Electrophysiological characterization of spontaneous recovery in deep dorsal horn interneurons after incomplete spinal cord injury

Rank, Michelle M; Flynn, Jamie R.; Galea, Mary P.; Callister, Robert J.

doi:10.1016/j.expneurol.2015.07.002

Cited by 15 publications

(16 citation statements)

References 70 publications

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“…Laminae VII interneurons within the intermediate gray matter of the lumbar cord integrate phasic afferent signals with supraspinal motor input to convey synaptic drive to motor neuron pools during walking (Jankowska, 1992 ; MacLean et al, 1995 ). Our findings of structural plasticity in these neuron networks extend previous electrophysiological findings that indicate maladaptive and hyperexcitable network communication after SCI (Rank et al, 2015 ). In response to lost supraspinal drive, dendritic outgrowth may reflect new connections that require greater metabolic or trophic support that is scavenged from the soma.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, the absence of descending axons produced marked atrophy and aberrant spine formations of the lumbar intermediate interneurons within the first week and worsened over 6 weeks. The interneuron phenotypes observed in intermediate gray matter indicated hyperexcitability and an increase in inappropriate connections (Hains and Waxman, 2006 ; Kim et al, 2006 ; Rank et al, 2015 ). Together, our work suggests that descending fibers preserve physiological function by promoting adaptive structural changes in lumbar neurons that allow learning.…”

Section: Discussionmentioning

confidence: 99%

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Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury

Hansen

Faw

White

et al. 2016

Front. Neural Circuits

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This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI). Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX). This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI). To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm (ILP). In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days) or late (42 days) after midthoracic SCI in a rodent model. Early after SCI or TX at 7 days, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between spared axonal systems and adaptive plasticity in locomotor networks and highlights a critical window for activity-based rehabilitation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury

Hansen

Faw

White

et al. 2016

Front. Neural Circuits

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“…An increase in sEPSC frequency is thought to indicate increased release probability or an increased number of synaptic connections. One possible factor that determines sEPSC width and decay time is the distance between the location of the synapse and the cell soma ( 42 , 43 ). Given the increased primary afferent connections within the dorsal horn ( 44 ) and increased dendritic-arbor size in SDH neurons during development ( 45 ) it is perhaps not surprising that we noted increases in sEPSC width and decay time.…”

Section: Discussionmentioning

confidence: 99%

Excitability of Rat Superficial Dorsal Horn Neurons Following a Neonatal Immune Challenge

et al. 2018

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Previous studies have shown that neonatal exposure to a mild inflammatory challenge, such as lipopolysaccharide (LPS, Salmonella enteriditis) results in altered pain behaviors later in life. To further characterize the impact of a neonatal immune challenge on pain processing, we examined the excitability of superficial dorsal horn (SDH) neurons following neonatal LPS exposure and subsequent responses to noxious stimulation at three time-points during early postnatal development. Wistar rats were injected with LPS (0.05 mg/kg i.p.) or saline on postnatal days (PNDs) 3 and 5, and later subjected to the formalin test at PNDs 7, 13, and 22. One hour after formalin injection into the plantar hindpaw, animals were euthanized (Ketamine, 100 mg/kg i.p.) and transverse slices from the lumbosacral spinal cord were prepared. Whole-cell patch-clamp recordings were made from SDH neurons (KCH3SO4-based internal, 22–24°C) on the ipsi- and contralateral sides of the spinal cord. Depolarising current steps were injected into SDH neurons to categorize action potential (AP) discharge. In both saline- and LPS-treated rats we observed age-related increases the percentage of neurons exhibiting tonic-firing, with concurrent decreases in single-spiking, between PND 7 and 22. In contrast, neonatal exposure to LPS failed to alter the proportions of AP discharge patterns at any age examined. We also assessed the subthreshold currents that determine AP discharge in SDH neurons. The rapid outward potassium current, IAr decreased in prevalence with age, but was susceptible to neonatal LPS exposure. Peak IAr current amplitude was greater in ipsilateral vs. contralateral SDH neurons from LPS-treated rats. Spontaneous excitatory synaptic currents (sEPSCs) were recorded to assess network excitability. Age-related increases were observed in sEPSC frequency and time course, but not peak amplitude, in both saline- and LPS-treated rats. Furthermore, sEPSC frequency was higher in ipsilateral vs. contralateral SDH neurons in LPS-treated animals. Taken together, these data suggest a neonatal immune challenge does not markedly affect the intrinsic properties of SDH neurons, however, it can increase the excitability of local spinal cord networks via altering the properties of rapid A-type currents and excitatory synaptic connections. These changes, made in neurons within spinal cord pain circuits, have the capacity to alter nociceptive signaling in the ascending pain pathway.

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“…Despite many examples of successful neurorehabilitative efforts to reengage locomotor activity, evidence suggests that neurorehabilitation in current settings has limited effectiveness. 60 Maladaptive forms of plasticity such as hyper-reflexia/spasticity and chronic central pain can emerge spontaneously after SCI, [61][62][63][64] and once established, maladaptive spinal cord plasticity may undermine the effectiveness of common forms of adaptive rehabilitation including stand training and swimming therapy. 65,66 Accumulating evidence suggests that afferent input in the acute phase of injury can also contribute to maladaptive forms of plasticity, thus making attempts at later adaptive training more difficult.…”

Section: Maladaptive Plasticitymentioning

confidence: 99%

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

Huie

Morioka

Haefeli

et al. 2017

Journal of Neurotrauma

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Spinal cord injury (SCI) is a devastating syndrome that produces dysfunction in motor and sensory systems, manifesting as chronic paralysis, sensory changes, and pain disorders. The multi-faceted and heterogeneous nature of SCI has made effective rehabilitative strategies challenging. Work over the last 40 years has aimed to overcome these obstacles by harnessing the intrinsic plasticity of the spinal cord to improve functional locomotor recovery. Intensive training after SCI facilitates lower extremity function and has shown promise as a tool for retraining the spinal cord by engaging innate locomotor circuitry in the lumbar cord. As new training paradigms evolve, the importance of appropriate afferent input has emerged as a requirement for adaptive plasticity. The integration of kinematic, sensory, and loading force information must be closely monitored and carefully manipulated to optimize training outcomes. Inappropriate peripheral input may produce lasting maladaptive sensory and motor effects, such as central pain and spasticity. Thus, it is important to closely consider the type of afferent input the injured spinal cord receives. Here we review preclinical and clinical input parameters fostering adaptive plasticity, as well as those producing maladaptive plasticity that may undermine neurorehabilitative efforts. We differentiate between passive (hindlimb unloading [HU], limb immobilization) and active ( peripheral nociception) forms of aberrant input. Furthermore, we discuss the timing of initiating exposure to afferent input after SCI for promoting functional locomotor recovery. We conclude by presenting a candidate rapid synaptic mechanism for maladaptive plasticity after SCI, offering a pharmacological target for restoring the capacity for adaptive spinal plasticity in real time.

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Electrophysiological characterization of spontaneous recovery in deep dorsal horn interneurons after incomplete spinal cord injury

Cited by 15 publications

References 70 publications

Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury

Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury

Excitability of Rat Superficial Dorsal Horn Neurons Following a Neonatal Immune Challenge

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

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