Letter | Published:

Prefrontal cortex output circuits guide reward seeking through divergent cue encoding

Nature volume 543, pages 103107 (02 March 2017) | Download Citation

Abstract

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species1,2,3. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus4. While connectivity among these structures contributes to appetitive behaviours5,6,7,8,9,10,11,12,13, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.

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Acknowledgements

We thank S. Smith and J. Stirman for helpful discussions. This study was funded by grants from the National Institutes of Health (NIDA: F32-DA041184, J.M.O.; R01-DA032750, G.D.S.; R01-DA038168, G.D.S.; NICHD: T32-HD079124, S.L.R.; NIMH: T32-MH093315, J.A.M.), the Brain and Behavior Research Foundation (G.D.S.), the Children’s Tumor Foundation (016-01-006, J.E.R.), the Foundation of Hope (G.D.S.), the UNC Neuroscience Center (Helen Lyng White Fellowship, V.M.K.N.), the UNC Neuroscience Center Microscopy Core (P30 NS045892), and the UNC Department of Psychiatry (G.D.S.).

Author information

Author notes

    • James M. Otis
    •  & Vijay M. K. Namboodiri

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • James M. Otis
    • , Vijay M. K. Namboodiri
    • , Ana M. Matan
    • , Elisa S. Voets
    • , Emily P. Mohorn
    • , Oksana Kosyk
    • , Jenna A. McHenry
    • , J. Elliott Robinson
    • , Shanna L. Resendez
    • , Mark A. Rossi
    •  & Garret D. Stuber
  2. Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Vijay M. K. Namboodiri
    •  & Garret D. Stuber
  3. Neuroscience Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • J. Elliott Robinson
    •  & Garret D. Stuber
  4. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Garret D. Stuber

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Contributions

V.M.K.N. wrote codes for analyses. V.M.K.N., A.M.M., E.S.V., E.P.M., O.K., J.A.M., J.E.R., S.L.R. and M.A.R. provided technical assistance for in vivo optogenetics, histology and immunohistochemistry. J.M.O. performed experiments and surgeries. J.M.O., V.M.K.N. and G.D.S. designed the experiments, analysed and interpreted the data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Garret D. Stuber.

Extended data

Supplementary information

Videos

  1. 1.

    Representative video revealing calcium dynamics of dorsal medial PFC GCaMP6s-expressing neurons

    Injection of AAV-CaMKII-GCaMP6s resulted in dynamic GCaMP6s fluorescence from hundreds of visible PFC neurons in vivo (see methods for details). Data acquisition occurred at 2.5Hz, and this representative video is shown at 10X normal speed (25 frames per second; 485 x 508 pixels; 373μmß x 390μm).

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DOI

https://doi.org/10.1038/nature21376

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