The Research Foundation of SUNY - SUNY at Stony Brook
Jeffrey Petruska

Locomotor circuitry after SCI and training or neurotrophins

Numerous studies have shown that physical training of patients following certain spinal cord injuries (SCI) can lead to significant improvements in condition - both in terms of restored function and alleviation of pathologic symptoms (e.g., spasticity and pain). In spite of this, little is known about the neural mechanisms underlying these changes. Using an animal model (rat) of SCI, we have demonstrated significant training-related changes in both motoneurons and their inputs. These changes may be part of the underlying mechanisms of the behavioral changes observed in both animal models and human subjects. Increasing our understanding of the neural mechanisms involved in training-related improvements could lead to enhanced treatments - improved training regimens and/or pharmacological interventions that could improve (or replace) the effects of training.

Previous work was a collaborative effort between the Mendell lab at SUNY Stony Brook and the Edgerton lab at UCLA. The UCLA lab performed complete transections of the rat pup (postnatal day 4) spinal cord at the mid-thoracic level. Neonatal animals were used initially because they responded better to the training protocols than did adults. One group of pups was then trained (treadmill stepping) for at least 6 weeks. Rats were then sent to the SUNY lab for electrophysiological analysis.

The rats that had been step trained performed significantly better then their non-trained littermates (who essentially could not step at all), some regaining significant weight support and stepping ability. Electrophysiological analysis was performed to examine the properties of the motoneurons innervating the calf muscles, as well as the inputs to those motoneurons from the muscles themselves and neurons in the spinal cord. We determined that some significant differences existed between the trained and non-trained groups. Specifically, certain properties of motoneurons related to their ability to properly signal to muscles, and also properties of the inputs from the muscles to the motoneurons, were returned closer to normal values in the trained rats.
It is known that the motoneurons and the neurons responsible for the measured inputs respond to the neurotrophin NT-3. It is also known that SCI decreases, and training increases, the NT-3 levels produced by the involved muscles and motoneurons. It is possible that the effects of training are due, at least in part, to influences on the amount of NT-3 in the system, and thus the properties of the NT-3-responsive neurons.

It is proposed that similar studies be carried out, with both neonatal and adult SCI rats (effective adult training protocols are now available), with manipulation (both artificial increases and decreases) of NT-3 levels available to the system. In this way, it should be possible to determine whether NT-3 levels actually play a role in the training-related changes in motoneurons and their inputs, as well as the behavioral outcomes.