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The Wiring and Working of Circuits for Action

Research Summary

Thomas Jessell's research explores the link between the assembly and organization of neural networks, and the behaviors they encode. He is examining these issues through an analysis of circuits that control movement.

Research in the Jessell lab explores the neural control of movement – with an emphasis on the wiring and function of motor circuits that provide mammals with the ability to act on demand. Studies focus on circuits that control two forms of skilled limb behavior: locomotion and goal-directed reaching. In one approach, the aim is to define cellular rules and molecular mechanisms that direct the intricate wiring of motor circuits. In parallel, insights into the molecular origins of neuronal identity are used to devise more precise genetic methods to monitor and manipulate the activity of defined neuronal classes. Together these developmental, physiological and behavioral studies probe the design and function of circuits and systems responsible for the planning and execution of movement.

Wiring Sensory-Motor Circuits
The precision that characterizes patterns of connectivity in the mammalian central nervous system has its origins in the diversification of developing neurons into distinct functional classes. The strategies and mechanisms used to translate neuron-subtype identity into selective connectivity remain unclear, however. We have addressed this general issue by analyzing the feedback connections formed between proprioceptive sensory neurons, interneurons, and their target motor neurons. Some fifty or so muscle groups endow the mammalian limb with its versatile biomechanics, and each muscle is innervated by a dedicated pool of motor neurons. Generating the profile of connections that direct limb movement requires that the sensory neurons that convey feedback from individual limb muscles form strong connections with self–motor neurons, weaker connections with motor neurons that innervate biomechanically-related muscles, and avoid motor neurons that innervate muscles with antagonistic functions. The exquisite specificity of sensory-motor connections is largely hardwired and reflects the acquisition of motor and sensory subtype identities.

But how are sensory-motor connections established? Recent findings from the lab indicate that intricate patterns of sensory-motor connectivity are established in two sequential stages: one relying on the positioning of neurons and the other on the surface labels they express. In the spinal cord, the positioning of motor neuron cell bodies exhibits a remarkable spatial register with the limb muscles they innervate. The motor neurons that innervate an individual limb muscle are clustered into spatially coherent columels and into pools, each occupying a stereotypic location along the dorso-ventral and mediolateral axes of the spinal cord. Incoming sensory axons are directed to appropriate dorso-ventral tiers in the ventral spinal cord independently of motor neuron surface labels. This tier-targeting strategy greatly limits the diversity of possible targets, simplifying the eventual task of motor neuron recognition. Appreciation of the key role of neuron-settling position in sensory-motor connectivity begins to make sense of the finding that neuron-subtype identity is revealed as much by distinctions in settling position as by surface label.

Within the constraints imposed by early neuronal positioning, programs of sensory-motor recognition can operate. The best example of sensory-motor target recognition is the expression of a repellent ligand, semaphorin 3E (Sema 3E) by certain motor pools, and the proprioceptive sensory expression of its cognate receptor, Plexin D1. Ectopic expression of Sema 3E in motor neurons markedly reduces the incidence of inputs from Plexin D1–marked sensory afferents, and conversely, genetic elimination of Sema 3E–Plexin D1 signaling permits illicit sensory-motor connections. Thus the potential for complementary matching of surface labels and resultant repellent recognition helps to determine the fine pattern of proprioceptive sensory inputs to motor pools. More generally, these findings establish that both neuronal position and surface label have roles in converting neuron-subtype identity into precise patterns of sensory-motor connectivity.

Diversity and Circuit Specificity of Premotor Interneurons
Inhibitory interneurons have major roles in shaping spinal motor circuitry, through the formation of local networks with highly selective synaptic input and output connectivity. The neuronal diversity implied by physiological descriptions has been complemented by a molecular delineation of four cardinal classes of ventral (V) spinal interneurons, each possessing a distinctive transcription factor character and variant patterns of local connectivity. We have used transcriptional identity as an entry point to probe additional interneuron diversity and principles of motor connectivity, focusing on V1 inhibitory interneurons. The V1 population can be fractionated into some fifty subpopulations on the basis of differential expression of nearly two dozen distinct transcription factors. Most of these V1 interneuron subsets settle in discrete dorsoventral and mediolateral domains of the spinal cord, establishing a complex spatial matrix of interneuron–motor neuron positions.

V1 interneuron–settling position has a defining role in establishing patterns of sensory input connectivity. As one example, Renshaw interneurons—the mediators of motor neuron recurrent inhibition—settle in an extreme ventral position and, accordingly, receive proprioceptive sensory input from afferents projecting to ventral but not dorsal motor neuron pools. Thus, interneuron circuits are constructed in a highly individualized, motor pool–selective manner, presumably to accommodate the distinct biomechanical demands of muscles controlling different limb joints.

Molecular determinants can also shape interneuron connectivity. Sensory terminals in the ventral spinal cord represent the sole target of presynaptic GABA interneurons, implying stringent recognition specificity in the assembly and organization of this specialized inhibitory microcircuit. The sensory expression of the contactin family protein NB2 and the contactin-associated protein Caspr4 are required to establish the normal high-density accumulation of GABApre-derived synaptic boutons on proprioceptive sensory terminals. Thus, these findings pinpoint a molecular recognition system that helps to direct the formation of a defined inhibitory synapse.

Mapping and Manipulating Circuits for Skilled Reach
Skilled forelimb movements have been refined over the course of evolution to the point that they represent some of the most impressive accomplishments of the mammalian motor system. The detailed design and function of relevant circuits remains obscure however.

One cornerstone of the logic of motor systems is the idea that the transition from central plan to smooth performance involves online validation by feedback signals which update the motor system about the fidelity of motor action. An inherent problem in supplying feedback information through the periphery is temporal delay - information arrives at motor planning centers too late to be of use in providing online updates. The motor system appears to have invented numerous tricks to overcome the delay problem—notably the relaying of internal copies of motor commands as forward models, to sensory processing centers. In addition, delays adversely impact the gain of feedback signals, invoking the introduction of sensory filtering systems that reduce the likelihood of gain deregulation. Our functional studies aim to probe the neural circuitry that accommodates feedback delay and the wide dynamic range of sensory input.

We have used genetic methods in mice to probe the neural basis and circuit logic of skilled reach. We have explored the small subset of GABAergic interneurons that form axo-axonic contacts with the terminals of sensory afferents. Despite the occurrence of axo-axonic contacts on most sensory terminals, the predominance of postsynaptic inhibition has left unresolved the motor behavioral significance of this presynaptic control system. One theoretical analysis of sensory-motor transformation has proposed that the gain of proprioceptive sensory feedback needs to be tightly constrained to prevent motor instability. In principle, presynaptic inhibition provides an effective means of imposing gain control, but without a means of selectively manipulating the relevant spinal inhibitory interneurons, it has not been possible to address whether or how presynaptic inhibition influences motor behavior.

We used the gene encoding the GABA synthetic enzyme GAD2 as a genetic entry point for activating and eliminating presynaptic inhibitory interneurons and assessing their role in motor behavior. We showed that GAD2 interneurons mediate presynaptic inhibition at sensory-motor synapses and that genetic stripping of presynaptic inhibitory boutons from sensory terminals uncovers a pronounced motor oscillation during goal-directed reaching. Our studies identify the GABApre neuron as a neural substrate for suppression of a sensory-motor oscillation that, when unleashed, undermines steady goal-directed forelimb movement. These findings provide insight into the mechanisms for scaling of sensory gain across a wide and dynamic range of afferent firing frequencies, as well as clues about the grain of neural circuitry that empowers presynaptic inhibitory control during sensory-motor transformation.

Cervical propriospinal neurons (PNs) represent a second class of spinal interneuron implicated in the control of forelimb behavior. PNs exhibit a bifurcated axonal output: one branch projecting to the cervical motor neurons that controls forelimb muscles, and the other projecting to neurons in the lateral reticular nucleus, which serves as a pre-cerebellar relay center. The duality of PN axonal projections raises the issue of whether information relayed by this internal copy branch has any impact on forelimb motor output. Molecular delineation provides a genetic means of manipulating the internal copy projections of PNs. We have found that one major population of excitatory PNs is contained in the V2a interneuron class—one of the cardinal subtypes of ventral interneurons implicated in locomotor control. Eliminating cervical V2a neurons elicits a reach-specific defect in forelimb movement, revealed by quantitative three-dimensional kinematics. Conversely, selective activation of the internal PN branch activates a rapid cerebellar feedback loop that excites motor neurons and degrades the fidelity of reaching movements. Thus excitatory PNs also form a neural module – providing an internal feedback circuit needed for mammalian reaching behavior.

Work in the Jessell lab is supported by grants from the National Institute of Neurological Disorders and Stroke, Project ALS, the Harold and Leila Mathers Foundation and the Tow Foundation.

As of March 24, 2016

Scientist Profile

Columbia University