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Concurrent activation of striatal direct and indirect pathways during action initiation

Nature volume 494, pages 238–242 (2013)Cite this article

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Abstract

The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders1,2,3,4. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum5,6—the so-called direct and indirect pathways—have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement1,2. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific6,7) and A2A-Cre (indirect-pathway-specific8,9) mice10. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.

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Figure 1: Optical measurement of neural-activity-dependent fluorescence changes in direct- and indirect-pathway SPNs in freely moving mice.
Figure 2: Sensory stimuli evoke brief activation in direct- and indirect-pathway SPNs.
Figure 3: GCaMP3 fluorescence transients in both direct- and indirect-pathway SPNs during action initiation in a lever-pressing task.
Figure 4: Both direct- and indirect-pathway SPNs show strong activation immediately before and during contraversive movement.

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Acknowledgements

We thank C. R. Gerfen for gifts of multiple bacterial artificial chromosome (BAC) transgenic mouse lines; L. L. Looger and the Howard Hughes Medical Institute (HHMI) for permission to use AAV GCaMP3 vectors and GCaMP3 mice; S. R. Ikeda for assistance with Ca2+ imaging in brain slices; G. Luo for mouse genotyping; C. Thaler for assistance with FLIM curve analysis; B. Mathur and M. Davis for assistance with brain slice electrophysiology and histology; and A. Martin for assistance with AAV vector injection. This work was supported by the Division of Intramural Clinical and Biological Research of the NIAAA, European Research Council STG 243393, an International Early Career Scientist grant from the Howard Hughes Medical Institute to R.M.C., a National Research Foundation of Korea grant (2011-0029485, 2012-0004003) and Smart IT Convergence System Research Center (SIRC-2011-0031866) from the Korean government (MEST) to S.B.J., and by an Ellison Medical Foundation grant (AG-NS-0944-12) to X.J.

Author information

Author notes

  1. Guohong Cui and Sang Beom Jun: These authors contributed equally to this work.

Authors and Affiliations

  1. Section on In Vivo Neural Function, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892-9412, USA,

    Guohong Cui, Xin Jin, Michael D. Pham, David M. Lovinger & Rui M. Costa

  2. Department of Electronics Engineering, Ewha Womans University, Seoul 120-750, Korea,

    Sang Beom Jun

  3. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA,

    Xin Jin

  4. Section on Cellular Biophotonics, Laboratory for Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda 20892-9412, Maryland, USA,

    Steven S. Vogel

  5. Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892-9412, USA,

    David M. Lovinger

  6. Champalimaud Neuroscience Programme at Instituto Gulbenkian de Ciência and Champalimaud Centre for the Unknown, Lisbon 1400-038, Portugal,

    Rui M. Costa

Authors
  1. Guohong Cui
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Contributions

R.M.C. and S.S.V. conceived the original idea of using the TCSPC technique for optical measurements in freely moving mice. G.C., D.M.L. and R.M.C. designed the experiments. G.C. and S.B.J. set up equipment and optimized procedures for in vivo optical recording. G.C. and S.B.J. carried out the in vivo experiments and analysed data. G.C. performed in vitro experiments and analysed data. X.J. helped with programming and data analysis. M.D.P. performed initial in vitro experiments using the TCSPC system and analysed data. G.C., S.S.V., D.M.L. and R.M.C. wrote the paper.

Corresponding authors

Correspondence to Steven S. Vogel, David M. Lovinger or Rui M. Costa.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-14. (PDF 1786 kb)

In-Vivo optical recording of striatal neural activity in an animal performing a two-lever free choice operant task

A food pellet was delivered into the food magazine when the animal had made a total of 10 lever-presses, regardless of left or right lever. (MOV 13846 kb)

Action potential-triggered GCAMP3 fluorescence transient in a striatal SPN evoked by current injection

A 400 pA, 487.5 ms square pulse current was injected through a patch pipette in tight-seal cell-attached configuration to evoke a burst of action potentials. See Supplementary Fig.10a,b for more detailed description. (MOV 20650 kb)

Action potential-triggered GCAMP3 fluorescence transient in a striatal SPN evoked by synaptic stimulation

A train of 3 pulses at 200 uA, 100 Hz was delivered by a concentric bipolar electrode to evoke a burst of action potentials. See Supplementary Fig.11a, b for more detailed description. (MOV 4275 kb)

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Cui, G., Jun, S., Jin, X. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013). https://doi.org/10.1038/nature11846

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