Zicong Zhang, Boston Children's Hospital, F.M. Kirby Neurobiology Center, Harvard Medical School, Boston, United States

Promoting regeneration and functional recovery of reticulospinal axons after spinal cord injury

Funded in: 2019, 2020, 2021


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Problem: Reticulospinal tract plays critical role in gross motor control, but is disrupted by axon damage in SCI

Target: Provide insight into the regeneration mechanism of reticulospinal axons and use Osteopontin (OPN) as a powerful treatment to sensitize neuronal responses to growth factors

Goal: Development of combinatorial treatments for achieving functional recovery

 

In spinal cord injury (SCI) patients, a major cause of paralysis is that the connections between brain and spinal cord are disrupted by axon damage. Long descending spinal axons connecting the brain and spinal cord originate from different brain regions and are responsible for diverse motor functions. Reticulospinal tract is one that derived from brainstem reticular formation and plays critical role in gross motor control such as locomotion and posture maintenance. As most SCI patients suffers from incomplete injury with varies degrees of spared reticulospinal axons, promoting regeneration of these axons may hold high promise for achieving functional recovery.

Our previous studies have identified osteopontin (OPN) as a powerful treatment to sensitize neuronal responses to growth factors in different types of neurons and lead to axon regeneration and functional recovery in mouse SCI models. Our target is to test if this treatment can be also applied to the reticulospinal axons where varies of cell types are intermingled. In an incomplete SCI mouse model with lateral transection at low thoracic level, we will examine how injured reticulospinal axons respond to the OPN-based growth factor treatments and regrowth, as well as the aspects of recovered motor functions resulted from such anatomical regrowth. This study will allow us to optimize the condition of OPN-based treatments for reticulospinal axon regeneration and recovery.

Functional neural networks rely on robust axon transmission and precise neuronal connections. It remained unresolved that regenerated axons have weak conduction and poor connections to the existing network. Our recent studies discovered that 4-aminopyridine (4-AP), a potassium channel blocker, and CLP290, a chloride-potassium cotransporter agonist, can improve nerve conduction and restore spared functional network, respectively. We will test if these compounds will amplify functional recovery with OPN-based treatment. Together, these results will provide insight into the regeneration mechanism of reticulospinal axons and lead to the development of combinatorial treatments for SCI patients.