1. Neuroscience
Download icon

A genetic link between discriminative fear coding by the lateral amygdala, dopamine, and fear generalization

  1. Graham L Jones
  2. Marta E Soden
  3. Cerise R Knakal
  4. Heather Lee
  5. Amanda S Zila
  6. Elliott B Merriam
  7. Larry S Zweifel  Is a corresponding author
  1. University of Washington, United States
Research Article
  • Cited 13
  • Views 1,944
  • Annotations
Cite this article as: eLife 2015;4:e08969 doi: 10.7554/eLife.08969

Abstract

The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

Article and author information

Author details

  1. Graham L Jones

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Marta E Soden

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Cerise R Knakal

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Heather Lee

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Amanda S Zila

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Elliott B Merriam

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Larry S Zweifel

    Department of Psychiatry and Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, United States
    For correspondence
    larryz@uw.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experimental procedures were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the University of Washington Institutional Animal Care and Use Committee protocol (#4249-01). All surgical procedures were performed under isolflurane anesthesia with analagesic pretreatment.All efforts were made to minimize suffering.

Reviewing Editor

  1. Eunjoon Kim, Korea Advanced Institute of Science and Technology, Republic of Korea

Publication history

  1. Received: May 24, 2015
  2. Accepted: September 23, 2015
  3. Accepted Manuscript published: September 24, 2015 (version 1)
  4. Version of Record published: October 27, 2015 (version 2)

Copyright

© 2015, Jones 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

  • 1,944
    Page views
  • 412
    Downloads
  • 13
    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. Developmental Biology
    2. Neuroscience

    Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance

    Hiroki Takechi et al.
    Research Article

    Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.

    1. Genetics and Genomics
    2. Neuroscience

    Sequential perturbations to mouse corticogenesis following in utero maternal immune activation

    Cesar P Canales et al.
    Research Article

    In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by six hours following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.

    1. Cell Biology
    2. Neuroscience

    Systematic functional analysis of Rab GTPases reveals limits of neuronal robustness to environmental challenges in flies

    Friederike Elisabeth Kohrs et al.
    Tools and Resources

    Rab GTPases are molecular switches that regulate membrane trafficking in all cells. Neurons have particular demands on membrane trafficking and express numerous Rab GTPases of unknown function. Here we report the generation and characterization of molecularly defined null mutants for all 26 rab genes in Drosophila. In flies, all rab genes are expressed in the nervous system where at least half exhibit particularly high levels compared to other tissues. Surprisingly, loss of any of these 13 nervous system-enriched Rabs yielded viable and fertile flies without obvious morphological defects. However, all 13 mutants differentially affected development when challenged with different temperatures, or neuronal function when challenged with continuous stimulation. We identified a synaptic maintenance defect following continuous stimulation for six mutants, including an autophagy-independent role of rab26. The complete mutant collection generated in this study provides a basis for further comprehensive studies of Rab GTPases during development and function in vivo.