Motor neuron circuits, movement

The Functional Logic of Inhibitory Microcircuits
2015 Scientific Innovations Award
Thomas Jessell, Ph.D.
Columbia University

Can a neurobiologist reconfigure functional motor circuits in the spinal cord of a patient who has suffered a traumatic spinal cord injury? Can motor circuits be rewired to delay or prevent the impact of degenerative diseases like ALS? It won’t be easy, and it may not happen soon, but Dr Thomas Jessell has plans to make it possible.

For 30 years Thomas Jessell, Ph.D., has been probing how nerve circuits function in the spinal cord. He’s continuing the journey with support from the Brain Research Foundation.

What types of molecules are at work in the embryonic nervous system and how do they come together as a functional system? How do subclasses of neurons choose specific pathways to send and receive messages and selectively connect with target cells? These are microcosmic questions that Dr. Thomas Jessell and his research team are pursuing to find macrocosmic answers.

Ultimately, he intends to define how motor circuits are constructed and how they function in enough detail to create what he calls a molecular wiring diagram: a diagram that one day could guide a neurologist in reconfiguring a patient’s motor circuits after traumatic spinal cord injury. Further down the road, similar diagrams might be used in the treatment of schizophrenia or attention deficit hyperactivity disorder.

Groundwork in place
Dr. Jessell and his team have designed methods for manipulating of two types of neurons that create nerve circuits that allow signals to travel to and from the spinal cord; these are called excitatory and inhibitory interneurons. The team has also found a way to assess changes in the body, in cell function, and behavior when neural circuits are not functioning normally.

Important hurdle in sight
Next, with support from the BRF, the team will look more closely at inhibitory interneurons—the structure of the motor circuits they form, how the circuits function, and what happened when they malfunction. If successful, this will be the first research that provides an in-depth understanding of the construction and behavior of inhibitory microcircuits controlling movement.

Getting there
This study involves innovative and as yet untested experimental theoretical techniques. A series of molecular genetic and cell biology experiments with mice will focus on documenting the molecular diversity of the developing spinal cord. This is a challenging undertaking since Dr. Jessell sees the possibility of 100 subtypes of inhibitory interneurons at work each with different input and output relationships for perhaps 50 distinct motor pools each with its own microcircuit architecture.

Future potential
The knowledge that Dr. Jessell hopes this study will yield would make a significant contribution to deciphering the logic that underlies how cells exchange information in the human central nervous system. Long term, in addition to paving the way to possible treatments for traumatic spinal cord injuries, the findings may help explain the origins and progression of both neuropsychiatric and neurodevelopmental disorders.

2015 Scientific Innovations Award recipient Thomas M. Jessell, Ph.D., is professor of neuroscience, and biochemistry and molecular biophysics at Columbia University, New York City. The mentoring that experienced scientists like Dr. Jessell provide for new investigators is crucial in the development of the next generation of researchers able to continue the process of advancing neuroscience.