Anatomical substrates of central nervous system plasticity induced by spinal cord reflex conditioning and sensorimotor cortex stimulation.

摘要

During development and throughout adult life, inputs from the brain combine with inputs from the periphery to induce activity-dependent plasticity in the spinal cord. This activity-dependent plasticity shapes spinal circuitry and helps in acquisition and maintenance of normal motor function. The neural pathways and processes responsible for induction and maintenance of plasticity in the spinal cord remain unclear. Understanding the mechanisms responsible for activity-dependent plasticity in the spinal cord is essential for developing therapies for spinal cord injury.;Operant conditioning of the H-reflex, the electrical analog of the spinal stretch reflex (SSR), provides a simple experimental model to study activity-dependent plasticity in the spinal cord. In response to an operant conditioning protocol, monkeys, humans, rats, and mice can gradually increase or decrease the SSR or the H-reflex. Operant-conditioning induces plasticity at multiple sites in the CNS including the spinal cord. Furthermore, conditioning appears to be dependent only on descending influence originating from the contralateral sensorimotor cortex via the corticospinal tract (CST). In addition, a recent study indicated that, like operant conditioning, direct electrical stimulation of the SMC also modulates H-reflex by inducing plasticity in the cortex and the spinal cord. The anatomical basis of spinal cord plasticity responsible for operant conditioning and SMC stimulation-induced modulation in the H-reflex remains to be elucidated.;The central goal of this study was to determine if the change in the soleus H-reflex subsequent to operant conditioning and SMC stimulation is associated with changes in the GABAergic terminals on soleus motoneurons. In accord with the central goal, the main hypotheses were that: (1) operant down-conditioning of the H-reflex is associated with an increase in the GABAergic terminals on soleus motoneurons; (2) operant up-conditioning of the H-reflex is associated with a decrease in the GABAergic terminals on soleus motoneurons; and (3) long-term SMC stimulation-induced increase in the H-reflex is associated with a decrease in the GABAergic terminals on soleus motoneurons. These hypotheses were tested by identifying GABAergic terminals based on their immunoreactivity to glutamic acid decarboxylase 67 (GAD67), the main isoform of the enzyme present in terminals on motoneurons.;With regard to the first hypothesis, results from operant conditioning studies indicate that successful down-conditioning was associated with an increase in the number, size, and GAD density of GABAergic terminals on motoneurons. These changes probably reflect the CST influence responsible for the decrease in the H-reflex. With regard to the second hypothesis, successful up-conditioning did not change the GABAergic terminal number, although there was an increase in the terminal diameter. Successful up-conditioning did not differ from unsuccessful up-conditioning in any of the measures. Therefore, the terminal changes could reflect non-specific effects of up-conditioning. Together, the results from these two studies support evidence from previous studies indicating that up- and down-conditioning are not mirror images of each other but rather have different mechanisms. With regard to the third hypothesis, results indicate that long-term SMC stimulation-induced increase in the H-reflex is associated with an increase in the GABAergic terminals on the soleus motoneurons. In addition, there was also a decrease in the GABA-B receptor expression on motoneurons. These changes probably reflect compensatory plasticity in response to the primary plasticity responsible for the SMC stimulation-induced increase in the H-reflex.;Overall, these results provide valuable insights about the anatomical substrates of plasticity responsible for operant conditioning and SMC stimulation-induced change in the H-reflex. Operant conditioning and SMC stimulation-induced modulation in the H-reflex helps in improvement of locomotor function after certain types of spinal cord injury and these results indicate that activity-dependent plasticity in the spinal GABAergic neural networks plays an important role in mediating this functional recovery.