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

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. [Display omitted] •Gastrin-releasing peptide (GRP) receptors are expressed in cortical VIP cells•GRP modulates cortical disinhibitory VIP cell activity and gene expression•Cortical VIP cells activate to novel sounds and shocks during fear conditioning•Ablation of GRP receptor in auditory cortex results in impaired fear memory Critical function of neuropeptides in cortex-dependent behaviors is demonstrated by local and long-range sources of the neuropeptide, GRP, selectively recruiting disinhibitory cortical microcircuits in auditory cortex to regulate fear memories in mice.