Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury

Abstract

Research has shown that spinal circuits have the capacity to adapt in response to training, nociceptive stimulation and peripheral inflammation. These changes in neural function are mediated by physiological and neurochemical systems analogous to those that support plasticity within the hippocampus (e.g., long-term potentiation and the NMDA receptor). As observed in the hippocampus, engaging spinal circuits can have a lasting impact on plastic potential, enabling or inhibiting the capacity to learn. These effects are related to the concept of metaplasticity. Behavioral paradigms are described that induce metaplastic effects within the spinal cord. Uncontrollable/unpredictable stimulation, and peripheral inflammation, induce a form of maladaptive plasticity that inhibits spinal learning. Conversely, exposure to controllable or predictable stimulation engages a form of adaptive plasticity that counters these maladaptive effects and enables learning. Adaptive plasticity is tied to an up-regulation of brain derived neurotrophic factor (BDNF). Maladaptive plasticity is linked to processes that involve kappa opioids, the metabotropic glutamate (mGlu) receptor, glia, and the cytokine tumor necrosis factor (TNF). Uncontrollable nociceptive stimulation also impairs recovery after a spinal contusion injury and fosters the development of pain (allodynia). These adverse effects are related to an up-regulation of TNF and a down-regulation of BDNF and its receptor (TrkB). In the absence of injury, brain systems quell the sensitization of spinal circuits through descending serotonergic fibers and the serotonin 1A (5HT 1A) receptor. This protective effect is blocked by surgical anesthesia. Disconnected from the brain, intracellular Cl- concentrations increase (due to a down-regulation of the cotransporter KCC2), which causes GABA to have an excitatory effect. It is suggested that BDNF has a restorative effect because it up-regulates KCC2 and re-establishes GABA-mediated inhibition.

Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury

“…In support of this idea, TNFα signaling initiates AMPA receptor insertion that mediates aberrant excitability (Beattie et al, 2002; Huie et al, 2012). Other inflammatory actions modulate synaptic activity by altering GABAergic activity (Grau et al, 2014). Here, we show that MMP9 KO mice display a frank reduction in vascular leakage alongside normalized expression of GAD67 within presumptive CPG laminae.…”

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

“…Ankle muscles which visually have the greatest activation during the vibration are innervated by motoneurons at L5, whereas L1 contains motoneurons innervating the hip musculature that visually appear to be the "driving" force behind the kicking response. It is possible that nociceptive signaling leads to increased excitability of the motor system that in long-term may have detrimental consequences, such as temporary loss of locomotor function in the stretched rats and when it occurs in uncontrollable fashion it leads to the disruption of spinal learning and locomotor function as has been clearly demonstrated in studies by Grau et al [250].…”

“…Moreover, nociceptive afferents undergo substantial plasticity after SCI that has been implicated in the development of neuropathic pain [247,248] and autonomic dysreflexia [249]. Activation of nociceptive afferents impairs locomotor recovery after SCI in rodents and spinal learning in rats [212,213,250] and humans [251]. Thus it would not be surprising that nociceptive afferents are also involved in mediation of the negative effects of stretching on locomotor function.…”

“…In addition Grau et al, has investigated the role of endogenous opioids in the mediation of spinal learning deficits as a result of uncontrollable nociceptive stimulation. They specifically found that kappa receptor (KOR) antagonist given immediately prior to the testing attenuates the learning impairments induced by uncontrollable stimulation but its administration a day prior to stimulation does not have a preventative effect [302] suggesting that KOR ligand mediates expression but not the induction of the learning impairment [250]. This observation, as suggested by Grau et al, demonstrates that NMDA-dependent adaptive plasticity remains functional since the spinal learning impairment was reversed with an opioid antagonist treatment and furthermore implies that this phenomenon is an example of metaplasticity as described by W. Abraham [250,303].…”

“…They specifically found that kappa receptor (KOR) antagonist given immediately prior to the testing attenuates the learning impairments induced by uncontrollable stimulation but its administration a day prior to stimulation does not have a preventative effect [302] suggesting that KOR ligand mediates expression but not the induction of the learning impairment [250]. This observation, as suggested by Grau et al, demonstrates that NMDA-dependent adaptive plasticity remains functional since the spinal learning impairment was reversed with an opioid antagonist treatment and furthermore implies that this phenomenon is an example of metaplasticity as described by W. Abraham [250,303]. In our experiments 4-5 weeks of stretching resulted only in transient locomotor deficits as the animals' recovered locomotor function within 2 weeks of cessation of daily stretching [218,254].…”