Our research interests mainly focus on CNS injury diseases, for instance, spinal cord injury (SCI), stroke and traumatic brain injury (TBI). It is important to develop new strategies to reconstruct the functional innervation of brain after CNS injury. Using gene therapy, cell therapy, small molecule drugs screening and brain-computer interface, we attempt to promote robust axon regeneration and stimulate regenerated and/or spared neural circuitry after CNS injury. 

1. Axon regeneration 

As the limited regeneration ability of the adult nervous system after injuries, the dysfunction of CNS is usually permanent for patients with CNS injuries. In the past few years, we have successfully promoted robust regeneration of the injured axons via up- or down-regulation of certain genes, using mice optic nerve injury model, SCI model and stroke model (Liu et al., Neuron 2017). We will take advantage of cross-species spinal cord/brain injury models, such as mouse, rat and non-human primate models, to develop new strategies to promote axon regeneration. Eventually, we hope to promote the transformation of the scientific research achievements, and achieve the functional recovery of CNS injured patients. 

2. Tissue repair 

In addition to improving the ability of neurons to regenerate, accelerating the repair of injured tissues can also promote nerve regeneration. Our study found that the repair process after spinal cord injury in neonatal mice was different from that in adult mice. We found that microglia were the organizer of the scar-less wound healing after spinal cord injury in neonatal mice (Li et al., Nature 2020). Our next step is to achieve more nerve regeneration by transplanting various neurons, glial cells and/or hydrogel to enhance the repairing ability of the CNS. 

3. Reactivation of the dormant neural circuits 

About 90% human SCIs are anatomically incomplete, with spared axons spanning the damaged spinal segments. Even with the residual connect tissue and nerve fibers at the injured site, about half of the paralyzed patients with SCI totally lose control of muscles and are confined to wheelchairs for the rest of their lives. Why cannot these residual nerve fibers mediate the motor functional recovery in patients? Why are these residual neural connections dormant? How to rebuilt these neural circuits? 

Using small molecule drugs screening, we found that manipulating the expression of KCC2, a potassium and chlorine co-transporter, could activate the residual neural dormant circuits after SCI (Bo et al., Cell 2018). These residual dormant neural circuits were due to the disruption of the excitatory and inhibitory balance. With compound treatment, gene therapy or chemical genetic operation, we re-established the excitation-inhibitory balance in the injured area, which could re-built the brain-propriospinal neurons-locomotion neural circuitry and achieve the functional recovery. Next, we will combine small molecule drugs screening with strategies of promoting axon regeneration to further facilitate the functional reconstruction after central nerve injuries. 

4. Brain-computer interface - Brain-spinal stimulation 

With advances in flexible electrodes, epidural stimulation, optogenetics and brain-computer interface, paraplegic patients are expected to be able to flexibly manipulate neural prostheses or limbs below the injured plane in the coming decades. Our laboratory will actively cooperate with relevant laboratories to combine brain-computer interface technology, deep brain stimulation, spinal epidural stimulation, neural prostheses and rehabilitation training, to achieve the functional reconstruction of animals or patients after central nerve injuries and paralysis. 

LI Yi, Ph.D.