Neural Basis of Motor Control
The Levine Lab
Levine Lab Research
We seek to understand the neural components of the spinal cord, reveal how they cooperatively mediate behavior, and use this knowledge to advance human health. Our team has created the first single cell atlases of the mouse and human spinal cord, characterized ascending and descending pathways that link the spinal cord and the brain, and helped to illuminate cell type-specific mechanisms of neurodegenerative disease and injury.
Throughout this phase of our research, we have always wondered: what is the point of the dramatic cellular diversity we observed? How is spinal function instantiated in these neuroanatomical elements? So, in parallel, we have been building a new generation of tools to probe the circuit mechanisms of spinal cell types in behavior, including new mouse lines to provide genetic access to specific cell types, a platform for quantitative analysis and closed-loop optogenetic perturbations during behavior; and methods for stable high density array recordings in the spinal cords of awake behaving mice.
Now, we are poised to integrate our deep knowledge of spinal cord neurons with a powerful foundation for probing motor control in health and in the context of disease or injury.
Spinal Cord Cell Types
We systematically defined the cellular components of the mouse and human spinal cord. We adapted new methods to profile the gene expression signatures that characterize each kind of cell, validated these patterns in tissue, and mapped their spatial distributions. This work established the first single cell "atlases" of the adult spinal cord and revealed that a fundamental organizing principle of spinal cord neural diversity is location. Neurons in the dorsal spinal cord represent discrete types while those in the ventral spinal cord are more similar to each other, forming complex and continuously varying patterns of gene expression.
This dorso-ventral difference reflects the dual developmental origin of spinal neurons. The ventral horn is formed earlier during embryogenesis and arises from a set of spatially arrayed canonical lineage domains. But the dorsal horn is different: we found that it develops later and arises from six progressive waves of neurogenesis. Then, newborn excitatory neurons transform their birthdate order into the anatomical and circuit structure to process sensory and cortical information. ​Together, these studies establish the foundation to link specific cell types and broader populations to sensori-motor function.
Spinal Circuits for Sensori-Motor Control
We are probing how particular cell types and pathways contribute to sensori-motor function and motor learning. This work began with our (re)discovery of the cerebello-spinal tract, the direct neural pathway that connects two of the most important regions of the nervous system for movement: the cerebellum and the spinal cord. Although the cerebello-spinal tract was first described a century ago, it fell out of the history books and had not been incorporated into most contemporary models of motor control. We found that this pathway is essential for normal reaching movements and for learning skilled locomotor tasks in mice. In the future, we are interested to discover how the cerebello-spinal pathway interacts with other descending cues from the brain to coordinate motor outputs through spinal networks.
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More recently, we studied the spinal neurons involved in a natural behavior in mice: gap crossing jumps. Our work revealed that this innate, highly conserved, voluntary behavior may appear to be continuous, but it has a modular organization composed of discrete phases such as propulsion and flight that are mediated by distinct neural regimes. We found that a single type of spinal cord neurons - dILB6 dorsal excitatory neurons - can drive coordinated multi-joint hindlimb flexion, the signature movement of flight. In fact, optogenetic excitation of dILB6 neurons evokes this behavior whether mice were at rest, engaged in propulsion, or even mid-air. This context-independent recruitment of a coordinated motor program ​suggests that dILB6 neurons may represent the long-sought cellular substrate for a spinal motor primitive.
Cellular Mechanisms of Spinal Cord Injury
Spinal cord injury is a devastating event that can leave patients paralyzed, in pain, and with dysregulation of their autonomic, bowel, bladder, and sexual systems. The injury damages local spinal tissue, but more importantly, it disrupts the long pathways from the brain that normally direct the proper workings of spinal circuits below the injury. If we imagine the spinal cord as an orchestra, injury removes the conductor. But: the musicians and their instruments remain on the stage, raising the hope that we can find new ways to draw out and shape their music.
To uncover new candidates for therapeutic modulation, we explored how each spinal cell type below an injury changed over time. Remarkably, we discovered a small group of spinal cord neurons that naturally turned on the genes for regeneration - a cellular property that is rarely observed in the adult central nervous system. They even grew new branches in the spinal cord and amongst their terminals in the cerebellar region of the brain. This work provides a brand new cellular target for translational investigation for spinal cord injury.