TY - JOUR T1 - Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories JF - bioRxiv DO - 10.1101/2020.10.26.355123 SP - 2020.10.26.355123 AU - Sarah Melzer AU - Elena Newmark AU - Grace Or Mizuno AU - Minsuk Hyun AU - Adrienne C. Philson AU - Eleonora Quiroli AU - Beatrice Righetti AU - Malika R. Gregory AU - Kee Wui Huang AU - James Levasseur AU - Lin Tian AU - Bernardo L. Sabatini Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/26/2020.10.26.355123.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -