Experimental investigation into the role of the subthalamic nucleus (STN) in motor control using optogenetics in mice

Adriane Guillaumin,Gian Pietro Serra,François Georges,Åsa Wallén-Mackenzie

doi:10.1016/j.brainres.2020.147226

Adriane Guillaumin, Gian Pietro Serra + Show 2 more

Open Access

https://doi.org/10.1016/j.brainres.2020.147226

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Abstract

The subthalamic nucleus (STN) is critical for the execution of intended movements. Loss of its normal function is strongly associated with several movement disorders, including Parkinson's disease for which the STN is an important target area in deep brain stimulation (DBS) therapy. Classical basal ganglia models postulate that two parallel pathways, the direct and indirect pathways, exert opposing control over movement, with the STN acting within the indirect pathway. The STN is regulated by both inhibitory and excitatory input, and is itself excitatory. While most functional knowledge of this clinically relevant brain structure has been gained from pathological conditions and models, primarily parkinsonian, experimental evidence for its role in normal motor control has remained more sparse. The objective here was to tease out the selective impact of the STN 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 STN were implemented in freely-moving mice. The results demonstrate that selective optogenetic inhibition of the STN enhances locomotion while its excitation reduces locomotion. These findings lend experimental support to basal ganglia models of the STN in terms of locomotion. In addition, optogenetic excitation in freely-exploring mice induced self-grooming, disturbed gait and a jumping/escaping behavior, while causing reduced motor coordination in advanced motor tasks, independent of grooming and jumping. This study contributes experimentally validated evidence for a regulatory role of the STN in several aspects of motor control.

Highlights

The subthalamic nucleus (STN) is a small but highly influential brain structure which exerts prominent impact over voluntary movement
Mice that displayed strong cellular enhanced yellow fluorescent protein (eYFP) labeling throughout the extent of the STN and op tical cannulas placed immediately above the STN were included in the statistical analyses while displaced cannula and/or lack of eYFP were set as criteria for exclusion
Strong eYFP labeling was identified in STN-projections reaching the ventral pallidum, entope duncular nucleus (EP, corresponding to internal segment of the globus pallidus (GPi) in primates), GP (GPe in primates), substantia nigra pars reticulata (SNr) and substantia nigra pars compacta (SNc) (Fig. 1E-H)

Summary

Introduction

The subthalamic nucleus (STN) is a small but highly influential brain structure which exerts prominent impact over voluntary movement. Damage or dysregulation of the STN is strongly associated with motor dysfunction and movement disorder. Unilateral damage to the STN causes strongly uncontrolled movements, so called hemiballismus (Hamada & DeLong, 1992), while degeneration of the STN is associated with supranuclear palsy and Huntington’s disease (Dickson et al, 2010; Lange et al, 1976). Surgical lesioning of the STN, so called subthalamotomy, improves motor symptoms in PD (Heywood & Gill, 1997; Parkin et al, 2001). Does deep brain stimulation (DBS), an electrical method in which high-frequency stimulation electrodes, when positioned in the STN, can correct its aberrant activity (Benazzouz et al, 2000; Filali et al, 2004). The high success rate of these clinical interventions con firms the critical role of the STN, yet its regulatory role over different motor parameters required to achieve willed movement remains to be fully established

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