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

Sarah Melzer, Elena R. 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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 may be 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 genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several 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 GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

Original languageEnglish (US)
Pages (from-to)5622-5634.e25
JournalCell
Volume184
Issue number22
DOIs
StatePublished - Oct 28 2021

Keywords

  • cortex
  • CRISPR-Cas9
  • disinhibition
  • fear memory
  • gastrin-releasing peptide
  • neuropeptide
  • VIP cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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