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 leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism's survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp^-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp^-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp^-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp^-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.