QnAs with Thomas Jessell.

Over long years, neuroscientists have attempted to trace in cartographic detail the neural circuitry underlying goal-oriented movements, such as reaching, grasping, and handling objects. The modularity, precision, and smoothness of such movements arise from motor commands that descend from the brain to muscles, triggering rapid and continual feedback, which in turn helps fine tune the impact of descending commands. Such interlacing flow of electrical signals through sprawling neuronal networks underlies the fine motor skills that mammals summon with seeming ease in the service of routine tasks. But the identity of the neurons that seem to effortlessly thread their way through limb muscles, the spinal cord, and the brain to furnish such rapid feedback has long remained veiled from the mapmakers’ view. Using molecular sleight of hand to manipulate individual groups of neurons in the spinal cord of mice, Columbia University neuroscientist Thomas Jessell and his team uncovered neuronal control systems that help rodents reach for objects with characteristic precision and smoothness. At the 14th Annual Sackler Lecture, titled “Deconstructing circuits for motor behavior,” presented to the National Academy of Sciences in Washington, DC in March 2014 as part of the Arthur M. Sackler Colloquium, “Epigenetic Changes in the Developing Brain: Effects on Behavior,” Jessell described his findings, which might help decode the logic of neuronal rewiring in people with crippling ailments such as spinal cord injury. PNAS spoke to Jessell about the significance of his discoveries. PNAS: Forelimb movements such as goaldirected reaching are considered sophisticated motor skills. Are such forms of movement uniquely mammalian? Jessell: Primitive vertebrates had fins instead of limbs with digits, and movement largely involved contraction of undulating muscles for buoyancy and swimming. The ability to perform dexterous movements, such as those involved in skilled reaching and object manipulation, are thought to be evolutionary accomplishments that reached a high level of sophistication with tool use in humans. All of the skills involved in exquisitely fine motor control—such as playing the violin or threading a needle—are thought to be emergent mammalian attributes. Some think of such emergent properties as the motor route to creativity and artistic expression. PNAS: In a recent paper with postdoctoral fellow Eiman Azim (1), you described the idea of “internally directed” copies of motor commands for reaching. Can you explain the concept of an internal copy of motor commands? Jessell: The fidelity of motor actions is evaluated by sensory feedback, which informs the motor system about how well motor actions have been executed; this is achieved by monitoring states of muscle contraction. But as motor information reaches the periphery, contracts the muscle, activates the sensory neurons, and returns to the motor planning centers, considerable time elapses. Such delays make it difficult for the sensory feedback system to update motor planning centers rapidly. Internal copies of motor commands provide a useful neural shortcut. Throughout their downward trajectory, descending commands for motor acts are accompanied by side pathways that project to sensory receiving centers, a strategy thought to help rapidly predict the outcome of the motor command and correct if necessary. We studied one particular internal pathway, in which neurons not only provide input to the motor neurons that control reaching, but also feed back to a processing center in the brainstem called the lateral reticular nucleus (LRN), which relays signals to the cerebellum. PNAS: What was previously known about the role of this internal pathway in controlling forelimb movement? Jessell: Previous studies in cats and primates had suggested the existence of such an internal pathway, but no one had manipulated the activity of the copy circuit, leaving its contribution to motor output uncertain. Our ability to genetically target branching interneurons in this pathway led us to dissect their behavioral role in skilled reaching. PNAS: How did you selectively manipulate the internal pathway? What did the manipulations reveal?