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Neural signals of extinction in the inhibitory microcircuit of the ventral midbrain

Nature Neuroscience volume 16, pages 71–78 (2013)Cite this article

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Abstract

Midbrain dopaminergic (DA) neurons are thought to guide learning via phasic elevations of firing in response to reward predicting stimuli. The mechanism for these signals remains unclear. Using extracellular recording during associative learning, we found that inhibitory neurons in the ventral midbrain of mice responded to salient auditory stimuli with a burst of activity that occurred before the onset of the phasic response of DA neurons. This population of inhibitory neurons exhibited enhanced responses during extinction and was anticorrelated with the phasic response of simultaneously recorded DA neurons. Optogenetic stimulation revealed that this population was, in part, derived from inhibitory projection neurons of the substantia nigra that provide a robust monosynaptic inhibition of DA neurons. Thus, our results elaborate on the dynamic upstream circuits that shape the phasic activity of DA neurons and suggest that the inhibitory microcircuit of the midbrain is critical for new learning in extinction.

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Figure 1: Discrete timing of sensory responses in the ventral midbrain during auditory trace conditioning.
Figure 2: Short-latency responses to the conditioned stimulus are enhanced during extinction.
Figure 3: The population response during extinction.
Figure 4: Opposing extinction signals emerge with similar time courses.
Figure 5: Light-evoked activity in ChR2-expressing GABAergic neurons, but not DA neurons in vitro.
Figure 6: Optogenetic tagging reveals that short-latency auditory responses are from GABAergic neurons.
Figure 7: The microcircuit of the SN is spatially extended and is sufficient to suppress the firing of DA neurons.

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Acknowledgements

J. Paton, W. Denk, A. Karpova, A. Lee, J. Magee and G. Murphy provided critical feedback at various stages of preparation of the manuscript and progression of the project. We are indebted to the extensive feedback from our colleagues following presentation of this work at internal seminars on the Janelia Farm Research Campus. We thank members of our laboratory for critical reading and feedback on the manuscript. J.B. receives funding from the Cambridge-Janelia Farm Graduate Program. This work was supported by funding from the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA

    Wei-Xing Pan, Jennifer Brown & Joshua Tate Dudman

  2. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Jennifer Brown

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  1. Wei-Xing Pan
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Contributions

W.-X.P. and J.T.D. designed the project. J.T.D., W.-X.P. and J.B. analyzed the data and wrote the manuscript. W.-X.P. performed the in vivo recording and behavioral experiments. J.B. performed the in vitro experiments. J.T.D. implemented the computational model and performed a minority of the experiments.

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Correspondence to Joshua Tate Dudman.

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Pan, WX., Brown, J. & Dudman, J. Neural signals of extinction in the inhibitory microcircuit of the ventral midbrain. Nat Neurosci 16, 71–78 (2013). https://doi.org/10.1038/nn.3283

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