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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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PN terminal photo-stimulation perturbs forelimb movement via a cerebellar-motor loopa, Experimental design. b, Photo-stimulation reduced success in the multi-reach task (n = 5 ChR2, n = 4 control). c, Kinematics from a representative AAV-ChR2 mouse. See Extended Data Fig. 6a. d, Mean number of reach phase direction reversals increased during photo-stimulation. See Extended Data Table 2 and Extended Data Fig. 6 for statistical analysis. e, Intracellular recording from forelimb MNs during PN terminal photo-stimulation revealed EPSPs with varying onset (upper black traces, bars; 0.8 ms between first two arrowheads, 2.5 ms between first and third arrowheads; n =11). Cervical photo-stimulation of PN cell bodies produced shorter latency fixed onset EPSPs (lower black traces, bars; onset (arrowhead) 0.6 ms from volley in field (arrow); n = 3). Field potentials recorded in C6/C7 ventral horn (gray traces, gray bars) had similar onset and duration as MN EPSPs (n = 27, LRN-light; n = 8, C4-light). f, Bilateral lesion of inferior cerebellar peduncles (ICP; gray traces) or cerebellar extirpation (CB; red traces) reduced field potential size (mean reduction in area; 56% +/− 8.8% s.d.; P = 0.001; n = 5; two-tailed paired t-test). Shortest latency fields (~3.6 to 4.7 ms) were eliminated after lesions (histogram, scatter plot). Error bars indicate s.e.m.
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Figure 6: PN terminal photo-stimulation perturbs forelimb movement via a cerebellar-motor loopa, Experimental design. b, Photo-stimulation reduced success in the multi-reach task (n = 5 ChR2, n = 4 control). c, Kinematics from a representative AAV-ChR2 mouse. See Extended Data Fig. 6a. d, Mean number of reach phase direction reversals increased during photo-stimulation. See Extended Data Table 2 and Extended Data Fig. 6 for statistical analysis. e, Intracellular recording from forelimb MNs during PN terminal photo-stimulation revealed EPSPs with varying onset (upper black traces, bars; 0.8 ms between first two arrowheads, 2.5 ms between first and third arrowheads; n =11). Cervical photo-stimulation of PN cell bodies produced shorter latency fixed onset EPSPs (lower black traces, bars; onset (arrowhead) 0.6 ms from volley in field (arrow); n = 3). Field potentials recorded in C6/C7 ventral horn (gray traces, gray bars) had similar onset and duration as MN EPSPs (n = 27, LRN-light; n = 8, C4-light). f, Bilateral lesion of inferior cerebellar peduncles (ICP; gray traces) or cerebellar extirpation (CB; red traces) reduced field potential size (mean reduction in area; 56% +/− 8.8% s.d.; P = 0.001; n = 5; two-tailed paired t-test). Shortest latency fields (~3.6 to 4.7 ms) were eliminated after lesions (histogram, scatter plot). 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)

PN terminal photo-stimulation perturbs forelimb movement via a cerebellar-motor loopa, Experimental design. b, Photo-stimulation reduced success in the multi-reach task (n = 5 ChR2, n = 4 control). c, Kinematics from a representative AAV-ChR2 mouse. See Extended Data Fig. 6a. d, Mean number of reach phase direction reversals increased during photo-stimulation. See Extended Data Table 2 and Extended Data Fig. 6 for statistical analysis. e, Intracellular recording from forelimb MNs during PN terminal photo-stimulation revealed EPSPs with varying onset (upper black traces, bars; 0.8 ms between first two arrowheads, 2.5 ms between first and third arrowheads; n =11). Cervical photo-stimulation of PN cell bodies produced shorter latency fixed onset EPSPs (lower black traces, bars; onset (arrowhead) 0.6 ms from volley in field (arrow); n = 3). Field potentials recorded in C6/C7 ventral horn (gray traces, gray bars) had similar onset and duration as MN EPSPs (n = 27, LRN-light; n = 8, C4-light). f, Bilateral lesion of inferior cerebellar peduncles (ICP; gray traces) or cerebellar extirpation (CB; red traces) reduced field potential size (mean reduction in area; 56% +/− 8.8% s.d.; P = 0.001; n = 5; two-tailed paired t-test). Shortest latency fields (~3.6 to 4.7 ms) were eliminated after lesions (histogram, scatter plot). Error bars indicate s.e.m.
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Figure 6: PN terminal photo-stimulation perturbs forelimb movement via a cerebellar-motor loopa, Experimental design. b, Photo-stimulation reduced success in the multi-reach task (n = 5 ChR2, n = 4 control). c, Kinematics from a representative AAV-ChR2 mouse. See Extended Data Fig. 6a. d, Mean number of reach phase direction reversals increased during photo-stimulation. See Extended Data Table 2 and Extended Data Fig. 6 for statistical analysis. e, Intracellular recording from forelimb MNs during PN terminal photo-stimulation revealed EPSPs with varying onset (upper black traces, bars; 0.8 ms between first two arrowheads, 2.5 ms between first and third arrowheads; n =11). Cervical photo-stimulation of PN cell bodies produced shorter latency fixed onset EPSPs (lower black traces, bars; onset (arrowhead) 0.6 ms from volley in field (arrow); n = 3). Field potentials recorded in C6/C7 ventral horn (gray traces, gray bars) had similar onset and duration as MN EPSPs (n = 27, LRN-light; n = 8, C4-light). f, Bilateral lesion of inferior cerebellar peduncles (ICP; gray traces) or cerebellar extirpation (CB; red traces) reduced field potential size (mean reduction in area; 56% +/− 8.8% s.d.; P = 0.001; n = 5; two-tailed paired t-test). Shortest latency fields (~3.6 to 4.7 ms) were eliminated after lesions (histogram, scatter plot). 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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