Abstract
The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLS dSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson's disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states.
Original language | English (US) |
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Pages (from-to) | 3966-3987 |
Number of pages | 22 |
Journal | Journal of Neuroscience |
Volume | 41 |
Issue number | 18 |
DOIs | |
State | Published - May 5 2021 |
Funding
This work was supported by National Institutes of Health R01 NS069777, R01 MH112768, R01 NS097901, R01 MH109466, and R01 NS088528 to C.S.C.; R01 MH107742, R01 MH108594, and U01 MH114829 to B.K.L.; R01 MH116176 to Y.K.; and T32 AG020506 to A.P. We thank Lily Amadio, Saivasudha Chalasani, Alyssa Bebenek, Kris Shah, Moises Melesio, and Coby Dodelson for assistance; and Dr. Tracy Gertler, Cooper Chan, and Cassidy Chan for supporting the completion of the fourth manuscript from the C.S.C. laboratory during the COVID-19 pandemic. The authors declare no competing financial interests. Correspondence should be addressed to C. Savio Chan at [email protected]. https://doi.org/10.1523/JNEUROSCI.2306-20.2021 Copyright © 2021 the authors
Keywords
- 6-OHDA
- Arkypallidal neurons
- Body kinematics
- GABAergic inhibition
- Hypokinesia
- Movement dynamics
ASJC Scopus subject areas
- General Medicine