Urocortin-3 neurons in the mouse perifornical area promote infant-directed neglect and aggression

  1. Anita E Autry
  2. Zheng Wu
  3. Vikrant Kapoor
  4. Johannes Kohl
  5. Dhananjay Bambah-Mukku
  6. Nimrod D Rubinstein
  7. Brenda Marin-Rodriguez
  8. Ilaria Carta
  9. Victoria Sedwick
  10. Ming Tang
  11. Catherine Dulac  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. Columbia University, United States
  3. Harvard University, United States
  4. The Francis Crick Institute, United Kingdom

Abstract

While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting, the regulation of infant-directed aggression and how it relates to adult-adult aggression is poorly understood. Here we show that urocortin-3 (Ucn3)-expressing neurons in the hypothalamic perifornical area (PeFAUcn3) are activated during infant-directed attacks in males and females, but not other behaviors. Functional manipulations of PeFAUcn3 neurons demonstrate the role of this population in the negative control of parenting in both sexes. PeFAUcn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send projections to hypothalamic and limbic areas. Optogenetic activation of PeFAUcn3 axon terminals in these regions triggers various aspects of infant-directed agonistic responses, such as neglect, repulsion and aggression. Thus, PeFAUcn3 neurons emerge as a dedicated circuit component controlling infant-directed neglect and aggression, providing a new framework to understand the positive and negative regulation of parenting in health and disease.

Data availability

- Microarray data have been deposited in GEO under accession code GSE161507 and analysis code can be found at https://gitlab.com/dulaclab/ucn3_neuron_microarray.- pS6 data have been deposited in GEO under accession code GSE161552 and analysis code is available on Github (https://gitlab.com/dulaclab/ucn3_neuron_microarray/-/tree/master/braimSourceCode/braim.R).

The following data sets were generated

Article and author information

Author details

  1. Anita E Autry

    Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    No competing interests declared.
  2. Zheng Wu

    Department of Neuroscience, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  3. Vikrant Kapoor

    Molecular and cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Johannes Kohl

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8222-0282
  5. Dhananjay Bambah-Mukku

    Molecular and cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Nimrod D Rubinstein

    Molecular and cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Brenda Marin-Rodriguez

    Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. Ilaria Carta

    Neuroscience, Albert Einstein College of Medicine, Bronx NY, United States
    Competing interests
    No competing interests declared.
  9. Victoria Sedwick

    Neuroscience, Albert Einstein College of Medicine, Bronx NY, United States
    Competing interests
    No competing interests declared.
  10. Ming Tang

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Catherine Dulac

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    For correspondence
    dulac@fas.harvard.edu
    Competing interests
    Catherine Dulac, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5024-5418

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99HD085188)

  • Anita E Autry

Brain and Behavior Research Foundation (NARSAD Young Investigator)

  • Anita E Autry

European Molecular Biology Laboratory (ALTF 1008-2014)

  • Johannes Kohl

Wellcome Trust (Sir Henry Wellcome Fellowship)

  • Johannes Kohl

National Institute of Mental Health (K99HD092542)

  • Dhananjay Bambah-Mukku

Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01HD082131-01A1)

  • Catherine Dulac

Howard Hughes Medical Institute (HHMI investigator)

  • Catherine Dulac

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

Ethics

Animal experimentation: All animal experiments were approved by the Harvard University Institutional Animal Care and Use Committee. All experiments were performed in compliance with our Harvard University IACUC approved protocols 97-03-3, 23-12-3, and 25-13-3

Copyright

© 2021, Autry 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

  • 7,102
    views
  • 769
    downloads
  • 38
    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. Anita E Autry
  2. Zheng Wu
  3. Vikrant Kapoor
  4. Johannes Kohl
  5. Dhananjay Bambah-Mukku
  6. Nimrod D Rubinstein
  7. Brenda Marin-Rodriguez
  8. Ilaria Carta
  9. Victoria Sedwick
  10. Ming Tang
  11. Catherine Dulac
(2021)
Urocortin-3 neurons in the mouse perifornical area promote infant-directed neglect and aggression
eLife 10:e64680.
https://doi.org/10.7554/eLife.64680

Share this article

https://doi.org/10.7554/eLife.64680

Further reading

    1. Neuroscience
    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.