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.

整个哺乳动物皮层的去抑制神经元是电路兴奋性和可塑性的强大增强剂。去抑制性、抑制性和兴奋性神经元中神经肽受体的差异表达表明，每个电路基序可能受不同的神经肽能系统控制。在这里，我们揭示了铃蟾肽样神经肽、胃泌素释放肽 (GRP) 通过选择性靶向和激活血管活性肠肽 (VIP) 表达细胞来招募去抑制性皮质微电路。使用基因编码的 GRP 传感器、光遗传学顺行刺激和跨突触追踪，我们发现 GRP 很可能通过来自几个本地和远程来源的突触外扩散来调节 VIP 细胞。体内光度测定和 CRISPR-Cas9 介导的听觉皮层 GRP 受体 (GRPR) 敲除表明，VIP 细胞被新的声音和厌恶性冲击强烈招募，GRP-GRPR 信号增强了听觉恐惧记忆。我们的数据建立了选择性去抑制皮层微电路的肽能募集作为调节恐惧记忆的机制。