Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Brainstem nucleus MdV mediates skilled forelimb motor tasks


Translating the behavioural output of the nervous system into movement involves interaction between brain and spinal cord. The brainstem provides an essential bridge between the two structures, but circuit-level organization and function of this intermediary system remain poorly understood. Here we use intersectional virus tracing and genetic strategies in mice to reveal a selective synaptic connectivity matrix between brainstem substructures and functionally distinct spinal motor neurons that regulate limb movement. The brainstem nucleus medullary reticular formation ventral part (MdV) stands out as specifically targeting subpopulations of forelimb-innervating motor neurons. Its glutamatergic premotor neurons receive synaptic input from key upper motor centres and are recruited during motor tasks. Selective neuronal ablation or silencing experiments reveal that MdV is critically important specifically for skilled motor behaviour, including accelerating rotarod and single-food-pellet reaching tasks. Our results indicate that distinct premotor brainstem nuclei access spinal subcircuits to mediate task-specific aspects of motor programs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Brainstem premotor distribution.
Figure 2: Selective motor pools contacted by MdV.
Figure 3: MdV regulated by upstream motor centres.
Figure 4: Role of MdV neurons in motor behaviour.
Figure 5: MdV required for single-pellet reaching task.
Figure 6: MdV required for task execution.


  1. Shik, M. L. & Orlovsky, G. N. Neurophysiology of locomotor automatism. Physiol. Rev. 56, 465–501 (1976)

    CAS  PubMed  Google Scholar 

  2. Orlovsky, G. N., Deliagina, T. G. & Grillner, S. Neuronal Control of Locomotion: From Mollusc to Man (Oxford Univ. Press, 1999)

    Google Scholar 

  3. Grillner, S. Biological pattern generation: the cellular and computational logic of networks in motion. Neuron 52, 751–766 (2006)

    CAS  PubMed  Google Scholar 

  4. Jordan, L. M., Liu, J., Hedlund, P. B., Akay, T. & Pearson, K. G. Descending command systems for the initiation of locomotion in mammals. Brain Res. Rev. 57, 183–191 (2008)

    CAS  PubMed  Google Scholar 

  5. Kuypers, H. G. J. M. in Handbook of Physiology: The Nervous System. Anatomy of the Descending Pathways 597–666 (American Physiological Society, 1981)

    Google Scholar 

  6. Lemon, R. N. Descending pathways in motor control. Annu. Rev. Neurosci. 31, 195–218 (2008)

    CAS  PubMed  Google Scholar 

  7. Rathelot, J. A. & Strick, P. L. Subdivisions of primary motor cortex based on cortico-motoneuronal cells. Proc. Natl Acad. Sci. USA 106, 918–923 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alstermark, B. & Isa, T. Circuits for skilled reaching and grasping. Annu. Rev. Neurosci. 35, 559–578 (2012)

    CAS  PubMed  Google Scholar 

  9. Iwaniuk, A. N. & Whishaw, I. Q. On the origin of skilled forelimb movements. Trends Neurosci. 23, 372–376 (2000)

    CAS  PubMed  Google Scholar 

  10. Mori, S., Sakamoto, T., Ohta, Y., Takakusaki, K. & Matsuyama, K. Site-specific postural and locomotor changes evoked in awake, freely moving intact cats by stimulating the brainstem. Brain Res. 505, 66–74 (1989)

    CAS  PubMed  Google Scholar 

  11. Noga, B. R., Kriellaars, D. J., Brownstone, R. M. & Jordan, L. M. Mechanism for activation of locomotor centers in the spinal cord by stimulation of the mesencephalic locomotor region. J. Neurophysiol. 90, 1464–1478 (2003)

    PubMed  Google Scholar 

  12. Skinner, R. D. & Garcia-Rill, E. The mesencephalic locomotor region (MLR) in the rat. Brain Res. 323, 385–389 (1984)

    CAS  PubMed  Google Scholar 

  13. Garcia-Rill, E. & Skinner, R. D. The mesencephalic locomotor region. I. Activation of a medullary projection site. Brain Res. 411, 1–12 (1987)

    CAS  PubMed  Google Scholar 

  14. Drew, T., Prentice, S. & Schepens, B. Cortical and brainstem control of locomotion. Prog. Brain Res. 143, 251–261 (2004)

    PubMed  Google Scholar 

  15. Holmqvist, B. & Lundberg, A. Differential supraspinal control of synaptic actions evoked by volleys in the flexion reflex afferents in alpha motoneurones. Acta Physiol. Scand. Suppl. 186, 1–15 (1961)

  16. Grillner, S. & Hongo, T. Vestibulospinal effects on motoneurones and interneurones in the lumbosacral cord. Prog. Brain Res. 37, 243–262 (1972)

    CAS  PubMed  Google Scholar 

  17. Jankowska, E., Hammar, I., Slawinska, U., Maleszak, K. & Edgley, S. A. Neuronal basis of crossed actions from the reticular formation on feline hindlimb motoneurons. J. Neurosci. 23, 1867–1878 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jankowska, E. & Edgley, S. A. How can corticospinal tract neurons contribute to ipsilateral movements? A question with implications for recovery of motor functions. Neuroscientist 12, 67–79 (2006)

    PubMed  PubMed Central  Google Scholar 

  19. Wickersham, I. R. et al. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53, 639–647 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wickersham, I. R., Sullivan, H. A. & Seung, H. S. Production of glycoprotein-deleted rabies viruses for monosynaptic tracing and high-level gene expression in neurons. Nature Protocols 5, 595–606 (2010)

    CAS  PubMed  Google Scholar 

  21. Ugolini, G. Advances in viral transneuronal tracing. J. Neurosci. Methods 194, 2–20 (2010)

    PubMed  Google Scholar 

  22. Stepien, A. E., Tripodi, M. & Arber, S. Monosynaptic rabies virus reveals premotor network organization and synaptic specificity of cholinergic partition cells. Neuron 68, 456–472 (2010)

    CAS  PubMed  Google Scholar 

  23. Tripodi, M., Stepien, A. E. & Arber, S. Motor antagonism exposed by spatial segregation and timing of neurogenesis. Nature 479, 61–66 (2011)

    ADS  CAS  PubMed  Google Scholar 

  24. Paxinos, G. & Franklin, K. B. The Mouse Brain in Stereotaxic Coordinates 4th edn (Elsevier, 2012)

    Google Scholar 

  25. Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pecho-Vrieseling, E., Sigrist, M., Yoshida, Y., Jessell, T. M. & Arber, S. Specificity of sensory-motor connections encoded by Sema3e–Plxnd1 recognition. Nature 459, 842–846 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. McKenna, J. E., Prusky, G. T. & Whishaw, I. Q. Cervical motoneuron topography reflects the proximodistal organization of muscles and movements of the rat forelimb: a retrograde carbocyanine dye analysis. J. Comp. Neurol. 419, 286–296 (2000)

    CAS  PubMed  Google Scholar 

  28. Greene, E. C. Anatomy of the Rat (Hafner, 1935)

    Google Scholar 

  29. Wall, N. R., Wickersham, I. R., Cetin, A., De La Parra, M. & Callaway, E. M. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc. Natl Acad. Sci. USA 107, 21848–21853 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gorski, J. A. et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Buitrago, M. M., Schulz, J. B., Dichgans, J. & Luft, A. R. Short and long-term motor skill learning in an accelerated rotarod training paradigm. Neurobiol. Learn. Mem. 81, 211–216 (2004)

    PubMed  Google Scholar 

  32. Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920–924 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Costa, R. M., Cohen, D. & Nicolelis, M. A. Differential corticostriatal plasticity during fast and slow motor skill learning in mice. Curr. Biol. 14, 1124–1134 (2004)

    CAS  PubMed  Google Scholar 

  34. Bretzner, F. & Brownstone, R. M. Lhx3-Chx10 reticulospinal neurons in locomotor circuits. J. Neurosci. 33, 14681–14692 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nature Methods 2, 419–426 (2005)

    CAS  PubMed  Google Scholar 

  36. Ruediger, S. et al. Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature 473, 514–518 (2011)

    ADS  CAS  PubMed  Google Scholar 

  37. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel-ligand interactions. Science 333, 1292–1296 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu, T. et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462, 915–919 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Whishaw, I. Q. & Pellis, S. M. The structure of skilled forelimb reaching in the rat: a proximally driven movement with a single distal rotatory component. Behav. Brain Res. 41, 49–59 (1990)

    CAS  PubMed  Google Scholar 

  41. Blanco, J. E., Anderson, K. D. & Steward, O. Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice. Exp. Neurol. 203, 333–348 (2007)

    PubMed  Google Scholar 

  42. Bui, T. V. et al. Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior. Neuron 78, 191–204 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kiehn, O. Development and functional organization of spinal locomotor circuits. Curr. Opin. Neurobiol. 21, 100–109 (2011)

    CAS  PubMed  Google Scholar 

  44. Goulding, M. Circuits controlling vertebrate locomotion: moving in a new direction. Nature Rev. Neurosci. 10, 507–518 (2009)

    CAS  Google Scholar 

  45. Yakovenko, S., Krouchev, N. & Drew, T. Sequential activation of motor cortical neurons contributes to intralimb coordination during reaching in the cat by modulating muscle synergies. J. Neurophysiol. 105, 388–409 (2011)

    PubMed  Google Scholar 

  46. Hyland, B. I. & Jordan, V. M. Muscle activity during forelimb reaching movements in rats. Behav. Brain Res. 85, 175–186 (1997)

    CAS  PubMed  Google Scholar 

  47. Roh, J., Cheung, V. C. & Bizzi, E. Modules in the brain stem and spinal cord underlying motor behaviors. J. Neurophysiol. 106, 1363–1378 (2011)

    PubMed  PubMed Central  Google Scholar 

  48. Zeilhofer, H. U. et al. Glycinergic neurons expressing enhanced green fluorescent protein in bacterial artificial chromosome transgenic mice. J. Comp. Neurol. 482, 123–141 (2005)

    CAS  PubMed  Google Scholar 

  49. Harris, J. A., Oh, S. W. & Zeng, H. Adeno-associated viral vectors for anterograde axonal tracing with fluorescent proteins in nontransgenic and Cre driver mice. Curr. Protoc. Neurosci. 59, 1.20.1–1.20.18 (2012)

    Google Scholar 

Download references


We are grateful to M. Mielich, B. Rapp, D. Salvador and M. Sigrist for expert technical help, L. Gelman, A. Ponti, N. Ehrenfeuchter, M. Kirschmann and R. Thierry for help and advice with image acquisition and analysis, and to P. Caroni for discussions and comments on the manuscript. We thank F. Donato, Y. Zuo, A. Takeoka, P. Tovote and P. Botta for advice on design of behavioral experiments, and S. Sternson for providing PSEM308 and advice for neuronal silencing experiments. M.S.E. was supported by a long-term fellowship of the Human Frontier Science Program, and all authors by a European Research Council Advanced Grant, the Swiss National Science Foundation, the Kanton Basel-Stadt and the Novartis Research Foundation.

Author information

Authors and Affiliations



M.S.E. was involved in design of experiments, carried out experiments, acquired and analysed data. P.C. carried out experiments, acquired and analysed data. S.A. initiated the project, designed experiments, analysed data and wrote the manuscript. All authors discussed the experiments and commented on the manuscript.

Corresponding author

Correspondence to Silvia Arber.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Individual brainstem reconstructions.

Two individual brainstem reconstructions are shown for FL and HL muscle injections. Colour code of brainstem structures and visualization identical to Fig. 1.

Extended Data Figure 2 Differential distribution of forelimb and hindlimb brainstem premotor neurons.

af, Direct comparative analysis of distinct FL (purple) and HL (cyan) premotor populations in sagittal ipsilateral (a, c, e) and top-down (b, d, f) view of brainstem reconstructions. Parvicellular reticular nucleus (PCRt) and MdV (a, b), spinal trigeminal nucleus (Sp5) (c, d), and vestibular nucleus (Ve) (e, f) brainstem areas are shown as examples.

Extended Data Figure 3 Contralateral distribution of brainstem premotor neurons.

ad, Top-down (a, b) and sagittal contralateral (c, d) views of three-dimensional brainstem reconstructions for FL (a, c) and HL (b, d) premotor neuron analysis. Colour code of displayed neuronal populations is identical to Fig. 1. e, Quantification of neurons contralateral to injected limb (n = 5 mice each). f, g, Pairwise comparison of ipsi- and contralateral premotor brainstem neuron populations by resident nucleus for FL (f) and HL (g) muscle injection.

Extended Data Figure 4 Distinct morphology of brainstem premotor neurons.

aj, Representative reconstructed neuronal morphologies acquired from sagittal sections of gigantocellular reticular nucleus (Gi) (a), magnocellular reticular nucleus (Mc) (b), pontine reticular nucleus (Pn) (c), Raphe (d), parvicellular reticular nucleus (PCRt) (e), spinal trigeminal nucleus (Sp5) (f), spinal vestibular nucleus (SpVe) (g), vestibular nucleus (Ve) (h), and MdV (i; j: from coronal section) are shown in colour according to colour code defined in Fig. 1. Mc cell morphologies showed marked diversity not analysed further in this study. k, Cell soma areas of different premotor populations in the brainstem are displayed (dots represent individual neurons analysed).

Extended Data Figure 5 Neuronal diversity in MdV.

ac, FL premotor neurons in MdV (purple) sparsely overlap with vGATON neurons (a), but colocalize extensively with vGlut2ON populations (b, c) in mice with transgenically marked subpopulations (nlsLacZ, cyan) (n = 4 mice each). d, Quantification of vGATON and vGlut2ON neuron percentages in MdV in relation to NeuN (left) or FL premotor labelling (right) (n = 4 mice each). e, Model illustrating direct connections between vGlutON but not vGATON MdV neurons and FL-innervating motor neurons.

Extended Data Figure 6 Differential distribution of biceps and triceps brainstem premotor neurons.

af, Top-down (a, b), sagittal ipsilateral (c, d) and contralateral (e, f) views of three-dimensional brainstem reconstructions for biceps (Bic; a, c, e) and triceps (Tri; b, d, f) premotor neuron analysis (n = 5 mice each). Colour code of displayed neuronal populations shown to the right and identical to Fig. 1. g, h, Quantification of neurons ipsi- (g, identical to Fig. 2g for overview purposes) and contralateral (h) to injected limb (n = 5 mice each; ipsi- and contralateral neurons analysed separately). in, Direct comparative analysis of distinct Bic (purple) and Tri (cyan) premotor populations in sagittal ipsilateral (i, k, m) and top-down (j, l, n) view of brainstem reconstructions. Sp5 (i, j), Ve (k, l) and Mc (m, n) brainstem areas are shown as examples.

Extended Data Figure 7 MdV connectivity to spinal interneurons.

a, Trajectory of descending spinal projections of vGlut2ON MdV neurons marked by coinjection of AAV-flex–Tomato and AAV-flex–Syn–GFP in vGlut2Cre mice. Triple colour immunohistochemistry to Tomato, EGFP and ChAT is shown at C5, C7 and lumbar spinal levels. b, Trans-synaptic rabies spreading from segmentally restricted vGlut2ON or vGATON interneurons at C7-8 levels. Scheme of experimental setup (top left), example pictures depicting MdV neurons connected to vGlut2ON (top middle) and vGATON (top right) spinal interneurons; and visualization of overall distribution (position of triple positive neurons over 3 consecutive sections shown) and example pictures of neurons triple-infected by AAV-TVA/G and EnvA-Rabies viruses in the spinal cord for both experiments (bottom row).

Extended Data Figure 8 Selective input to vGlut2ON MdV neurons.

ac, Experimental setup for analysis of forebrain synaptic input to FL premotor MdV neurons (a) and synaptic input quantification to MdV, Pn and Gi FL premotor neurons (GFPON/vGlut1ON synapse density opposed to premotor neurons; n = 2 mice; b, c). dg, Example pictures of neurons in paratrochlear nucleus (Pa4) (d), parvicellular reticular nucleus (PCRt) and intermediate reticular nucleus (IRt) (e) connecting to vGlut2ON MdV neurons. Pa4 connecting neurons are not glutamatergic (d). PCRt and IRt neurons are glycinergic or glutamatergic (f, g) as identified by expression of GFP or LacZ in GlyT2GFP or vGlut2Cre transgenic mouse lines.

Extended Data Figure 9 Motor activity recruits MdV neurons.

a, Scheme of experimental setup for c-Fos analysis. b, Quantification of percentage of c-Fos-positive NeuNON (left), vGlut2ON (middle) and vGlut2OFF (right) neurons (dots in graphs represent individual mice). Note that c-Fos is upregulated by motor tasks preferentially in vGlut2ON neurons.

Extended Data Figure 10 Interference with glutamatergic Mc neurons does not perturb single-pellet reaching task performance.

a, Many premotor Mc neurons are glutamatergic (vGlut2ON). b, Specificity of injection site and recombination in Mc of vGlut2Cre mice upon AAV-flex–Tomato injection (py: pyramidal tract). c, Experimental time line for virus injections and task performance of single-pellet reaching task with ablation of glutamatergic Mc neurons. d, Quantitative analysis of different task phases for control (n = 6) and Mc-DTR (n = 6) mice on day 8 of task. Right plot shows FL grip strength analysis.

Supplementary information

Limb premotor neurons in the brainstem

Visualization of 3D distribution of FL (purple) and HL (cyan) premotor neurons in the brainstem. (MOV 27965 kb)

FL premotor neurons in the brainstem

Visualization of 3D distribution of different subpopulations of FL premotor neurons in the brainstem. Color code for neuronal identity as in Fig. 1. (MOV 23956 kb)

HL premotor neurons in the brainstem

Visualization of 3D distribution of different subpopulations of HL premotor neurons in the brainstem. Color code for neuronal identity as in Fig. 1. (MOV 17756 kb)

Single pellet reaching task categories

Video showing representative examples of different categories for the single pellet-reaching task illustrated in Fig. 5 and 6. Two representative successes, one miss, five no grasp and one drop are shown in sequence. (MP4 13179 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Esposito, M., Capelli, P. & Arber, S. Brainstem nucleus MdV mediates skilled forelimb motor tasks. Nature 508, 351–356 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing