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. 2023 Nov 22;43(47):7967-7981.
doi: 10.1523/JNEUROSCI.0734-23.2023.

Selective Activation of Subthalamic Nucleus Output Quantitatively Scales Movements

Alexander D Friedman  1 , Henry H Yin  2   3
Affiliations

Selective Activation of Subthalamic Nucleus Output Quantitatively Scales Movements

Alexander D Friedman et al. J Neurosci. .

Abstract

The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. According to the dominant model, the STN output can suppress movement by enhancing inhibitory basal ganglia (BG) output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson's patients. But the mechanisms underlying STN DBS remain poorly understood, as previous studies usually relied on electrical stimulation, which cannot selectively target STN output neurons. Here, we selectively stimulated STN projection neurons using optogenetics and quantified behavior in male and female mice using 3D motion capture. STN stimulation resulted in movements with short latencies (10-15 ms). A single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematic measures. Unilateral stimulation caused movement in the ipsiversive direction (toward the side of stimulation) and quantitatively determined head yaw and head roll, while stimulation of either STN raises the head (pitch). Bilateral stimulation does not cause turning but raised the head twice as high as unilateral stimulation of either STN. Optogenetic stimulation increased the firing rate of STN neurons in a frequency-dependent manner, and the increased firing is responsible for stimulation-induced movements. Finally, stimulation of the STN's projection to the brainstem mesencephalic locomotor region was sufficient to reproduce the behavioral effects of STN stimulation. These results question the common assumption that the STN suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.SIGNIFICANCE STATEMENT Our results question the common assumption that the subthalamic nucleus (STN) suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.

Keywords: basal ganglia; deep brain stimulation; kinematics; movement; optogenetics; subthalamic nucleus.

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Figures

Figure 1.
Figure 1.
Placement of viral injections, optic fibers, and electrodes. A, Schematic of surgery strategy for bilateral STN stimulation experiments, along with representative histology and optic fiber tip locations. B, Schematic of surgery strategy for left hemisphere STN optrode stimulation experiment, along with representative histology and electrophysiological recording locations. C, Schematic of surgery strategy for STN-MLR projection stimulation experiments, along with optic fiber tip locations.
Figure 2.
Figure 2.
Quantifying movement kinematics using 3D motion capture. A, Schematic of the experimental setup. B, Body angle calculation. A right triangle was made in the X-Y plane with the tail marker and center of the left and right head markers (head center) as vertices. The angle at the tail marker was shifted into the proper polar quadrant based on the mouse's orientation and was used as body angle. C, To calculate yaw, a triangle was made in the X-Y plane with the tail marker, right head marker, and head center as vertices. The angle at head center minus 90 was used as yaw. D, To compute roll, a triangle was made in the X-Z plane with the left head marker, head center, and a float point 10 mm below head center as vertices. The angle at head center minus 90 was used as roll. E, To calculate pitch, a triangle was made in 3D space with the top head marker, head center, and a float point 10 mm in front of head center as vertices. The angle at head center minus 90 was used as pitch. F, Illustration of the key measures: body angle, head yaw, roll, and pitch.
Figure 3.
Figure 3.
Photo-stimulation of STN ChR2+ neurons causes movement (frequency manipulation). A, left, Linear relationship between unilateral stimulation frequency and ipsiversive turning. Middle left, 40-Hz unilateral stimulation causes significant ipsiversive turning versus controls. Middle right, No relationship between stimulation frequency and turning with bilateral stimulation. Right, 20-Hz bilateral stimulation does not cause turning. B, Left, Linear relationship between unilateral stimulation frequency and ipsiversive head yaw. Middle left, 40-Hz unilateral stimulation causes significant ipsiversive head yaw across hemispheres. Middle right, No relationship between stimulation frequency and head yaw with bilateral stimulation. Right, 20-Hz bilateral stimulation does not cause head yaw. C, Left, Linear relationship between unilateral stimulation frequency and ipsiversive head roll. Middle left, 40-Hz unilateral stimulation causes significant ipsiversive head roll versus controls. Middle right, No relationship between stimulation frequency and head roll with bilateral stimulation. Right, 20-Hz bilateral stimulation does not cause head roll. D, Left, Linear relationship between unilateral stimulation frequency and upwards head pitch. Middle left, 40-Hz unilateral stimulation causes significant upwards head pitch versus controls. Left hemisphere stimulation increases head pitch more than right. Middle right, Nonsignificant linear relationship between stimulation frequency and upwards head pitch with bilateral stimulation. Right, 20-Hz bilateral stimulation causes a significant increase in head pitch versus controls. n = 7 ChR2 and 4 control mice. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars indicate SEM.
Figure 4.
Figure 4.
Left STN ChR2 stimulation drives firing in a frequency dependent manner, and this firing underlies the stimulation-induced movement. A, Linear relationship between stimulation frequency and firing rate in tagged units. B, Mean opto-evoked spike latency measured from the onset of the first pulse in each laser train. C, D, Representative unit. Left, Spontaneous and evoked action potentials have the same shape. Right, Stimulation drives firing at all frequencies. E–H, Linear relationship between stimulation frequency and changes in all kinematic variables, except yaw. n = 24 units (17 tagged) recorded from 2 mice. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars indicate SEM.
Figure 5.
Figure 5.
Photo-stimulation of STN ChR2+ neurons causes movement (pulse width manipulation). A, Left, Linear relationship between unilateral stimulation pulse width and ipsiversive turning. Middle left, 40-ms unilateral stimulation causes significant ipsiversive turning versus controls. Middle right, Linear relationship between pulse width and leftwards turning with bilateral stimulation. Right, 40-ms bilateral stimulation does not cause significant turning versus controls. B, Left, Linear relationship between pulse width and ipsiversive head yaw with right STN stimulation. Middle left, 40-ms unilateral stimulation causes significant ipsiversive head yaw across hemispheres, and versus controls in the right hemisphere. Middle right, No relationship between pulse width and head yaw with bilateral stimulation. Right, 40-ms bilateral stimulation does not cause head yaw. C, Left, Linear relationship between unilateral stimulation pulse width and ipsiversive head roll. Middle left, 40-ms unilateral stimulation causes significant ipsiversive head roll across hemispheres, and versus controls in the left hemisphere. Middle right, Linear relationship between pulse width and leftwards head roll with bilateral stimulation. Right, 40-ms bilateral stimulation does not cause significant head roll versus controls. D, Left, Linear relationship between pulse width and upwards head pitch with unilateral stimulation. Middle left, 40-ms unilateral stimulation causes significant upwards head pitch versus controls. Middle right, Linear relationship between pulse width and upwards head pitch with bilateral stimulation. Right, 40-ms bilateral stimulation causes a significant increase in head pitch versus controls. n = 7 ChR2 and 4 control mice. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars indicate SEM.
Figure 6.
Figure 6.
Mean latency to move from the onset of a single STN-targeted 40-ms laser pulse. n = 7 ChR2 mice. *p < 0.05. Error bars indicate SEM.
Figure 7.
Figure 7.
Single pulse photo-stimulation of STN. A, Mean turning velocity. Left, Linear relationship between pulse width and ipsiversive turning velocity 60 ms after left STN stimulation. No relationship 120 ms poststimulation. Middle left, Significant interaction (see Table 5) between time point and experimental group on turning velocity following left STN 40-ms pulse stimulation. Significant ipsiversive turning velocity at 60-ms time point. Middle right, Linear relationship between pulse width and ipsiversive turning velocity 60 and 120 ms after right STN stimulation. Right, Significant interaction between time point and experimental group on turning velocity following right STN 40-ms pulse stimulation. Significant ipsiversive turning velocity only at the 60-ms time point. B, Mean head yaw velocity. Left, No relationship between pulse width and yaw velocity 60 or 120 ms after left STN stimulation. Middle left, No effect of time point or experimental group on yaw velocity following left STN 40-ms pulse stimulation. Middle right, Linear relationship between pulse width and ipsiversive yaw velocity 60 ms after right STN stimulation. Right, Significant interaction between time point and experimental group on yaw velocity following right STN 40-ms pulse stimulation. Stimulation caused significant ipsiversive and contraversive yaw velocity at the 60- and 120-ms time points, respectively. C, Mean head roll velocity. Left, Linear relationships between pulse width and roll velocity 60 and 120 ms after left STN stimulation, respectively. Middle left, Significant interaction between time point and experimental group on roll velocity following left STN 40-ms pulse stimulation. Stimulation caused significant ipsiversive and contraversive roll velocity at the 60- and 120-ms time points, respectively. Middle right, Linear relationships between pulse width and ipsiversive and contraversive roll velocity 60 and 120 ms after right STN stimulation, respectively. Right, Significant interaction between time point and experimental group on roll velocity following right STN 40-ms pulse stimulation. Stimulation caused significant ipsiversive and contraversive roll velocity at the 60- and 120-ms time points, respectively. D, Mean head pitch velocity. Left, Linear relationships between pulse width and upwards and downwards pitch velocity 60 and 120 ms after left STN stimulation, respectively. Middle left, Significant interaction between time point and experimental group on pitch velocity following left STN 40-ms pulse stimulation. Stimulation caused significant upwards and downwards pitch velocity at the 60- and 120-ms time points, respectively. Middle right, Linear relationship between pulse width and upwards pitch velocity 60 ms after right STN stimulation. Right, Significant interaction between time point and experimental group on pitch velocity following right STN 40-ms stimulation. Stimulation caused significant upwards and downwards pitch velocity at the 60- and 120-ms time points, respectively. n = 7 ChR2 and 4 control mice. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars indicate SEM.
Figure 8.
Figure 8.
Individual laser pulses delivered to STN ChR2+ neurons as part of 10-Hz photo-stimulation trains cause head rebound movement. Left, Mean velocity change caused by left STN stimulation. Middle left, Mean velocity change caused by right STN stimulation. Middle right, Mean angular change caused by left STN stimulation. Right, Mean angular change caused by right STN stimulation. A, Body angle. B, Head yaw. C, Head roll. D, Head pitch. n = 7 ChR2 and 4 control mice. Error bars indicate SEM.
Figure 9.
Figure 9.
Photo-stimulation of STN ChR2+ terminals in the MLR reproduces the effect of STN cell body stimulation. A, Left, Linear relationship between unilateral stimulation frequency and ipsiversive turning (right hemisphere trending). Middle left, 40-Hz unilateral stimulation causes significant ipsiversive turning versus controls. Middle right, No relationship between stimulation frequency and turning with bilateral stimulation. Right, 40-Hz bilateral stimulation does not cause turning. B, Left, No clear linear relationship between unilateral stimulation frequency and ipsiversive head yaw. Middle left, 40-Hz unilateral stimulation causes significant ipsiversive head yaw across hemispheres, and versus controls in the left hemisphere. Middle right, No relationship between stimulation frequency and head yaw with bilateral stimulation. Right, 40-Hz bilateral stimulation does not cause head yaw. C, Left, Linear relationship between unilateral stimulation frequency and ipsiversive head roll. Middle left, 40-Hz unilateral stimulation causes significant ipsiversive head roll versus controls. Middle right, No relationship between stimulation frequency and head roll with bilateral stimulation. Right, 40-Hz bilateral stimulation does not cause head roll. D, Left, Linear relationship between unilateral stimulation frequency and upwards head pitch. Middle left, 40-Hz bilateral stimulation significantly increases head pitch versus controls. Middle right, Linear relationship between stimulation frequency and upwards head pitch with bilateral stimulation. Right, 40-Hz bilateral stimulation significantly increases head pitch versus controls. n = 4 ChR2 and 4 control mice. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars indicate SEM.
Figure 10.
Figure 10.
Individual laser pulses delivered to STN ChR2+ terminals in the MLR as part of 10-Hz photo-stimulation trains also cause head rebound movement. Left, Mean angular change caused by left hemisphere STN-MLR stimulation. Right, Mean angular change caused by right hemisphere STN-MLR stimulation. (A) Body angle. (B) Head yaw. (C) Head roll. (D) Head pitch. n = 4 ChR2 and 4 control mice. Error bars indicate SEM.
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