Optogenetic investigation into the role of the subthalamic nucleus in motor control

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The subthalamic nucleus (STN) is a major regulator of intended movements. The STN is controlled by both excitatory and inhibitory inputs. Dysregulation of the STN contributes to motor deficiency in Parkinson’s disease (PD). Both STN-lesioning and high-frequency electrical stimulation of the STN improve motor symptoms in PD.</jats:p><jats:p>However, despite a pivotal clinical target, the natural role of the STN in motor regulation has remained elusive. In fact, controlled excitatory or inhibitory manipulations have been poorly explored. By controlled regulation, new functional knowledge of the STN can be reached.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To uncover the role of the STN in several aspects of motor function during non-pathological conditions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The Pitx2-Cre mouse model has been described as a transgenic tool to direct genetic targeting events to the STN. Here, Pitx2-Cre mice were used to direct optogenetic excitation and inhibition to the STN. The impact of each type of stimulation on motor output was recorded and compared.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Optogenetic excitation of the STN triggered action potentials in a key component of the basal ganglia. Optogenetic excitation of the STN in the freely-moving animal reduced vertical and horizontal movement, induced immediate grooming and caused loss of motor coordination. In contrast, optogenetic inhibition increased general locomotion and reduced natural grooming. Opposite rotations were observed upon unilateral excitation and inhibition of the STN.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Optogenetic excitation and inhibition of the STN give rise to opposite motor responses in several parameters relevant to voluntary motor control that are commonly disturbed in PD.</jats:p></jats:sec>

Aversion encoded in the subthalamic nucleus

“…Confirming the selectivity of the Pitx2-Cre transgene in directing opsin expression to the STN, we have previously shown that photostimulation of the STN results in post-synaptic currents and glutamate release in basal ganglia target areas (Schweizer et al, 2016(Schweizer et al, , 2014Viereckel et al, 2018). In a recent report, we show that optogenetic excitation and inhibition result in opposite locomotor effects (Guillaumin et al, 2020). Surprisingly, we also observed that STN excitation could induce an avoidance-like behavior.…”

“…In a recent study, we could experimentally confirm the long-assumed role of the STN in locomotion by demonstrating directly opposite motor effects by optogenetic excitation and inhibition of the STN (Guillaumin et al, 2020). We found that STN excitation was generally correlated with significant reduction in locomotor activity, while STN inhibition enhanced locomotion, just as classical models of the regulatory role of the STN in basal ganglia motor loops propose.…”

“…When placed in an open and novel arena, mice displayed a strong escaping behavior, characterized by attempts to jump out of the apparatus. This unexpected outcome was evident immediately upon STN excitation (Guillaumin et al, 2020).…”

Movement-related increases in subthalamic activity optimize locomotion

“…No effect of optogenetic inhibition was observed in resting mice, arguing that STN hypoactivity generally and cessation of type 2 neuron activity specifically are not sufficient to initiate locomotion. At first sight, this observation appears contrary to the effects of STN lesions or prolonged pharmacological/optogenetic/chemogenetic inhibition of the STN 4,[12][13][14][15][16] . One possibility is that the dysregulated movement that accompanies STN lesions or prolonged subthalamic inhibition requires volitional motor commands for its expression.…”

“…In addition, basal ganglia hyperdirect and indirect pathwaymediated elevations of STN activity have been posited to facilitate the execution of a specific action through the suppression of all others, prevent an imminent action, or rapidly stop an action in the process of execution [5][6][7][8]10,11 . Consistent with these concepts 1) lesions or prolonged pharmacological, optogenetic or chemogenetic inhibition of the STN leads to dyskinesia, hyperkinesia, premature or inappropriate responding, and stereotyped behaviors, such as excessive grooming 4,[12][13][14][15][16] 2) brief or prolonged optogenetic excitation of the STN prevents, reduces, or terminates movement 6,15 3) a subset of STN neurons exhibits elevated activity during passive or voluntary movement, whereas the activity of a mostly non-overlapping subset of neurons is linked to stop signaling 5,7,12,[17][18][19] . Together, these data argue that the STN can suppress movement in some contexts but whether it also optimizes volitional movement is less clear 12,20 .…”