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Genetic dissection of the circuit for hand dexterity in primates


It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates1,2,3. However, the role of the ‘phylogenetically older’ indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs)4,5,6 , which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex–PN–motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

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Figure 1: The pathway-specific and reversible blockade of synaptic transmission.
Figure 2: Reversible impairment of reach and grasp movements during doxycycline administration.
Figure 3: Blockade of synaptic transmission through the PNs.
Figure 4: Visualization of the blocked PNs.


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We thank S. Nakanishi, H. Jingami and C. Akazawa for continuous encouragement. We thank P. Redgrave for comments on the earlier version of the manuscript. This study was supported by the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. B.A. was supported by the Swedish Research Council. We thank T. Oishi for providing macaque brain sample tissue. We thank P. Phongphanphanee, M. Togawa, Y. Yamanishi, T. Katoh, K. Shimizu, N. Takahashi and K. Takada for technical support.

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Authors and Affiliations



Author Contributions M.K., D.W., K.K., B.A. and T.I. designed the experiments and wrote the paper. M.K., B.A., K.I. and T.I. conducted the surgery, behavioural, electrophysiological and histological experiments and analysed the data. R.M., T.H., S.K., H.K., D.W. and K.K. made the viral vectors. A.W. and T.Y. contributed to the histological processing. Y.N. contributed to behavioural analysis and electrophysiological experiments.

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Correspondence to Tadashi Isa.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8, Supplementary Tables 1-2, and Supplementary References. (PDF 1318 kb)

Supplementary Movie 1

This movie shows examples of “precision grip errors” in monkey H. (MOV 5473 kb)

Supplementary Movie 2

This movie shows examples of “slit-hit errors” in monkey K. (MOV 4970 kb)

Supplementary Movie 3

This movie shows examples of “wandering errors” in monkey K. (MOV 5003 kb)

Supplementary Movie 4

This movie shows movement deficit and recovery in monkey H, which mainly showed “precision grip errors”. Reach and grasp movements of monkey H, on days 0, 2, and 5 after the start of Dox administration. Note that extension of the thumb was impaired on day 2, but the movements became normal again on day 5. (MOV 6419 kb)

Supplementary Movie 5

This movie shows movement deficit and recovery in monkey K, which mainly showed “slit-hit errors” and “wandering errors”. Reach and grasp movements of monkey K on days 0, 4, and 8 of the first Dox round (Dox1), days 3 and 7 of the 2nd Dox round (Dox2) and days 2 and 5.5 of the 3rd Dox round (Dox3). Note that the deficit in reaching was repeated and recovered. (MOV 14113 kb)

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Kinoshita, M., Matsui, R., Kato, S. et al. Genetic dissection of the circuit for hand dexterity in primates. Nature 487, 235–238 (2012).

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