Neuroplasticity

Spinal cord injury (SCI) results in chronic functional deficits as axotomized central nervous system (CNS) neurons fail to regenerate their axons after trauma due to the inhibitory environment in the mature CNS and the low intrinsic growth capacity of adult CNS neurons. Despite the lack of long distance axon regeneration, partial spontaneous recovery of function is observed sub-acutely in humans and in animal SCI models. Structural plasticity of intact brain and spinal circuitry has been suggested to drive this phenomenon. However, the endogenous molecular mechanisms that drives formation of these de novo anatomical pathways remain unknown, and thus, represent a significant barrier to therapeutic intervention.

In the Cafferty lab we use two broad complimentary approaches to restore function after SCI. We use transcriptional profiling of functionally defined subsets of intact neurons undergoing functional plasticity within the central motor apparatus to identify novel cell autonomous growth activators. Subsequent in silico and functional in vitro interrogation of these novel pro-axon growth modulators streamlines the identification of lead candidates for transgenic and pharmacological interventions that target these molecular axes to enhance functional axon growth in experimental SCI models. To understand how these new plastic pathways integrate into remaining CNS circuitry we use chronic in vivo two-photon microscopy in awake behaving mice that have undergone partial SCI and experimental therapeutic intervention. Using calcium and voltage imaging we can specifically map de novo circuits and assess their functional impact on defined behaviors via additional probing with chemo/pharmaco/opto-genetics. Below is a summary of ongoing projects.