Martyn D. Goulding
Molecular Neurobiology Laboratory
Frederick W. and Joanna J. Mitchell Chair
The Goulding lab has a long-term interest in the development and functioning of neuronal circuits in the mammalian spinal cord. Our studies are centered on the spinal circuits that control locomotion and movement, protective reflexes and posture. Not only are these circuits important for movement disorders such as spinal cord injury and Parkinson's Disease, but they also provide neuroscientists with an ideal model system to explore how the nervous system generates complex behaviors. For this reason, we refer to these circuits as the "spinal brain". Studies in the lab use cutting edge genetic techniques, coupled with electrophysiology, circuit mapping, imaging and behavior to explore how the motor system works and how the spinal brain transforms sensory signals into discrete motor behaviors. Research in the lab is currently addressing: 1) The nature of the genetic programs that generate interneuron diversity in the spinal cord. 2) The identity and function of genetically-defined premotor interneurons that are core elements of motor networks in the spinal cord. 3) The structure and functional organization of sensorimotor circuits in the dorsal horn that process cutaneous sensory information.
"Studies in my lab are directed at understanding how different types of spinal cord 'interneurons'—neurons that bridge communications between sensory and motor neurons—control how we move and how we respond to touch and pain. Knowing more about how these cells develop and function is a critical step in devising new therapies to regenerate and activate circuits in the spinal cord following injury."
Investigating how movement is controlled lies at the center of our quest for understanding how our nervous system works. We now know that a hierarchy of "motor" networks in the nervous system controls movements. Among these are specialized networks of interneurons in the spinal cord—commonly referred to as central pattern generators (CPGs)—that direct the rhythmic muscle movements that underlie locomotion. These spinal CPGs are engaged and controlled by the brain to produce the coordinated muscle movements that allow us to walk, talk and play an instrument.
Although scientists have known about the locomotor CPG for nearly 100 years, the identity of the neurons that make up the circuitry had remained a mystery. Goulding's lab, in pioneering efforts to break the molecular code that generates these different interneuron cell types, has begun unraveling the wiring of the spinal cord. Previously, Goulding and his team discovered that a subset of interneurons, called V0 neurons, governs the left-right alternating pattern of activity that is needed for stepping, as opposed to hopping, movements. They have also analyzed the function of other neurons, including V1 neurons that set the pace at which animals walk.
However, identifying the cells that control our ability to flex and extend our limbs has proven more difficult. These have an essential role in movement, as without them we would not be able to bend and stretch our arms and legs. In a recent series of experiments, Goulding's team identified a second class of inhibitory neuron that cooperates with the V1 neurons to control muscle activity that is needed to move the limbs and walk. Strikingly, they found that the same neurons are present in the spinal cords of swimming vertebrates, leading Goulding to propose that the "walking" CPG is an evolutionary adaptation of the "swimming" CPG circuit. More recently, efforts in the lab have turned to understanding how the spinal CPG is activated both by touch and pain pathways that are important for protective reflexes, and by descending pathways from the brain–knowledge that is essential for developing new treatments for spinal cord injury.
Left to right:
Tomoko Velasquez, Delphine Crappe, Stéphanie Annet, Jingming Zhang, Martyn Goulding, Florien Stam, Sophie Creyssels, Christopher Padilla, Jovanny Bourane, Lidia Garcia Campmany
Gross, M.K., Moran-Rivard, L., Velasquez, T., Nakatsu, M.N., Jagla, K., and Goulding, M.D. (2000). Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127, 413-424.
Moran-Rivard, L., Kagawa, T., Saueressig, H., Gross, M.K., Burrill, J., and Goulding, M.D. (2001). Evx1 is a postmitotic determinant of V0 interneuron identity in the spinal cord. Neuron 29, 385-399.
Dottori, M., Gross, M.K., Labosky, P., and Goulding, M.D. (2001). The winged-helix transcription factor Foxd3 suppresses interneuron differentiation and promotes neural crest cell fate. Development 128, 4127-4138.
Gross, M.K., Dottori, M., and Goulding, M.D. (2002). Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535-549.
Sapir, T., Geiman, E.J., Wang, Z., Velasquez, T., Mitsui, S., Yoshihara, Y., Frank, E., Alvarez, F.J., and Goulding, M. (2004). Pax6 and Engrailed 1 regulate two distinct aspects of Renshaw cell development. J. Neurosci. 24, 1255-1264.
Cheng, L., Arata, A., Mizuguchi, R., Qian, Y., Karunaratne, A., Gray, P.A., Arata, S., Shirasawa, S., Bouchard, M., Luo, P., Chen, C.L., Busslinger, M., Goulding, M., Onimaru, H., and Ma, Q. (2004). Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat. Neurosci. 7, 510-517.
Lanuza, G.M., Gosgnach, S., Pierani, A., Jessell, T.M., and Goulding, M. (2004). Genetic identification of spinal interneurons that coordinate left-right locomotor activity necessary for walking movements. Neuron 42, 375-386.
Goulding, M., and Pfaff, S.L. (2005). Development of circuits that generate simple rhythmic behaviors in vertebrates. Curr. Opin. Neurobiol. 15, 14-20.
Kriks, S., Lanuza, G.M., Mizuguchi, R., Nakafuku, M., Goulding, M. (2005). Gsh2 is required for the repression of Ngn1 and specification of dorsal interneuron fate in the spinal cord. Development 132, 2991-3002.
Gosgnach, S., Lanuza, G.M., Butt, S.J., Saueressig, H., Zhang, Y., Velasquez, T., Riethmacher, D., Callaway, E.M., Kiehn, O., Goulding, M. (2006). V1 spinal neurons regulate the speed of vertebrate locomotor outputs. Nature 440, 215-219.
Mizuguchi, R., Kriks, S., Cordes, R., Gossler, A., Ma, Q., and Goulding, M. (2006). Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat. Neurosci. 9, 770-778.
Zhang, Y., Narayan, S., Geiman, E., Lanuza, G.M., Velasquez, T., Shanks, B., Akay, T., Dyck, J., Pearson, K., Gosgnach, S., Fan, C.M., and Goulding, M. (2008). V3 spinal neurons establish a robust and balanced locomotor rhythm during walking. Neuron 60, 84-96.
Goulding, M. (2009). Circuits controlling vertebrate locomotion: moving in a new direction. Nat Rev Neurosci. 10, 507-518.
Stam, F.J., Hendricks, T.J., Zhang, J., Geiman, E.J., Francius, C., Labosky, P.A., Clotman, F., Goulding, M. (2012) Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program. Development 139, 179-190.
Zhang, J., Lanuza, G.M., Britz, O., Wang, Z., Siembab, V., Zhang, Y., Velasquez, T., Alvarez, F.A., Frank, E. and Goulding, M. (2014) V1 and V2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron, 82, 138-150.
Cargagno, A.L., di Bella, D.J., Goulding, M., Guillemot, F. and Lanuza, G.M. (2014) Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain. J. Neurosci. 34, 15223-15233.
Duan, B., Cheng, L., Bourane, S., Britz, O., Padilla, C., Garcia-Campmany, L., Krashes, M., Knowlton, W., Velasquez, T., Ren, X., Ross, S., Lowell, B.B., Wang, Y., Goulding, M. and Ma, Q. (2014) Identification of spinal circuits transmitting and gating mechanical pain. Cell 159, 1417-1432.
Bourane, S., Grossmann, K.S., Britz, O., Dalet, A., Garcia del Barrio, M., Stam, F.J., Garcia-Campmany, L., Koch, S. and Goulding, M. (2015) Identification of a circuit for light touch and fine motor control. Cell 160, 503-515
Salk News Releases
Walking on ice takes more than brains
January 29, 2015
Salk and Harvard scientists chart spinal circuitry responsible for chronic pain
December 4, 2014
Salk scientists reveal circuitry of fundamental motor circuit
May 1, 2014
Prestigious endowed chairs awarded to Salk scientists
March 30, 2012
A fine balance
October 8, 2008
Salk neurobiologist receives Javits Neuroscience Investigator Award
June 15, 2006
Striking the right balance between excitation and inhibition
May 31, 2006
Salk researchers make fast strides towards understanding how our body controls walking
March 14, 2006
Awards and Honors
- Pew Scholar, 1994-1998
- Basil O'Connor Research Award, 1993-1995
- Jacob Javits Neuroscience Investigator Award, 2006