RT Journal Article
SR Electronic
T1 Altered Dopamine Signaling in Extinction-Deficient Mice
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0174-25.2025
DO 10.1523/ENEURO.0174-25.2025
VO 12
IS 11
A1 Gunduz-Cinar, Ozge
A1 Fritz, Eva Maria
A1 Xia, Maya
A1 Van Leer, Elise
A1 Crow, Nevin
A1 Holmes, Andrew
A1 Singewald, Nicolas
YR 2025
UL http://www.eneuro.org/content/12/11/ENEURO.0174-25.2025.abstract
AB A central mechanism of exposure-based cognitive behavioral therapy for anxiety and trauma-related disorders is fear extinction. However, the mechanisms underlying fear extinction are deficient in some individuals, leading to treatment resistance. Recent animal studies demonstrate that upon omission of the aversive, unconditioned stimulus (US) during fear extinction, dopamine (DA) neurons in the ventral tegmental area (VTA) produce a prediction error (PE)-like signal. However, whether this VTA-DA neuronal PE-like signal is altered in animals exhibiting deficient fear extinction has not been studied. Here, we used a mouse model of impaired fear extinction [129S1/SvImJ (S1) inbred mouse strain] to monitor and manipulate VTA-DA neurons during extinction. Male DAT-Cre mice backcrossed onto an S1 background (S1-DAT-Cre) exhibited impaired extinction but normal VTA-DA neuron number, as compared with BL6-DAT-Cre mice. In vivo fiber photometry showed that impaired extinction in male S1-DAT-Cre mice was associated with abnormally sustained US omission-related VTA-DA neuronal calcium activity during extinction training and retrieval. Neither in vivo optogenetic photoexcitation of VTA-DA neuronal cell bodies nor their axons in the infralimbic cortex was sufficient to rescue deficient extinction in male S1-DAT-Cre mice, at least within the optogenetic and behavioral parameters used. These data suggest that alterations in the activity of VTA-DA neurons during extinction learning and retrieval may be associated with deficient fear extinction in male S1 mice and could potentially contribute to extinction impairments in patient populations.