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Skilled reaching relies on a V2a propriospinal internal copy circuit.

Azim E, Jiang J, Alstermark B, Jessell TM - Nature (2014)

Bottom Line: The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear.Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics.Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.

ABSTRACT
The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

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Selective photo-stimulation of PN terminals in the LRN perturbs reachinga, Mean reach kinematics from a representative mouse with perturbed reach trajectory and large fluctuations in velocity and acceleration during PN terminal photo-stimulation. See Fig. 6c for individual reach plots from the same mouse. As shown in Fig. 6b, photo-stimulation reduced success in the multi-reach task in ChR2 vs. control mice (no light, 35.7% +/− 6.5% s.e.m.; light, 18.3% +/− 3.8% s.e.m.; n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, interaction of group × light: F1,7 = 8.65, P = 0.02; post-hoc Bonferroni test, ChR2: P < 0.001). There were no successful reaches in the kinematic assay during PN terminal photo-stimulation (Supplementary Note 4). b, Individual and mean reach kinematics from a representative control mouse show no effects of LRN photo-stimulation. Shaded regions indicate s.d. c, As shown in Fig. 6d, the mean number of direction reversals during the reach phase increased during photo-stimulation in ChR2 mice, relative to control mice (n = 5 ChR2, n = 4 control; two-way ANOVA, interaction of group × condition, reach phase: F2,19 = 5.24, P = 0.02; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01; grab phase: F2,19 = 2.70, P = 0.09). In addition, photo-stimulation resulted in severe kinematic perturbation during the entire movement (reach and grab phases) in ChR2 mice relative to control mice, including increases in: the mean amount of time spent moving away from the pellet (F2,19 = 4.07, P = 0.03; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01); the mean minimum distance from the paw to the pellet (F2,19 = 6.37, P = 0.008; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.001); the mean peak velocity away from the pellet (F2,19 = 9.08, P = 0.002; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.001); the mean s.d. of the velocity (F2,18 = 25.02, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); the mean peak acceleration and deceleration (acceleration: F2,19 = 10.08, P = 0.001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.0001; deceleration: F2,19 = 21.53, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); and the mean s.d. of the acceleration (F2,18 = 29.21, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001). Shapes represent individual mice. Black circles indicate means across mice. See Extended Data Table 2. d, Digit abduction (maximum distance between digits 2 and 4) during grasp attempts was unaffected by photo-stimulation (n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, F1,7 = 3.71, P = 0.10). Error bars indicate s.e.m.
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Figure 12: Selective photo-stimulation of PN terminals in the LRN perturbs reachinga, Mean reach kinematics from a representative mouse with perturbed reach trajectory and large fluctuations in velocity and acceleration during PN terminal photo-stimulation. See Fig. 6c for individual reach plots from the same mouse. As shown in Fig. 6b, photo-stimulation reduced success in the multi-reach task in ChR2 vs. control mice (no light, 35.7% +/− 6.5% s.e.m.; light, 18.3% +/− 3.8% s.e.m.; n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, interaction of group × light: F1,7 = 8.65, P = 0.02; post-hoc Bonferroni test, ChR2: P < 0.001). There were no successful reaches in the kinematic assay during PN terminal photo-stimulation (Supplementary Note 4). b, Individual and mean reach kinematics from a representative control mouse show no effects of LRN photo-stimulation. Shaded regions indicate s.d. c, As shown in Fig. 6d, the mean number of direction reversals during the reach phase increased during photo-stimulation in ChR2 mice, relative to control mice (n = 5 ChR2, n = 4 control; two-way ANOVA, interaction of group × condition, reach phase: F2,19 = 5.24, P = 0.02; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01; grab phase: F2,19 = 2.70, P = 0.09). In addition, photo-stimulation resulted in severe kinematic perturbation during the entire movement (reach and grab phases) in ChR2 mice relative to control mice, including increases in: the mean amount of time spent moving away from the pellet (F2,19 = 4.07, P = 0.03; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01); the mean minimum distance from the paw to the pellet (F2,19 = 6.37, P = 0.008; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.001); the mean peak velocity away from the pellet (F2,19 = 9.08, P = 0.002; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.001); the mean s.d. of the velocity (F2,18 = 25.02, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); the mean peak acceleration and deceleration (acceleration: F2,19 = 10.08, P = 0.001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.0001; deceleration: F2,19 = 21.53, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); and the mean s.d. of the acceleration (F2,18 = 29.21, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001). Shapes represent individual mice. Black circles indicate means across mice. See Extended Data Table 2. d, Digit abduction (maximum distance between digits 2 and 4) during grasp attempts was unaffected by photo-stimulation (n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, F1,7 = 3.71, P = 0.10). Error bars indicate s.e.m.

Mentions: To examine the behavioral impact of activating the PN internal branch we analyzed the influence of LRN photo-stimulation on reach kinematics (Fig. 6a). Application of light pulses severely degraded reach success in the multi-reach task and eliminated success in the kinematic assay, with no impact on control, virus-spared, mice (Fig. 6b). Indeed, photo-stimulation in virally-transduced, but not in control, mice severely perturbed motor performance (Fig. 6c,d, Extended Data Fig. 6a-c, Extended Data Table 2, Supplementary Video 4: no light, Supplementary Video 5: light). We detected an ~4.5-fold increase in the incidence of paw direction reversals during the reach phase (Fig. 6d, Extended Data Table 2). Certain other kinematic parameters, notably variations in velocity, were perturbed in both reach and grab phases (Fig. 6c, Extended Data Fig. 6a,c, Extended Data Table 2) – nevertheless digit abduction was not affected (Extended Data Fig. 6d, Supplementary Video 5), revealing an element of selectivity. These findings indicate that imposed activation of the internally-directed PN branch severely disrupts forelimb reaching movements (Supplementary Discussion).


Skilled reaching relies on a V2a propriospinal internal copy circuit.

Azim E, Jiang J, Alstermark B, Jessell TM - Nature (2014)

Selective photo-stimulation of PN terminals in the LRN perturbs reachinga, Mean reach kinematics from a representative mouse with perturbed reach trajectory and large fluctuations in velocity and acceleration during PN terminal photo-stimulation. See Fig. 6c for individual reach plots from the same mouse. As shown in Fig. 6b, photo-stimulation reduced success in the multi-reach task in ChR2 vs. control mice (no light, 35.7% +/− 6.5% s.e.m.; light, 18.3% +/− 3.8% s.e.m.; n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, interaction of group × light: F1,7 = 8.65, P = 0.02; post-hoc Bonferroni test, ChR2: P < 0.001). There were no successful reaches in the kinematic assay during PN terminal photo-stimulation (Supplementary Note 4). b, Individual and mean reach kinematics from a representative control mouse show no effects of LRN photo-stimulation. Shaded regions indicate s.d. c, As shown in Fig. 6d, the mean number of direction reversals during the reach phase increased during photo-stimulation in ChR2 mice, relative to control mice (n = 5 ChR2, n = 4 control; two-way ANOVA, interaction of group × condition, reach phase: F2,19 = 5.24, P = 0.02; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01; grab phase: F2,19 = 2.70, P = 0.09). In addition, photo-stimulation resulted in severe kinematic perturbation during the entire movement (reach and grab phases) in ChR2 mice relative to control mice, including increases in: the mean amount of time spent moving away from the pellet (F2,19 = 4.07, P = 0.03; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01); the mean minimum distance from the paw to the pellet (F2,19 = 6.37, P = 0.008; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.001); the mean peak velocity away from the pellet (F2,19 = 9.08, P = 0.002; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.001); the mean s.d. of the velocity (F2,18 = 25.02, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); the mean peak acceleration and deceleration (acceleration: F2,19 = 10.08, P = 0.001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.0001; deceleration: F2,19 = 21.53, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); and the mean s.d. of the acceleration (F2,18 = 29.21, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001). Shapes represent individual mice. Black circles indicate means across mice. See Extended Data Table 2. d, Digit abduction (maximum distance between digits 2 and 4) during grasp attempts was unaffected by photo-stimulation (n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, F1,7 = 3.71, P = 0.10). Error bars indicate s.e.m.
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Figure 12: Selective photo-stimulation of PN terminals in the LRN perturbs reachinga, Mean reach kinematics from a representative mouse with perturbed reach trajectory and large fluctuations in velocity and acceleration during PN terminal photo-stimulation. See Fig. 6c for individual reach plots from the same mouse. As shown in Fig. 6b, photo-stimulation reduced success in the multi-reach task in ChR2 vs. control mice (no light, 35.7% +/− 6.5% s.e.m.; light, 18.3% +/− 3.8% s.e.m.; n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, interaction of group × light: F1,7 = 8.65, P = 0.02; post-hoc Bonferroni test, ChR2: P < 0.001). There were no successful reaches in the kinematic assay during PN terminal photo-stimulation (Supplementary Note 4). b, Individual and mean reach kinematics from a representative control mouse show no effects of LRN photo-stimulation. Shaded regions indicate s.d. c, As shown in Fig. 6d, the mean number of direction reversals during the reach phase increased during photo-stimulation in ChR2 mice, relative to control mice (n = 5 ChR2, n = 4 control; two-way ANOVA, interaction of group × condition, reach phase: F2,19 = 5.24, P = 0.02; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01; grab phase: F2,19 = 2.70, P = 0.09). In addition, photo-stimulation resulted in severe kinematic perturbation during the entire movement (reach and grab phases) in ChR2 mice relative to control mice, including increases in: the mean amount of time spent moving away from the pellet (F2,19 = 4.07, P = 0.03; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.01, ChR2 no light misses vs. light misses, P < 0.01); the mean minimum distance from the paw to the pellet (F2,19 = 6.37, P = 0.008; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.001); the mean peak velocity away from the pellet (F2,19 = 9.08, P = 0.002; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.001); the mean s.d. of the velocity (F2,18 = 25.02, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); the mean peak acceleration and deceleration (acceleration: F2,19 = 10.08, P = 0.001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.001, ChR2 no light misses vs. light misses, P < 0.0001; deceleration: F2,19 = 21.53, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001); and the mean s.d. of the acceleration (F2,18 = 29.21, P < 0.0001; post-hoc Tukey test, ChR2 no light hits vs. light misses, P < 0.0001, ChR2 no light misses vs. light misses, P < 0.0001). Shapes represent individual mice. Black circles indicate means across mice. See Extended Data Table 2. d, Digit abduction (maximum distance between digits 2 and 4) during grasp attempts was unaffected by photo-stimulation (n = 5 ChR2, n = 4 control; two-way repeated-measures ANOVA, F1,7 = 3.71, P = 0.10). Error bars indicate s.e.m.
Mentions: To examine the behavioral impact of activating the PN internal branch we analyzed the influence of LRN photo-stimulation on reach kinematics (Fig. 6a). Application of light pulses severely degraded reach success in the multi-reach task and eliminated success in the kinematic assay, with no impact on control, virus-spared, mice (Fig. 6b). Indeed, photo-stimulation in virally-transduced, but not in control, mice severely perturbed motor performance (Fig. 6c,d, Extended Data Fig. 6a-c, Extended Data Table 2, Supplementary Video 4: no light, Supplementary Video 5: light). We detected an ~4.5-fold increase in the incidence of paw direction reversals during the reach phase (Fig. 6d, Extended Data Table 2). Certain other kinematic parameters, notably variations in velocity, were perturbed in both reach and grab phases (Fig. 6c, Extended Data Fig. 6a,c, Extended Data Table 2) – nevertheless digit abduction was not affected (Extended Data Fig. 6d, Supplementary Video 5), revealing an element of selectivity. These findings indicate that imposed activation of the internally-directed PN branch severely disrupts forelimb reaching movements (Supplementary Discussion).

Bottom Line: The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear.Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics.Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.

ABSTRACT
The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

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Related in: MedlinePlus