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A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus

Nature volume 400, pages 677–682 (1999)Cite this article

Abstract

The subthalamic nucleus of the basal ganglia (STN) is important for normal movement1,2 as well as in movement disorders3,4,5. Lesioning6 or deep-brain stimulation7,8 of the STN can alleviate resting tremor in Parkinson's disease. The STN5 and its target nuclei9,10 display synchronized oscillatory burst discharge at low frequencies, some of which correlate with tremor, but the mechanism underlying this synchronized bursting is unknown. Here we show that the excitatory STN and inhibitory, external globus pallidus (GPe) form a feedback system that engages in synchronized bursting. In mature organotypic cortex–striatum–STN–GPe cultures, neurons in the STN and GPe spontaneously produce synchronized oscillating bursts at 0.4, 0.8 and 1.8 Hz. Pallidal lesion abolishes this bursting, whereas cortical lesion favours bursting at 0.8 Hz. Pallidal bursts, although weaker than STN bursts, were required for synchronized oscillatory burst generation by recruitment of subthalmic rebound excitation. We propose that the STN and GPe constitute a central pacemaker modulated by striatal inhibition of GPe neurons. This pacemaker could be responsible for synchronized oscillatory activity in the normal and pathological basal ganglia.

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Figure 1: STN units display periods of oscillatory bursting, synchronized with other STN and GPe units.
Figure 2: Quantitative analysis of synchronized oscillatory bursting in the STN and GPe.
Figure 3: Synchronized oscillatory bursting does not depend on cortical input but on intact STN–GPe connectivity.
Figure 4: The mechanism of synchronized oscillatory burst generation in the STN–GPe pacemaker.

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References

  1. Matsumura, M. Kojima, J., Gardiner, T. W. & Hikosaka, O. Visual and oculomotor functions of the monkey subthalamic nucleus. J. Neurophysiol. 67, 1615–1632 (1992).

    Article  CAS  Google Scholar 

  2. Wichmann, T., Bergman, H. & DeLong, M. R. The primate subthalamic nucleus. I. Functional properties in intact animals. J. Neurophysiol. 72, 494–506 (1994).

    Article  CAS  Google Scholar 

  3. Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).

    Article  CAS  Google Scholar 

  4. Wichmann, T. & DeLong, M. R. Functional and pathophysiological models of the basal ganglia. Curr. Opin. Neurobiol. 6, 751–758 (1989).

    Article  Google Scholar 

  5. Bergman, H., Wichmann, T., Karmon, B. & DeLong, M. R. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J. Neurophysiol. 72, 507–520 (1994).

    Article  CAS  Google Scholar 

  6. Bergman, H., Wichmann, T. & DeLong, M. R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249, 1436–1438 (1990).

    Article  CAS  ADS  Google Scholar 

  7. Limousin, P.et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N. Engl. J. Med. 339, 1105–1111 (1998).

    Article  CAS  Google Scholar 

  8. Rodriguez, M. C.et al. The subthalamic nucleus and tremor in Parkinson's disease. Mov. Disord. 13, 111–118 (1998).

    Article  Google Scholar 

  9. Nini, A., Feingold, A., Slovin, H. & Bergman, H. Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of Parkinson. J. Neurophysiol. 74, 1800–1805 (1995).

    Article  CAS  Google Scholar 

  10. Hurtado, J. M., Gray, C. M., Tamas, L. B. & Sigvardt, K. A. Dynamics of tremor-related oscillations in the human globus pallidus: A single case study. Proc. Natl Acad. Sci. USA 96, 1674–1679 (1999).

    Article  CAS  ADS  Google Scholar 

  11. Plenz, D., Herrera-Marschitz, M. & Kitai, S. T. Morphological organization of the globus pallidus–subthalamic nucleus system studied in organotypic cultures. J. Comp. Neurol. 397, 437–457 (1998).

    Article  CAS  Google Scholar 

  12. Kitai, S. T. & Deniau, J. M. Cortical inputs to the subthalamus: intracellular analysis. Brain Res. 214, 411–415 (1981).

    Article  CAS  Google Scholar 

  13. Kita, H. Responses of globus pallidus neurons to cortical stimulation: intracellular study in the rat. Brain Res. 589, 84–90 (1992).

    Article  CAS  Google Scholar 

  14. Kita, H., Chang, H. T. & Kitai, S. T. Pallidal inputs to subthalamus: intracellular analysis. Brain Res. 264, 255–265 (1983).

    Article  CAS  Google Scholar 

  15. Parent, A. & Hazrati, L. N. Functional anatomy of the basal ganglia. II. The place of the subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res. Rev. 20, 128–154 (1995).

    Article  CAS  Google Scholar 

  16. Shink, E., Bevan, M. D., Bolam, J. P. & Smith, Y. The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience 73, 335–357 (1996).

    Article  CAS  Google Scholar 

  17. Nakanishi, H., Kita, H. & Kitai, S. T. Electrical membrane properties of rat subthalamic neurons in an in vitro slice preparation. Brain. Res. 437, 35–44 (1987).

    Article  CAS  Google Scholar 

  18. Beurrier, C., Congar, P., Bioulac, B. & Hammond, C. Subthalamic nucleus neurons switch from single-spike activity to burst firing mode. J. Neurosci. 15, 599–609 (1999).

    Article  Google Scholar 

  19. Ruskin, D. N.et al. Multisecond oscillations in firing rate in the basal ganglia: Robust modulation by dopamine receptor activation and anaesthesia. J. Neurophysiol. 81, 2046–2055 (1999).

    Article  CAS  Google Scholar 

  20. DeLong, M. R. Activity of pallidal neurons during movement. J. Neurophysiol. 34, 414–427 (1971).

    Article  CAS  Google Scholar 

  21. Filion, M. Effects of the interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey. Brain Res. 178, 425–441 (1978).

    Article  Google Scholar 

  22. Aldridge, J. W. & Gilman, S. The temporal structure of spike trains in the primate basal ganglia: Afferent regulation of bursting demonstrated with precentral cerebral cortical ablation. Brain Res. 543, 123–138 (1991).

    Article  CAS  Google Scholar 

  23. Hollerman, J. R. & Grace, A. A. Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activity and resonse to haloperidol. Brain Res. 590, 291–299 (1992).

    Article  CAS  Google Scholar 

  24. Hassani, O.-K., Mouroux, M. & Féger, J. Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neurosci. 72, 105–115 (1996).

    Article  CAS  Google Scholar 

  25. Chesselet, M. F. & Delfs, J. M. Basal ganglia and movement disorders: an update. Trends Neurosci. 10, 417–422 (1996).

    Article  Google Scholar 

  26. Pan, H. S. & Walters, J. R. Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of globus pallidus neurons in the rat. Synapse 2, 650–656 (1988).

    Article  CAS  Google Scholar 

  27. Miller, W. C. & DeLong, M. R. in The Basal Ganglia II (eds Carpenter, M. B. & Jayaraman, A.) 415–427 (Plenum, New York, 1987).

    Book  Google Scholar 

  28. Wurtz, R. H. & Hikosaka, O. Role of the basal ganglia in the initiation of saccadic eye movements. Prog. Brain Res. 64, 175–190 (1986).

    Article  CAS  Google Scholar 

  29. Chevalier, G. & Deniau, J. M. Disinhibition as a basic process in the expression of striatal functions. Trends Neurosci. 13, 277–280 (1990).

    Article  CAS  Google Scholar 

  30. Abeles, M. Quantification, smoothing, and confidence limits for single-units' histograms. J. Neurosci. Methods 5, 317–325 (1982).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Teng for technical assistance with the preparation of cultures and for immunohistochemistry, and H. Steiner for discussions. This work was supported by grants from the National Parkinson Foundation (to D.P.) and the NINDS (to D.P. and S.T.K.).

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Author notes

  1. Dietmar Plenz

    Present address: Unit of Neural Network Physiology, Laboratory of Systems Neuroscience, National Institute of Mental Health, Bldg 36 2D-30, Bethesda, Maryland, 20892, USA

  2. Dietmar Plenz: Correspondence and requests for materials should be addressed to D.P.

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Tennessee, College of Medicine, Memphis, 38163, Tennessee, USA

    Dietmar Plenz & Stephen T. Kital

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Correspondence to Dietmar Plenz.

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Plenz, D., Kital, S. A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 400, 677–682 (1999). https://doi.org/10.1038/23281

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