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Start/stop signals emerge in nigrostriatal circuits during sequence learning

Abstract

Learning new action sequences subserves a plethora of different abilities such as escaping a predator, playing the piano, or producing fluent speech. Proper initiation and termination of each action sequence is critical for the organization of behaviour, and is compromised in nigrostriatal disorders like Parkinson’s and Huntington’s diseases. Using a self-paced operant task in which mice learn to perform a particular sequence of actions to obtain an outcome, we found neural activity in nigrostriatal circuits specifically signalling the initiation or the termination of each action sequence. This start/stop activity emerged during sequence learning, was specific for particular actions, and did not reflect interval timing, movement speed or action value. Furthermore, genetically altering the function of striatal circuits disrupted the development of start/stop activity and selectively impaired sequence learning. These results have important implications for understanding the functional organization of actions and the sequence initiation and termination impairments observed in basal ganglia disorders.

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Figure 1: Mice learn to perform a specific sequence of actions.
Figure 2: Lever-press-related activity in nigrostriatal circuits.
Figure 3: Neural activity signalling the initiation and termination of action sequences emerges in nigrostriatal circuits during learning.
Figure 4: Sequence start/stop-related activity does not reflect differences in expected value and can be action specific.
Figure 5: Striatal-specific deletion of NMDA receptors disrupts the development of start/stop activity and impairs sequence learning.

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Acknowledgements

We thank Y. Li for the RGS9-Cre mice, C. Gerfen for the TH-Cre mice, K. Nakazawa for the NMDAR1-loxP mice, F. Tecuapetla and S. Lima for help in the optogenetics experiment, G. Luo for genotyping, and D. Lovinger, G. Cui, C. French, C. Gremel and E. Dias-Ferreira for comments on the manuscript. This research was supported by the NIAAA Division of Intramural Clinical and Biological Research, the Champalimaud Neuroscience Programme at Institute Gulbenkian de Ciência and European Research Council Grant 243393 to R.M.C.

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X.J. performed the experiments and analysed the data. R.M.C. conducted the optogenetics experiment. X.J. and R.M.C. designed the experiments and wrote the paper.

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Correspondence to Rui M. Costa.

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The authors declare no competing financial interests.

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This file contains Supplementary Methods, References, Supplementary Statistics for Figures 1-5 in the main paper, Supplementary Figures 1-18 with legends and Supplementary Tables 1-2. (PDF 1412 kb)

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Jin, X., Costa, R. Start/stop signals emerge in nigrostriatal circuits during sequence learning. Nature 466, 457–462 (2010). https://doi.org/10.1038/nature09263

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