Neural Circuit Unit (Yutaka Yoshida)

Research Overview

Our research is centered on the neural circuits underlying locomotor and skilled motor behaviors in mammals, and the precise signaling by spinal motor neurons required for coordinating the upwards of fifty different muscle groups in our limbs to create movement. The motor neuron pools projecting axons to specific muscles are located in clusters within the ventral spinal cord, which are regulated by synaptic inputs from three main pathways: local interneuron circuits, proprioceptive sensory feedback, and descending fibers from the brain, including the corticospinal tract. Our work has been primarily focused on formation, function, and regeneration of sensory-motor and corticospinal circuits.

1) Monosynaptic sensory-motor circuits.

In monosynaptic sensory-motor circuits, group Ia proprioceptive afferent fibers form strong connections with motor neurons supplying the same muscle, and weaker connections with motor neurons supplying synergistic muscles, but afferent connections are typically not formed with motor neurons supplying functionally unrelated or antagonistic muscles. Previously, we have demonstrated molecular mechanisms underlying axon guidance (Yoshida et al., 2006, Neuron; Leslie et al., 2011, Development), synaptic specificity (Fukuhara et al., 2013, Cell Reports), synapse formation (Imai et al., 2016, J. Neurosci), and maintenance (Imai et al., 2016, Cell Reports) of monosynaptic sensory-motor circuits.

2) Corticospinal circuits

Corticospinal neurons located in layer V of the sensorimotor cortex are the essential conveyers of motor instructions controlling skilled movements.  In early postnatal rodents, corticospinal axons decussate at the caudal medulla, and reach the spinal cord through the dorsal funiculus where they innervate spinal interneurons.  This di-synaptic pathway is found in all mammals and is essential for the generation of proper skilled movements in rodents, cats, and primates.  Direct monosynaptic connections between CS axons and motor neurons were thought to occur only in some primate species including humans. We recently showed how evolutionally-specific corticospinal circuits could be formed in mice and primates (Gu et al., 2017, Science). We also showed how corticospinal circuits are reorganized during development (Gu et al., 2017, Neuron) and which spinal interneurons are connected with corticospinal axons (Ueno et al., 2018, Cell Reports).

3)Spinal cord injury

We have also been interested in reorganization and regeneration of neural circuits after spinal cord injury.  Immune suppression has been shown to be a leading cause of morbidity and mortality after spinal cord injury, however, the neuronal substrates responsible for post-injury immune suppression was unknown.  We previously showed that profound plasticity develops within spinal autonomic circuitry innervating the spleen and, that chemogenetic silencing of excitatory spinal interneurons blocked post-spinal cord injury immune suppression.  These data provide new insights and potential therapeutic options for limiting the severe consequences of post-injury immune suppression (Ueno et al., 2016, Nature Neuroscience). Moreover, we are also interested in understanding how to promote regeneration of motor circuits after spinal cord injury.