Dorsal Raphe 5-HT Neurons Utilize, But Do Not Generate, Negative Aversive Prediction Errors

• Published in: eNeuro 2022-01, Vol.9 (1), p.ENEURO.0132-21.2022
• Main Authors: Walker, Rachel A, Suthard, Rebecca L, Perison, Taylor N, Sheehan, Nora M, Dwyer, Caitlin C, Lee, Jillian K, Enabulele, Eghosa K, Ray, Madelyn H, McDannald, Michael A
• Format: Article
• Language: English
• Subjects: Animals; Dorsal Raphe Nucleus - metabolism; Female; Humans; Male; Neurons - metabolism; New Research; Optogenetics; Rats; Serotonin - physiology; Tryptophan Hydroxylase - genetics; Tryptophan Hydroxylase - metabolism
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0132-21.2022

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, DRN 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  = 0.00, uncertainty  = 0.375, and danger  = 1.00. Rats then received selective extinction to the uncertainty cue, a behavioral manipulation designed to probe -PE. Deleting DRN 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 DRN 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. DRN 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 DRN 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 DRN cells in using, but not generating, -PE to weaken cue-shock associations.