Behavioral role of PACAP reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

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Abstract

The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures.

The following previously published data sets were used

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http://help.brain-map.org/display/mousebrain/In+Situ+Hybridization+%28ISH%29+Data.

https://mouse.brain-map.org

Article and author information

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Limei Zhang

Medicine-Physiology, National Autonomous University of Mexico, Mexico City, Mexico

For correspondence
limei@unam.mx

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7422-5136
Vito S Hernandez

Medicine-Physiology, National Autonomous University of Mexico, Mexico City, Mexico

Competing interests
The authors declare that no competing interests exist.
Charles R Gerfen

Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Sunny Z Jiang

Section on Molecular Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Lilian Zavala

Medicine-Physiology, National Autonomous University of Mexico, Mexico City, Mexico

Competing interests
The authors declare that no competing interests exist.
Rafael A Barrio

Department of complex systems, Institute of Physics, National Autonomous University of Mexico, Mexico City, Mexico

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0987-0785
Lee E Eiden

Section on Molecular Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, United States

For correspondence
eidenl@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7524-944X

Funding

Consejo Nacional de Ciencia y Tecnología (CB238744)

Limei Zhang

National Institute of Mental Health (NIMH-IRP-1ZIAMH002386)

Lee E Eiden

Universidad Nacional Autónoma de México (IN216918)

Limei Zhang

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

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 experiments were approved by the NIMH Institutional Animal Care and Use Committee (ACUC, LCMR-08) and conducted in accordance with the NIH guidelines.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.