Ventral Tegmental Dopamine Initiates Fear Extinction by Activating Reward-Processing Circuits in the Amygdala
Background: Extinguishing conditioned fear responses is vital for adaptive behavior, and its failure contributes to anxiety disorders such as PTSD. The basolateral amygdala (BLA) contains anterior Rspo2⁺ neurons driving fear and posterior Ppp1r1b⁺ neurons encoding reward and extinction. Although extinction memory forms in the Ppp1r1b⁺ neurons, the signal that initiates this process was unknown. Dopaminergic activity from the ventral tegmental area (VTA) has been proposed to provide such a teaching signal.
Hypothesis: This study hypothesized that the omission of expected aversive stimuli during fear extinction increases dopaminergic activity from the VTA onto Ppp1r1b⁺ BLA neurons, thereby initiating extinction learning.
Methods: The authors used viral circuit tracing, optogenetics and in vivo fiber photometry in genetically defined mouse lines to examine dopamine signaling between the VTA and BLA. Fluorescence and cell-count analyses were performed with NeuroInfo and Stereo Investigator for brain mapping and quantification, respectively, and fiber photometry data were acquired using a single-site recording system.
Results: Anterograde and retrograde tracing showed topographically distinct VTA dopamine projections to Rspo2⁺ and Ppp1r1b⁺ neurons. Dopamine receptor mapping revealed stronger D1 receptor expression in Ppp1r1b⁺ neurons. Fiber photometry demonstrated that dopamine activity in Ppp1r1b⁺ neurons, but not Rspo2⁺ neurons, increased following freezing cessation and correlated with extinction learning strength. Optogenetic activation of VTA terminals in the posterior BLA accelerated extinction, whereas inhibition impaired it. Manipulating D1 receptor expression bidirectionally modulated extinction behavior.
Conclusions: Dopaminergic input from the VTA to BLA Ppp1r1b⁺ neurons acts as a teaching signal that drives fear extinction learning through D1 receptor–mediated excitation, identifying a circuit mechanism by which dopamine promotes the transition from fear to safety.
Zhang X, Flick K, Rizzo M, Pignatelli M, Tonegawa S. Dopamine induces fear extinction by activating the reward-responding amygdala neurons. Proc Natl Acad Sci USA 2025;122(18):e2501331122. doi: 10.1073/pnas.2501331122.
