Abstract
The subthalamic nucleus is important achieve intended movements. Loss of its normal function is strongly associated with several movement disorders. Classical basal ganglia models postulate that two parallel pathways, the direct and indirect pathways, exert opposing control over movement, with the subthalamic nucleus part of the indirect pathway through which competing motor programs are prevented. The subthalamic nucleus is regulated by both inhibitory and excitatory projections but experimental evidence for its role in motor control has remained sparse. The objective here was to tease out the selective impact of the subthalamic nucleus on several motor parameters required to achieve intended movement, including locomotion, balance and motor coordination. Optogenetic excitation and inhibition using both bilateral and unilateral stimulations of the subthalamic nucleus were implemented in freely-moving mice. The results demonstrate that selective optogenetic inhibition of the subthalamic nucleus enhances locomotion while its excitation reduces locomotion. These findings lend experimental support to basal ganglia models in terms of locomotion. However, further analysis of subthalamic nucleus excitation revealed grooming and disturbed gait. Selective excitation also caused reduced motor coordination, independent of grooming, in advanced motor tasks. This study contributes experimental evidence for a regulatory role of the subthalamic nucleus in motor control.
Highlights
Bilateral optogenetic excitation of the subthalamic nucleus in freely-moving mice reduces forward locomotion while optogenetic inhibition leads to its increase.
Unilateral optogenetic excitation and inhibition of the subthalamic nucleus cause opposite rotational behavior.
Bilateral optogenetic excitation, but not inhibition, of the subthalamic nucleus induces jumping and self-grooming behavior.
Engaged in advanced motor tasks, bilateral optogenetic excitation causes mice to lose motor coordination.
The results provide experimental support for predictions by the basal ganglia motor model on the role of the subthalamic nucleus in locomotion, and identifies a causal role for the subthalamic nucleus in self-grooming.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Communicating author: Åsa Wallén-Mackenzie, E-mail: asa.mackenzie{at}ebc.uu.se
Competing interests: All authors declare no competing interests.
Funding: This work was supported by Uppsala University and by grants to Å.W.M from the Swedish Research Council (SMRC 2017-02039), the Swedish Brain Foundation (Hjärnfonden), Parkinsonfonden, and the Research Foundations of Bertil Hållsten, Zoologiska and Åhlén.
Abbreviations: 6-OHDA: 6-Hydroxydopamine; AAV2: adeno-associated virus 2; ALT: Alternated Light; BS: Baseline; ChR2: Channelrhodopsin 2; CONT: Continuous Light; DBS: deep brain stimulation; eArch3.0: Archaerhodopsin 3.0; eYFP: enhanced yellow fluorescent protein; EP: entopeduncular nucleus; GPe: external segment of the globus pallidus; GPi: internal segment of the globus pallidus; OCD: obsessive compulsive disorder; PD: Parkinson’s disease; PRIOR: Prior Stimulation; PSTH: peri-stimulus time histograms; pSTN: para-subthalamic nucleus; SNc: substantia nigra pars compacta; SNr: substantia nigra pars reticulate; STN: subthalamic nucleus; Vglut2: Vesicular glutamate transporter 2.
The text has been updated and extended. The previous version was very short due to a journal format but did not sufficiently explain the background, objective and conclusions. This has now been clarified, and limitation to the study added as well. The figures are the same as before, only a slight modification to Fig. 4.