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 a threat is no longer present; its impairment is linked to exaggerated fear in animals and PTSD in humans. Dopamine is essential for fear extinction, yet the underlying circuits and intracellular pathways are not well defined. Using gastrin-releasing peptide (Grp) knockout mice, the authors show enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm. In vivo fiber photometry revealed increased basolateral amygdala (BLA) dopaminergic binding/signals during conditioning and early extinction in Grp knockouts. Optogenetics and ex vivo electrophysiology indicated increased presynaptic ventral tegmental area (VTA)-to-BLA connectivity in knockouts, implicating dysregulated VTA input to BLA without GRP. RNA-seq and qPCR after long-term SEFL memory recall showed concerted downregulation of dopamine-related genes (including Th, Nurr1, Drd1/2) in BLA of knockouts, not seen in naïve conditions. The GRP thus regulates dopamine function during 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