Project Summary
The recovery of function after damage is an important, yet elusive goal in motor control. Spinal motor neurons
are particularly vulnerable to damage thanks to long axons that innervate peripheral muscles. Motor neurons
also have central axon collaterals that impact motor output, but we know little of their response to injury. This
is important because changes in motor neuron excitability accompany spinal injury, contributing to short-term
spasticity and long-term recovery. The goal of this exploratory R21 proposal is to develop a new model system
to understand how central spinal circuits reorganize after injury, beginning with an overlooked motor neuron
response to injury. Like all vertebrates, zebrafish have slow, intermediate and fast types of spinal motor units
defined by their target musculature and each type exhibits central axon collaterals. However, unlike all other
vertebrates it is possible to track the same spinal motor neurons and their central and peripheral connections
before and after injury in living, growing zebrafish. In pilot experiments using two-photon axotomies, we found
that some motor neurons regrow and successfully re-innervate target musculature, while others fail to exit
spinal cord and instead grow elaborate central axons and form synapses. This mirrors a phenomenon also
observed in axotomized spinal motor neurons of adult cats. These observations suggest that some axotomized
motor neurons are creating ectopic circuits that could impact motor control. But what conditions predict
peripheral versus central regeneration and do ectopic central motor axons integrate into functional circuits? In
Aim 1, we will assess the relative contribution of time of development and motor unit identity to axotomy
responses. In Aim 2, we will determine if axotomized motor neurons are recruited and connected to other
spinal neurons. These aims will characterize the capacity for motor neurons to form ectopic recurrent circuits
and will inform studies exploring maladaptive and adaptive changes in spinal circuit structure following injury.