A striatal circuit balances learned fear in the presence and absence of sensory cues

  1. Michael Kintscher
  2. Olexiy Kochubey
  3. Ralf Schneggenburger  Is a corresponding author
  1. École Polytechnique Fédérale de Lausanne, Switzerland

Abstract

During fear learning, defensive behaviors like freezing need to be finely balanced in the presence or absence of threat-predicting cues (conditioned stimulus, CS). Nevertheless, the circuits underlying such balancing are largely unknown. Here, we investigate the role of the ventral tail striatum (vTS) in auditory-cued fear learning of male mice. In-vivo Ca2+ imaging showed that sizable sub-populations of direct (D1R+) and indirect pathway neurons (Adora+) in the vTS responded to footshocks, and to the initiation of movements after freezing; moreover, a sub-population of D1R+ neurons increased its responsiveness to an auditory CS during fear learning. In-vivo optogenetic silencing shows that footshock-driven activity of D1R+ neurons contributes to fear memory formation, whereas Adora+ neurons modulate freezing in the absence of a learned CS. Circuit tracing identified the posterior insular cortex (pInsCx) as an important cortical input to the vTS, and recording of optogenetically-evoked EPSCs revealed long-term plasticity with opposite outcomes at the cortical synapses onto D1R+ - and Adora+ neurons. Thus, direct- and indirect pathways neurons of the vTS show differential signs of plasticity after fear learning, and balance defensive behaviors in the presence and absence of learned sensory cues.

Data availability

The underlying raw data is available at doi:10.5281/zenodo.4003654.

Article and author information

Author details

  1. Michael Kintscher

    Laboratory for Synaptic Mechanisms, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2355-1369
  2. Olexiy Kochubey

    Laboratory of Synaptic Mechanisms, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Ralf Schneggenburger

    Laboratory of Synaptic Mechanisms, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    For correspondence
    ralf.schneggenburger@epfl.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6223-2830

Funding

European Molecular Biology Organization (ALTF 224-2015)

  • Michael Kintscher

Swiss National Science Foundation (31003A_176332 / 1)

  • Ralf Schneggenburger

NCCR Synapsy - The Synaptic Bases of Mental disease (Project P28)

  • Ralf Schneggenburger

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

Reviewing Editor

  1. Mario A Penzo, National Institute of Mental Health, United States

Ethics

Animal experimentation: All experimental procedures with laboratory animals (Mus musculus) were performed under authorizations for animal experimentation by the veterinary office of the Canton of Vaud, Switzerland (authorizations VD3274 and VD3518).

Version history

  1. Received: November 19, 2021
  2. Preprint posted: December 9, 2021 (view preprint)
  3. Accepted: January 16, 2023
  4. Accepted Manuscript published: January 19, 2023 (version 1)
  5. Version of Record published: February 3, 2023 (version 2)

Copyright

© 2023, Kintscher 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

  • 1,496
    Page views
  • 236
    Downloads
  • 1
    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. Michael Kintscher
  2. Olexiy Kochubey
  3. Ralf Schneggenburger
(2023)
A striatal circuit balances learned fear in the presence and absence of sensory cues
eLife 12:e75703.
https://doi.org/10.7554/eLife.75703

Share this article

https://doi.org/10.7554/eLife.75703

Further reading

    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.

    1. Cell Biology
    2. Neuroscience
    Zhenyong Wu, Grant F Kusick ... Shigeki Watanabe
    Research Article

    Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.