Timing in the absence of supraspinal input II: regularly spaced stimulation induces a lasting alteration in spinal function that depends on the NMDA receptor, BDNF release, and protein synthesis.

The detection of temporal regularity allows organisms to predict the occurrence of future events. When events occur in an irregular manner, uncertainty is increased, and negative outcomes can ensue (e.g., stress). The present study shows that spinal neurons can discriminate between variable- and fixed-spaced stimulation and that the detection of regularity requires training and engages a form of NMDA receptor-mediated plasticity. The impact of stimulus exposure was assessed using a spinally mediated instrumental response, wherein spinally transected rats are given legshock whenever one hindlimb is extended. Over time, they learn to maintain the leg in a flexed position that minimizes net shock exposure. Prior exposure to 180-900 tailshocks given in a variable (unpredictable) manner inhibited this learning. A learning deficit was not observed when 900 tailshocks were applied using a fixed (predictable) spacing. Fixed-spaced stimulation did not have a divergent effect when fewer (180) shocks were presented, implying that the abstraction of temporal regularity required repeated exposure (training). Moreover, fixed-spaced stimulation both prevented and reversed the learning deficit. The protective effect of fixed-spaced shock lasted 48 h, and was prevented by pretreatment with the NMDA receptor antagonist MK-801. Administration of the protein synthesis inhibitor cycloheximide after training blocked the long-term effect. Inhibiting BDNF function, using TrkB-IgG, also eliminated the beneficial effect of fixed-spaced stimulation. The results suggest that spinal systems can detect regularity and that this type of stimulation promotes adaptive plasticity, which may foster recovery after spinal injury.