The subiculum is a patchwork of discrete subregions

  1. Mark S Cembrowski  Is a corresponding author
  2. Lihua Wang
  3. Andrew L Lemire
  4. Monique Copeland
  5. Salvatore F DiLisio
  6. Jody Clements
  7. Nelson Spruston
  1. Janelia Research Campus, Howard Hughes Medical Institute, United States

Abstract

In the hippocampus, the classical pyramidal cell type of the subiculum acts as a primary output, conveying hippocampal signals to a diverse suite of downstream regions. Accumulating evidence suggests that the subiculum pyramidal cell population may actually be comprised of discrete subclasses. Here, we investigated the extent and organizational principles governing pyramidal cell heterogeneity throughout the mouse subiculum. Using single-cell RNA-seq, we find that the subiculum pyramidal cell population can be deconstructed into eight separable subclasses. These subclasses were mapped onto abutting spatial domains, ultimately producing a complex laminar and columnar organization with heterogeneity across classical dorsal-ventral, proximal-distal, and superficial-deep axes. We further show that these transcriptomically defined subclasses correspond to differential protein products and can be associated with specific projection targets. This work deconstructs the complex landscape of subiculum pyramidal cells into spatially segregated subclasses that may be observed, controlled, and interpreted in future experiments.

Data availability

Raw and processed scRNA-seq datasets have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus under GEO: GSE113069.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Mark S Cembrowski

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    For correspondence
    cembrowskim@janelia.hhmi.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8275-7362
  2. Lihua Wang

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew L Lemire

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Monique Copeland

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Salvatore F DiLisio

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jody Clements

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nelson Spruston

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3118-1636

Funding

Howard Hughes Medical Institute

  • Mark S Cembrowski
  • Lihua Wang
  • Andrew L Lemire
  • Monique Copeland
  • Salvatore F DiLisio
  • Jody Clements
  • Nelson Spruston

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

Reviewing Editor

  1. Laura Colgin, The University of Texas at Austin, Center for Learning and Memory, United States

Ethics

Animal experimentation: Experimental procedures were approved by the Institutional Animal Care and Use Committee at the Janelia Research Campus.(protocols 14-118 and 17-159).

Version history

  1. Received: April 19, 2018
  2. Accepted: October 27, 2018
  3. Accepted Manuscript published: October 30, 2018 (version 1)
  4. Version of Record published: November 9, 2018 (version 2)

Copyright

© 2018, Cembrowski 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

  • 5,727
    views
  • 905
    downloads
  • 72
    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. Mark S Cembrowski
  2. Lihua Wang
  3. Andrew L Lemire
  4. Monique Copeland
  5. Salvatore F DiLisio
  6. Jody Clements
  7. Nelson Spruston
(2018)
The subiculum is a patchwork of discrete subregions
eLife 7:e37701.
https://doi.org/10.7554/eLife.37701

Share this article

https://doi.org/10.7554/eLife.37701

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Sara Ibañez, Nilapratim Sengupta ... Christina M Weaver
    Research Article

    Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

    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.