Although most patients exhibit some spontaneous behavioral improvements during the first several months after stroke,their recovery is generally incomplete.Unfortunately,there are no efficacious therapies available for the vast majority of stroke patients during their convalescence.For decades,the primary approach and goal of therapy for stroke have focused on neuroprotection,namely treating the injured tissue,with interventions designed to reduce the volume of cerebral infarction.Enormous effort in the laboratory has been devoted to the development of neuroprotective agents in an attempt to salvage ischemic neurons in the brain from irreversible injury;however,all these efforts have failed to demonstrate efficacy in clinical trials of stroke.Because the hemiparesis after stroke is a consequence of the loss or interruption of motor signals from the motor cortex to the spinal motoneurons,reestablishment of synaptic connections between cerebral neurons and their periph-eral targets provides a physical substrate for functional recovery.The corticospinal tract (CST),the long axons of the cortical pyramidal neurons extending to the spinal cord,connecting with the spinal motoneurons directly or indirectly,is the prima-ry transmission tract from the sensorimotor cortex,and thus,forms the neuroanatomical basis for brain controlled voluntary movements of the peripheral muscles.Therefore,focusing on the CST axonal remodeling in the denervated side of the spinal cord,we injected neuronal tracers DiI (Liu et al.,2007) and biotinylated dextran amine (Liu et al.,2008) into the cerebral cortex to label the CST axons,and employed a transgenic mouse line,in which the CST axons are specifically and completely labeled by yellow florescent protein (Liu et al.,2009) to directly monitor the axonal morphological change after stroke.We found that instead of long-distance axonal regeneration of injured CST in the white matter of the CNS,the denervated spinal motoneurons may be rewired with CST axons through local short-range axonal sprouting and outgrowth of the neighbor-ing uninjured fibers within the spinal gray matter,to form new synaptic connections and thereby restore innervation from the motor cortex (Liu et al.,2013).In addition,tissue plasminogen activator administered intranasally as a neurorestorative agent into the brain parenchymal tissue during subacute phase post stroke significantly enhanced CST axonal remodeling in the spinal gray matter,which was associated with the improvement in neurological outcomes (Liu et al.,2012).Thus,the neurorestorative strategy may provide a major paradigm shift in treatment targeting the intact or compromised tissue of the brain and spinal cord to promote neuronal plasticity to compensate for the damaged tissue and re-establish the corticospinal innervation,and thereby enhancing functional recovery during the subacute and chronic phases after stroke.