Electrophysiological Evidence of Hebbian Plasticity in Awake Adult Rats.

Hebbian stimulation, based on principles of spike timing-dependent plasticity (STDP), has been successfully used to enhance functional recovery in individuals with spinal cord injury (SCI). To advance therapies using Hebbian stimulation, this study aimed to establish STDP-based protocols targeting spinal motoneuron synapses in awake rats. Adult male and female Sprague Dawley rats were implanted with stainless steel screws through the skull over the hindlimb area of the left motor cortex to enable epidural cortical stimulation. A custom-made cuff with embedded fine-wire electrodes was placed around the right posterior tibial nerve for peripheral stimulation. Fine-wire electrodes were inserted in the soleus muscle to record motor-evoked potentials (MEPs), H-reflexes, and the maximal motor response. During Hebbian stimulation, descending volleys evoked by cortical stimulation were timed to reach spinal motoneurons either 2.5 ms before (Hebbian+) or 15 ms after (Hebbian-) the arrival of antidromic potentials evoked by tibial nerve stimulation on different days. Rats received 180 paired pulses over 30 minutes, with measurements taken at baseline and every 10 minutes up to 40 minutes post-stimulation. We found that MEP size increased by an average of 30% over baseline during the 40-minute post-stimulation period with Hebbian+ stimulation and decreased by an average of 27% with Hebbian- stimulation. These findings provide the first evidence that paired stimulation based on Hebbian STDP principles can bidirectionally modulate MEPs in awake rats. Our rat model of Hebbian stimulation paves the way for exploring experimental combination therapies to enhance motor recovery following SCI and other neurological disorders.