Timing in the absence of supraspinal input I: Variable, but not fixed, spaced stimulation of the sciatic nerve undermines spinally-mediated instrumental learning

Abstract

Rats with complete spinal transections are capable of acquiring a simple instrumentally trained response. If rats receive shock to one hindlimb when the limb is extended (controllable shock), the spinal cord will learn to hold the leg in a flexed position that minimizes shock exposure. If shock is delivered irrespective of leg position, subjects do not exhibit an increase in flexion duration and subsequently fail to learn when tested with controllable shock (learning deficit). Just 6 min of variable intermittent shock produces a learning deficit that lasts 24 hrs. Evidence suggests that the neural mechanisms underlying the learning deficit may be related to those involved in other instances of spinal plasticity (e.g., wind-up, long-term potentiation). The present paper begins to explore these relations by demonstrating that direct stimulation of the sciatic nerve also impairs instrumental learning. Six minutes of electrical stimulation (mono- or biphasic direct current [DC]) of the sciatic nerve in spinally transected rats produced a voltage-dependent learning deficit that persisted for 24 hr (Experiments 1–2) and was dependent on C-fiber activation (Experiment 7). Exposure to continuous stimulation did not produce a deficit, but intermittent burst or single pulse (as short as 0.1 ms) stimulation (delivered at a frequency of 0.5 Hz) did, irrespective of the pattern (fixed or variable) of stimulus delivery (Experiments 3–6, 8). When the duration of stimulation was extended from 6 to 30 min, a surprising result emerged; shocks applied in a random (variable) fashion impaired subsequent learning whereas shocks given in a regular pattern (fixed spacing) did not (Experiments 9–10). The results imply that spinal neurons are sensitive to temporal relations and that stimulation at regular intervals can have a restorative effect.

Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats

“…For subjects in the fixed spaced condition, shocks occurred at regular (2-s) intervals. Variable stimulation was created using a rectangular distribution that varied between 0.2 and 3.8 s, with a mean interstimulus interval (ISI) of 2 s. Prior work has shown that variable shock undermines learning (Crown et al, 2002; Baumbauer et al, 2007; Baumbauer et al, 2008; Ferguson et al, 2008; Baumbauer et al, 2009), while fixed shock does not (Baumbauer et al, 2008; Baumbauer et al, 2009). …”

“…peripheral capsaicin or carrageenan) impair this learning (Ferguson et al, 2006; Hook et al, 2008). Interestingly, variable intermittent shock at an intensity that activates C-fibers also impairs instrumental learning and this effect lasts at least 24 hr (Crown et al, 2002; Baumbauer et al, 2008). …”

“…We recently discovered that the impact of intermittent shock on learning depends on whether the stimulation occurs in a regular or irregular manner; subjects given 900 intermittent 80-msec shocks in a variable manner (0.2–3.8 s [mean 2 s], rectangular distribution) later fail to learn whereas subjects exposed to an equal number of shocks at a regular (fixed 2 s) exhibit no learning impairment (Baumbauer et al, 2008). Rather, exposure to fixed spaced shock engages an opponent-like process that enables learning and blocks the induction of the learning deficit for up to 24 hr (Baumbauer et al, 2009).…”

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

“…In an attempt to uncover a pharmacological target for stimulus-dependent maladaptive plasticity in SCI, our team recently tested the impact of below-level nociceptive stimulation on ventral spinal motor neurons after SCI, using the same uncontrollable C-fiber-strength electronociceptive stimulation paradigm extensively described by Grau and colleagues. 82,[115][116][117][118] Our hypothesis was that aberrant stimulation would generate intrinsic ventral horn motorneuron changes after SCI similar to those known to be involved in maladaptive sensory plasticity in the dorsal horn in pain syndromes. Pain plasticity has been shown to be mediated by rapid alterations in synaptic AMPA receptor (AM-PAR) levels and phosphorylation similar to those observed in brain-dependent learning and memory.…”

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

“…Specific cellular mechanisms involved in the maladaptive plasticity as determined by Grau et al, are dependent on post-synaptic activation of group I metabotropic glutamate receptor (mGluR) as well as substance P receptor neurokinin 1 (NK1R) which leads to an increased intracellular calcium, activation of protein kinase C (PKC), CamKII and phosphoinositide 3-kinase (PI3K) [293][294][295]. It is proposed that the activity of calcium-dependent kinases leads to an altered NMDA and AMPA receptor function [296,297].…”