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Research ArticleResearch Article: New Research, Cognition and Behavior

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

Rachel A. Walker, Rebecca L. Suthard, Taylor N. Perison, Nora M. Sheehan, Caitlin C. Dwyer, Jillian K. Lee, Eghosa K. Enabulele, Madelyn H. Ray and Michael A. McDannald
eNeuro 25 January 2022, 9 (1) ENEURO.0132-21.2022; DOI: https://doi.org/10.1523/ENEURO.0132-21.2022
Rachel A. Walker
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Rebecca L. Suthard
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Taylor N. Perison
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Nora M. Sheehan
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Caitlin C. Dwyer
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Jillian K. Lee
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Eghosa K. Enabulele
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Madelyn H. Ray
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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Michael A. McDannald
Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA 02467
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  • Figure 1.
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    Figure 1.

    YFP versus Caspase baseline nose poke rates. Mean ± SEM baseline nose poke rates for YFP (gray) and caspase rats (green) are plotted for the two preexposure (p), 16 discrimination, and eight selective extinction sessions. No group differences were detected in baseline nose poke behavior.

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    Figure 2.

    DRNtph2+ deletion does not impact discrimination but impairs extinction of uncertainty. A, Representative image shows cre-YFP (yellow) labeling of neurons in the DRN against tph2 immunohistochemistry (red) in a TPH2-cre rat. Fluorescent Nissl staining (NeuroTrace) shows neuronal cell bodies (blue). B, Representative image shows DRNtph2+ deletion via cre-caspase with labeling as in A. C, Mean ± SEM suppression ratios for YFP rats to danger (red), uncertainty (purple), and safety (blue) are shown for the two preexposure sessions (p), 16 discrimination sessions, and eight selective extinction sessions. D, Caspase suppression ratio data shown as in A.

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    Figure 3.

    YFP versus eNpHR baseline nose poke rates. Mean ± SEM baseline nose poke rates for YFP (gray) and eNpHR rats (green) are plotted for the two preexposure (p), 18 discrimination, and eight selective extinction sessions. Rats were acclimated to the cables on discrimination sessions 11–12 by tethering to “dummy cables” without light illumination.

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    Figure 4.

    YFP and eNpHR viral expression and fiber placements. A, Viral transfection extent is shown throughout the DRN for rats in the YFP (gray tracings) group. Bilateral ferrule placements (gray filled rectangles) for individual rats are denoted by colored outlines. B, Viral transfections (green tracings) and ferrule placements (green filled rectangles) for eNpHR rats as in A.

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    Figure 5.

    Inhibition of DRNtph2+ does not impact +PE-mediated fear discrimination. A, Representative image shows ferrule implant sites (white dashes outlines) and viral transfection in DRN neurons (YFP, yellow) against tph2 immunohistochemistry (red) in a TPH2-cre rat. Fluorescent Nissl staining (NeuroTrace) shows neuronal cell bodies (blue). B, During the +PE optogenetic manipulation, green-light illumination began at danger and uncertainty-shock cue offset, continued during the 0.5-s shock (yellow period), and lasted 1.5 s after shock for a total of 4 s. For the –PE optogenetic manipulation, green-light illumination began at uncertainty and safety cue offset for a total of 4 s. The uncertainty cue was selectively extinguished during these sessions. Note illumination never occurred during cue periods. C, Mean ± SEM suppression ratios for YFP rats to danger (red), uncertainty (purple), and safety (blue) are shown for the two preexposure (p) and 18 discrimination sessions. Rats were acclimated to the cables on discrimination sessions 11–12 by tethering to “dummy cables” without light illumination. D, eNpHR suppression ratio data shown as in C. Both groups achieved discrimination, and light illumination during foot shock did not impact fear behavior.

  • Figure 6.
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    Figure 6.

    Inhibition of DRNtph2+ during –PE alters extinction of uncertainty. A, Mean ± SEM suppression ratios for YFP rats to danger (red), uncertainty (purple), and safety (blue) are shown for the last fear discrimination (18) and eight selective extinction sessions. DRN illumination occurred during omission periods in sessions 1–4 for the –PE optogenetic manipulation. B, eNpHR suppression ratio data shown as in A. C, Change in fear to the uncertainty cue between –PE optogenetics sessions and postillumination selective extinction sessions 5–8 for YFP (gray) and eNpHR (green) rats. Bars show group average and circles indicate individual difference scores *p < 0.05 between groups. D, Change in fear to the safety cue as shown in C.

Tables

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    Table 1

    Statistical table

    Data structureType of testPower
    aNormal distributionRepeated-measures ANOVA1.00
    bNormal distributionRepeated-measures ANOVA1.00
    cNormal distributionRepeated-measures ANOVA0.82
    dNormal distributionRepeated-measures ANOVA1.00
    eNormal distributionRepeated-measures ANOVA1.00
    fNormal distributionRepeated-measures ANOVA1.00
    gNormal distributionRepeated-measures ANOVA1.00
    hNormal distributionRepeated-measures ANOVA0.52
    iNormal distributionIndependent samples t test[−0.35, −0.026]
    jNormal distributionIndependent samples t test[−0.19, 0.14]
    kNormal distributionRepeated-measures ANOVA0.20
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Dorsal Raphe 5-HT Neurons Utilize, But Do Not Generate, Negative Aversive Prediction Errors
Rachel A. Walker, Rebecca L. Suthard, Taylor N. Perison, Nora M. Sheehan, Caitlin C. Dwyer, Jillian K. Lee, Eghosa K. Enabulele, Madelyn H. Ray, Michael A. McDannald
eNeuro 25 January 2022, 9 (1) ENEURO.0132-21.2022; DOI: 10.1523/ENEURO.0132-21.2022

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Dorsal Raphe 5-HT Neurons Utilize, But Do Not Generate, Negative Aversive Prediction Errors
Rachel A. Walker, Rebecca L. Suthard, Taylor N. Perison, Nora M. Sheehan, Caitlin C. Dwyer, Jillian K. Lee, Eghosa K. Enabulele, Madelyn H. Ray, Michael A. McDannald
eNeuro 25 January 2022, 9 (1) ENEURO.0132-21.2022; DOI: 10.1523/ENEURO.0132-21.2022
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Keywords

  • discrimination
  • extinction
  • fear
  • prediction error
  • serotonin
  • Tph2-cre

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