Dopamine release and dopamine-related gene expression in the amygdala are modulated by the gastrin-releasing peptide in opposite directions during stress-enhanced fear learning and extinction

Fear extinction reduces conditioned fear responses when threat is no longer present; its deficits contribute to PTSD. While dopamine has emerged as essential for fear extinction, underlying circuits and intracellular pathways are unclear. Using Grp gene knockout mice, we show enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm. In vivo fiber photometry revealed increased basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction in Grp knockouts. Optogenetics with ex vivo electrophysiology demonstrated increased presynaptic VTA-BLA connectivity in knockouts, implicating dysregulated VTA input to BLA without GRP. RNA-seq and qPCR showed concerted downregulation of dopamine-related genes in BLA after long-term SEFL memory recall in Grp knockouts, not seen in naive conditions. Thus, GRP regulates dopamine in stress-enhanced fear processing and Grp is the first gene identified to regulate dopaminergic control of fear extinction.

Yoshikazu Morishita, Ileana Fuentes, Sofia Gonzalez-Salinas, John Favate, Jennifer Mejaes, Ko Zushida, Akinori Nishi, Charles Hevi, Noriko Goldsmith, Steve Buyske, Stephanie E. Sillivan, Courtney A. Miller, Eric R. Kandel, Shusaku Uchida, Premal Shah, Juan Marcos Alarcon, David J. Barker, Gleb P. Shumyatsky