554/eLife.36064

Abstract

Memorable positive and negative experiences produce different profiles of gene expression in brain areas associated with long-term memory.

Main text

Try to recall your earliest memory. Chances are this experience took place a few decades ago. How did your brain register this event, and then keep a record of it over so many years? These fundamental questions have long been the focus of neuroscience research.

A memory is created when a significant signal is received from the environment and then activates groups of neurons in the brain. Next, genes called ‘immediate-early genes’ are activated in the neurons, and go on to produce a range of proteins that change the strength of the synapses that connect neurons with each other (Sheng and Greenberg, 1990; Kang and Schuman, 1996). It is this synaptic plasticity that drives how memories are created and stored (Martin et al., 2000). Immediate-early gene activation is used as a marker of when and where synaptic plasticity is taking place (Flavell and Greenberg, 2008; Minatohara et al., 2015). Yet, it is not known whether this genetic response includes any specific information about the environmental stimuli that triggered it (Okuno, 2011), or if it is the same regardless of the signal.

Now, in eLife, Ami Citri and colleagues from the Hebrew University of Jerusalem and the Canadian Institute for Advanced Research – including Diptendu Mukherjee, Bogna Marta Ignatowska-Jankowska and Eyal Itskovits as joint first authors – report that different experiences lead to different expression profiles of the immediate-early genes in various regions of brain that are involved in memory in mice (Mukherjee et al., 2018). This makes it possible to infer the type of experience that produced a given expression profile.

First, the mice were given either cocaine (a positive experience) or a substance that made them sick (a negative experience). A method called quantitative polymerase chain reaction (qPCR) was then used to measure the expression of each immediate-early gene in response to the experience. The analysis focused on five brain areas which react to memorable events and play a crucial role in long-term memory (Catani et al., 2013).

Based on these results, Mukherjee et al. selected five immediate-early genes for further analysis. They found that, across the different brain areas, the expression profiles of these five genes were unique for each experience (Figure 1). In fact, the patterns were so specific that it was possible to use them to predict with high accuracy which experience the mouse had gone through. This suggests that the activation profiles for these genes contain information about the specific experiences that an animal encountered.

Figure 1
Download asset Open asset
Positive and negative events produce unique gene expression profiles for immediate-early genes in mice.

Two groups of mice are exposed to either a positive experience (left) or negative experience (right). This triggers the activation of five immediate-early genes (Arc, Egr2, Egr4, Fos and Fosb; different color triangles) in the neurons of brain regions that are involved in the formation of long-term memories. The level of expression of each gene is quantified using quantitative polymerase chain reaction (qPCR). The expression pattern of these five genes (bottom) is specific to the event experienced by the mice.

IMAGE CREDIT: Vivek Sagar and Thorsten Kahnt.

To confirm these results, further experiments were conducted in which mice were exposed to additional positive and negative experiences (such as being given sucrose or an electric shock). Again, each event was associated with a characteristic gene activation profile, and the specific experience could be predicted on the basis of gene expression patterns. Strikingly, positive experiences (e.g. cocaine and sucrose) produced gene expression profiles that were similar to each other across the five brain areas; so did the negative events. However, the profiles produced by negative and positive signals were different from each other. Moreover, it was still possible to discriminate between the patterns created by different types of positive (or negative) experiences.

In a final step, Mukherjee et al. used their decoding model to identify the smallest combination of genes and brain areas that was sufficient to predict individual experiences with high accuracy. This minimal subset contained only eight gene-brain area combinations, and was better at predicting experiences than any of the genes or brain regions in isolation.

The results of this study suggest that immediate-early genes are not merely indicators of synaptic plasticity. Rather, the expression profiles for these genes contain fairly specific information about the stimulus that created them. This is similar to what has been observed with patterns of neural activity (Howard et al., 2015). This specificity provides important insights into how to store the identity of an experience.

These experiments provide a solid foundation from which to explore the mechanisms related to the activation of immediate-early genes in greater detail. For example, we do not know whether the same processes will operate in regions of the brain that are not associated with memory. It also remains unclear if highly similar experiences would still produce distinguishable genetic signatures.

References

Article and author information

Author details

  1. Vivek Sagar

    Vivek Sagar is in the Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, United States
    For correspondence
    VivekSagar2016@u.northwestern.edu
    Competing interests
    No competing interests declared

  2. Thorsten Kahnt

    Thorsten Kahnt is in the Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, United States and the Department of Psychology, Northwestern University, Weinberg College of Arts and Sciences, Evanston, United States
    For correspondence
    thorsten.kahnt@northwestern.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3575-2670

Publication history

  1. Version of Record published: March 21, 2018 (version 1)

Copyright

© 2018, Sagar et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,663
    Page views
  • 244
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Neuroscience

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

    Diptendu Mukherjee et al.
    Research Article Updated

    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.

    1. Neuroscience

    Unsupervised changes in core object recognition behavior are predicted by neural plasticity in inferior temporal cortex

    Xiaoxuan Jia et al.
    Research Article Updated

    Temporal continuity of object identity is a feature of natural visual input and is potentially exploited – in an unsupervised manner – by the ventral visual stream to build the neural representation in inferior temporal (IT) cortex. Here, we investigated whether plasticity of individual IT neurons underlies human core object recognition behavioral changes induced with unsupervised visual experience. We built a single-neuron plasticity model combined with a previously established IT population-to-recognition-behavior-linking model to predict human learning effects. We found that our model, after constrained by neurophysiological data, largely predicted the mean direction, magnitude, and time course of human performance changes. We also found a previously unreported dependency of the observed human performance change on the initial task difficulty. This result adds support to the hypothesis that tolerant core object recognition in human and non-human primates is instructed – at least in part – by naturally occurring unsupervised temporal contiguity experience.

    1. Genetics and Genomics
    2. Neuroscience

    Neuropeptide ACP facilitates lipid oxidation and utilization during long-term flight in locusts

    Li Hou et al.
    Research Article Updated

    Long-term flight depends heavily on intensive energy metabolism in animals; however, the neuroendocrine mechanisms underlying efficient substrate utilization remain elusive. Here, we report that the adipokinetic hormone/corazonin-related peptide (ACP) can facilitate muscle lipid utilization in a famous long-term migratory flighting species, Locusta migratoria. By peptidomic analysis and RNAi screening, we identified brain-derived ACP as a key flight-related neuropeptide. ACP gene expression increased notably upon sustained flight. CRISPR/Cas9-mediated knockout of ACP gene and ACP receptor gene (ACPR) significantly abated prolonged flight of locusts. Transcriptomic and metabolomic analyses further revealed that genes and metabolites involved in fatty acid transport and oxidation were notably downregulated in the flight muscle of ACP mutants. Finally, we demonstrated that a fatty-acid-binding protein (FABP) mediated the effects of ACP in regulating muscle lipid metabolism during long-term flight in locusts. Our results elucidated a previously undescribed neuroendocrine mechanism underlying efficient energy utilization associated with long-term flight.