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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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Cervical V2a IN ablation perturbs reachinga, Experimental design. b, After C3-T1 AAV-FLEX-DTR-GFP injection 83% (+/− 0.3% s.e.m.; n = 2) of tdT+ V2a INs co-expressed GFP and DTR (arrows), and GFP+ projections were detected in LRN. c, Post-DT, 84% (+/− 9% s.e.m.; n = 2) of C3-T1 tdT+ V2a INs and GFP+ LRN projections were eliminated (arrowhead, spared V2a IN). d, Ablation reduced success in the multi-reach task (n = 3 DTR, n = 4 control). e, Kinematics from a representative V2a IN-ablated mouse. See Extended Data Fig. 3e. f, Mean number of direction reversals increased during reach, but not grab, phase in V2a IN-ablated mice. Shapes represent individual mice. Error bars indicate s.e.m. See Extended Data Table 1 and Extended Data Fig. 3 for statistical analysis.
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Figure 4: Cervical V2a IN ablation perturbs reachinga, Experimental design. b, After C3-T1 AAV-FLEX-DTR-GFP injection 83% (+/− 0.3% s.e.m.; n = 2) of tdT+ V2a INs co-expressed GFP and DTR (arrows), and GFP+ projections were detected in LRN. c, Post-DT, 84% (+/− 9% s.e.m.; n = 2) of C3-T1 tdT+ V2a INs and GFP+ LRN projections were eliminated (arrowhead, spared V2a IN). d, Ablation reduced success in the multi-reach task (n = 3 DTR, n = 4 control). e, Kinematics from a representative V2a IN-ablated mouse. See Extended Data Fig. 3e. f, Mean number of direction reversals increased during reach, but not grab, phase in V2a IN-ablated mice. Shapes represent individual mice. Error bars indicate s.e.m. See Extended Data Table 1 and Extended Data Fig. 3 for statistical analysis.

Mentions: We targeted cervical V2a INs for elimination by unilateral injection of a viral vector that directed conditional expression of a diphtheria toxin receptor (DTR)-GFP fusion (AAV-FLEX-DTR-GFP) into C3-T1 levels of Chx10::tdT mice (Fig. 4a, Extended Data Fig. 3a)35. Seven days after viral injection >80% of tdT+ V2a INs selectively expressed DTR-GFP, and the LRN contained a dense network of GFP+ axons (Fig. 4b, Extended Data Fig. 3b). Diphtheria toxin (DT; 400 ng) administration 14-21 days after DTR transduction resulted, 7 days later, in a >80% elimination of C3-T1 tdT+ V2a INs and a virtually complete loss of GFP+ axons within the LRN (Fig. 4c, Extended Data Fig. 3b,c).


Skilled reaching relies on a V2a propriospinal internal copy circuit.

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

Cervical V2a IN ablation perturbs reachinga, Experimental design. b, After C3-T1 AAV-FLEX-DTR-GFP injection 83% (+/− 0.3% s.e.m.; n = 2) of tdT+ V2a INs co-expressed GFP and DTR (arrows), and GFP+ projections were detected in LRN. c, Post-DT, 84% (+/− 9% s.e.m.; n = 2) of C3-T1 tdT+ V2a INs and GFP+ LRN projections were eliminated (arrowhead, spared V2a IN). d, Ablation reduced success in the multi-reach task (n = 3 DTR, n = 4 control). e, Kinematics from a representative V2a IN-ablated mouse. See Extended Data Fig. 3e. f, Mean number of direction reversals increased during reach, but not grab, phase in V2a IN-ablated mice. Shapes represent individual mice. Error bars indicate s.e.m. See Extended Data Table 1 and Extended Data Fig. 3 for statistical analysis.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4230338&req=5

Figure 4: Cervical V2a IN ablation perturbs reachinga, Experimental design. b, After C3-T1 AAV-FLEX-DTR-GFP injection 83% (+/− 0.3% s.e.m.; n = 2) of tdT+ V2a INs co-expressed GFP and DTR (arrows), and GFP+ projections were detected in LRN. c, Post-DT, 84% (+/− 9% s.e.m.; n = 2) of C3-T1 tdT+ V2a INs and GFP+ LRN projections were eliminated (arrowhead, spared V2a IN). d, Ablation reduced success in the multi-reach task (n = 3 DTR, n = 4 control). e, Kinematics from a representative V2a IN-ablated mouse. See Extended Data Fig. 3e. f, Mean number of direction reversals increased during reach, but not grab, phase in V2a IN-ablated mice. Shapes represent individual mice. Error bars indicate s.e.m. See Extended Data Table 1 and Extended Data Fig. 3 for statistical analysis.
Mentions: We targeted cervical V2a INs for elimination by unilateral injection of a viral vector that directed conditional expression of a diphtheria toxin receptor (DTR)-GFP fusion (AAV-FLEX-DTR-GFP) into C3-T1 levels of Chx10::tdT mice (Fig. 4a, Extended Data Fig. 3a)35. Seven days after viral injection >80% of tdT+ V2a INs selectively expressed DTR-GFP, and the LRN contained a dense network of GFP+ axons (Fig. 4b, Extended Data Fig. 3b). Diphtheria toxin (DT; 400 ng) administration 14-21 days after DTR transduction resulted, 7 days later, in a >80% elimination of C3-T1 tdT+ V2a INs and a virtually complete loss of GFP+ axons within the LRN (Fig. 4c, Extended Data Fig. 3b,c).

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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