RT Journal Article
SR Electronic
T1 Dorsal Raphe 5-HT Neurons Utilize, But Do Not Generate, Negative Aversive Prediction Errors
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0132-21.2022
DO 10.1523/ENEURO.0132-21.2022
VO 9
IS 1
A1 Walker, Rachel A.
A1 Suthard, Rebecca L.
A1 Perison, Taylor N.
A1 Sheehan, Nora M.
A1 Dwyer, Caitlin C.
A1 Lee, Jillian K.
A1 Enabulele, Eghosa K.
A1 Ray, Madelyn H.
A1 McDannald, Michael A.
YR 2022
UL http://www.eneuro.org/content/9/1/ENEURO.0132-21.2022.abstract
AB The dorsal raphe nucleus (DRN) contains the largest population of serotonin (5-HT) neurons in the central nervous system. 5-HT, synthesized via tryptophan hydroxylase 2 (Tph2), is a widely functioning neuromodulator implicated in fear learning. Here, we sought to investigate whether DRN 5-HT is necessary to reduce fear via negative prediction error (–PE). Using male and female TPH2-cre rats, DRNtph2+ cells were selectively deleted via cre-caspase (rAAV5-Flex-taCasp3-TEVp) in experiment 1. Rats then underwent fear discrimination during which three cues were associated with unique foot shock probabilities: safety p = 0.00, uncertainty p = 0.375, and danger p = 1.00. Rats then received selective extinction to the uncertainty cue, a behavioral manipulation designed to probe –PE. Deleting DRNtph2+ cells had no impact on initial discrimination but slowed selective extinction. In experiment 2, we used a within-subjects optogenetic inhibition design to causally implicate DRNtph2+ cells in prediction error signaling. Male and female TPH2-cre rats received intra-DRN infusions of cre-dependent halorhodopsin (rAAV5-Ef1a-DIO-eNpHR3.0-eYFP) or cre-YFP. DRNtph2+ cells were inhibited specifically during the time of prediction error or a control period. Illumination during either positive prediction error (+PE) or control periods had no impact on fear to the uncertainty cue. Inhibition of DRNtph2+ cells at the time of –PE did not impact immediate fear, but facilitated selective extinction in postillumination sessions. Together, these results demonstrate a role for DRNtph2+ cells in using, but not generating, –PE to weaken cue-shock associations.