Abstract

Calcium is a critical second messenger in neurons that contributes to learning and memory, but how the coordination of action potentials of neuronal ensembles with the hippocampal local field potential (LFP) is reflected in dynamic calcium activity remains unclear. Here, we recorded hippocampal calcium activity with endoscopic imaging of the genetically encoded fluorophore GCaMP6 with concomitant LFP in freely behaving mice. Dynamic calcium activity was greater in exploratory behavior and REM sleep than in quiet wakefulness and slow wave sleep, behavioral states that differ with respect to theta and septal cholinergic activity, and modulated at sharp wave ripples (SWRs). Chemogenetic activation of septal cholinergic neurons expressing the excitatory hM3Dq DREADD increased calcium activity and reduced SWRs. Furthermore, inhibition of muscarinic acetylcholine receptors (mAChRs) reduced calcium activity while increasing SWRs. These results demonstrate that hippocampal dynamic calcium activity depends on behavioral and theta state as well as endogenous mAChR activation.

Data availability

Imaging data has been deposited into Dryad, and is available at doi:10.5061/dryad.8ct101p

The following data sets were generated

Article and author information

Author details

  1. Heng Zhou

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kevin R Neville

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nitsan Goldstein

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shushi Kabu

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Naila Kausar

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Rong Ye

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Thuan Tinh Nguyen

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Noah Gelwan

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Bradley T Hyman

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Stephen N Gomperts

    Department of Neurology, Massachusetts General Hospital, Charlestown, United States
    For correspondence
    sgomperts@partners.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0083-0077

Funding

National Institute on Aging (1R01 AG054551)

  • Stephen N Gomperts

Fidelity Biosciences

  • Bradley T Hyman
  • Stephen N Gomperts

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, 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 an approved institutional animal care and use committee (IACUC) protocol (2012N000206) of the Massachusetts General Hospital. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: July 2, 2018
  2. Accepted: February 15, 2019
  3. Accepted Manuscript published: March 7, 2019 (version 1)
  4. Version of Record published: March 26, 2019 (version 2)

Copyright

© 2019, Zhou 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

  • 4,986
    Page views
  • 899
    Downloads
  • 21
    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)

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. Heng Zhou
  2. Kevin R Neville
  3. Nitsan Goldstein
  4. Shushi Kabu
  5. Naila Kausar
  6. Rong Ye
  7. Thuan Tinh Nguyen
  8. Noah Gelwan
  9. Bradley T Hyman
  10. Stephen N Gomperts
(2019)
Cholinergic modulation of hippocampal calcium activity across the sleep-wake cycle
eLife 8:e39777.
https://doi.org/10.7554/eLife.39777

Share this article

https://doi.org/10.7554/eLife.39777

Further reading

    1. Neuroscience
    Harry Clark, Matthew F Nolan
    Research Article

    Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently of the task reference frame. Anchoring varied between and within sessions, while spatial firing of non-grid cells was either coherent with the grid population, or was stably anchored to the task environment. We took advantage of the variability in task-anchoring to evaluate whether and when encoding of location by grid cells might contribute to behaviour. We find that when reward location is indicated by a visual cue, performance is similar regardless of whether grid cells are task-anchored or not, arguing against a role for grid representations when location cues are available. By contrast, in the absence of the visual cue, performance was enhanced when grid cells were anchored to the task environment. Our results suggest that anchoring of grid cells to task reference frames selectively enhances performance when path integration is required.

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.