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GluN2B in corticostriatal circuits governs choice learning and choice shifting

Nature Neuroscience volume 16, pages 1101–1110 (2013)Cite this article

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Abstract

A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2B antagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior.

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Figure 1: Choice learning, shifting and relearning in a choice task.
Figure 2: Dynamic corticostriatal activation with choice learning and relearning.
Figure 3: In vivo striatal single-unit activity shifts with choice learning.
Figure 4: Striatal synaptic plasticity changes with choice learning.
Figure 5: Corticostriatal or striatal Grin2b deletion impairs choice learning.
Figure 6: Striatal GluN2B blockade impairs choice learning.
Figure 7: Cortical Grin2b deletion impairs choice shifting.
Figure 8: Orbitofrontal GluN2B blockade impairs choice shifting.

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Acknowledgements

We are very grateful to G. Schoenbaum and A. Kravitz for discussions of the in vivo recording results and to G. Luo for mutant genotyping. J.L.B., C.G., T.W., M.I.D., R.A.D., M.P., O.G.-C., D.M.L. and A.H. were supported by the NIAAA Intramural Research Program. L.M.S. and T.J.B. were supported by The Wellcome Trust. Z.J. and K.N. were supported by the National Institute of Mental Health Intramural Research Program.

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Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), US National Institutes of Health (NIH), Bethesda, Maryland, USA

    Jonathan L Brigman, Rachel A Daut, Tara Wright, Ozge Gunduz-Cinar, Carolyn Graybeal, Matthew Pease & Andrew Holmes

  2. Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, Maryland, USA

    Margaret I Davis & David M Lovinger

  3. Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, NIH, Bethesda, Maryland, USA

    Zhihong Jiang, Seiichiro Jinde & Kazu Nakazawa

  4. Department of Experimental Psychology, University of Cambridge, Cambridge, UK

    Lisa M Saksida & Timothy J Bussey

  5. Medical Research Council and Wellcome Trust Behavioral and Clinical Neuroscience Institute, Cambridge, UK

    Lisa M Saksida & Timothy J Bussey

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  1. Jonathan L Brigman
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Contributions

J.L.B. conducted behavioral, c-Fos, in vivo electrophysiological and in situ hybridization experiments and contributed to writing the manuscript; R.A.D., C.G. and M.P. conducted behavioral experiments; T.W. conducted the slice electrophysiological experiments; O.G.-C. conducted RT-PCR and western blot experiments; M.I.D. contributed to the c-Fos experiments; Z.J. and S.J. contributed to the in situ hybridization experiments; L.M.S. and T.J.B. provided behavioral analysis software; D.M.L. supervised the slice electrophysiological experiments and contributed to writing the manuscript; K.N. supervised the in situ hybridization experiments, provided mutant mice and contributed to writing the manuscript; A.H. supervised the study and contributed to writing the manuscript.

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Correspondence to Andrew Holmes.

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Brigman, J., Daut, R., Wright, T. et al. GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci 16, 1101–1110 (2013). https://doi.org/10.1038/nn.3457

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