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Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories

View ORCID ProfileSarah Melzer, Elena Newmark, View ORCID ProfileGrace Or Mizuno, View ORCID ProfileMinsuk Hyun, Adrienne C. Philson, View ORCID ProfileEleonora Quiroli, Beatrice Righetti, Malika R. Gregory, View ORCID ProfileKee Wui Huang, James Levasseur, View ORCID ProfileLin Tian, View ORCID ProfileBernardo L. Sabatini
doi: https://doi.org/10.1101/2020.10.26.355123
Sarah Melzer
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Elena Newmark
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Grace Or Mizuno
2Departments of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA
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Minsuk Hyun
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Adrienne C. Philson
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Eleonora Quiroli
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Beatrice Righetti
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Malika R. Gregory
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Kee Wui Huang
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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James Levasseur
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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Lin Tian
2Departments of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA
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Bernardo L. Sabatini
1Dept. of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA
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  • For correspondence: bsabatini@hms.harvard.edu
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Summary

Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory and excitatory neurons suggests that each circuit motif is controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a newly-developed genetically-encoded GRP sensor and trans-synaptic tracing we reveal that GRP regulates VIP cells via extrasynaptic diffusion from several putative local and long-range sources. In vivo photometry and CRISPR/Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and that GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 26, 2020.
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Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories
Sarah Melzer, Elena Newmark, Grace Or Mizuno, Minsuk Hyun, Adrienne C. Philson, Eleonora Quiroli, Beatrice Righetti, Malika R. Gregory, Kee Wui Huang, James Levasseur, Lin Tian, Bernardo L. Sabatini
bioRxiv 2020.10.26.355123; doi: https://doi.org/10.1101/2020.10.26.355123
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Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories
Sarah Melzer, Elena Newmark, Grace Or Mizuno, Minsuk Hyun, Adrienne C. Philson, Eleonora Quiroli, Beatrice Righetti, Malika R. Gregory, Kee Wui Huang, James Levasseur, Lin Tian, Bernardo L. Sabatini
bioRxiv 2020.10.26.355123; doi: https://doi.org/10.1101/2020.10.26.355123

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