Experimental neurology
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Experimental neurology · Jul 2017
Inflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A.
Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca2+ permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. ⋯ Inflammation induced an increase in synaptic GluA1, but not GluA2. Although total GluA4 also increased with inflammation, co-localization of GluA4 with synaptophysin, fell short of significance. Taken together these data suggest that peripheral inflammation induces a PI3K and PKA dependent TNFR1 activated pathway that culminates with trafficking of calcium permeable AMPAr into synapses of nociceptive dorsal horn projection neurons.
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Experimental neurology · Jul 2017
Supraspinal respiratory plasticity following acute cervical spinal cord injury.
Impaired breathing is a devastating result of high cervical spinal cord injuries (SCI) due to partial or full denervation of phrenic motoneurons, which innervate the diaphragm - a primary muscle of respiration. Consequently, people with cervical level injuries often become dependent on assisted ventilation and are susceptible to secondary complications. However, there is mounting evidence for limited spontaneous recovery of respiratory function following injury, demonstrating the neuroplastic potential of respiratory networks. ⋯ Electrophysiological mapping of the ventrolateral medulla showed a reorganization of inspiratory and expiratory sites ipsilateral to injury. These changes included i) decreased respiratory activity within the caudal ventral respiratory group (cVRG; location of bulbospinal expiratory neurons); ii) increased proportion of expiratory phase activity within the rostral ventral respiratory group (rVRG; location of inspiratory bulbo-spinal neurons); iii) increased respiratory activity within ventral reticular nuclei, including lateral reticular (LRN) and paragigantocellular (LPGi) nuclei. We conclude that disruption of descending and ascending connections between the medulla and spinal cord leads to immediate functional reorganization within the supraspinal respiratory network, including neurons within the ventral respiratory column and adjacent reticular nuclei.
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Experimental neurology · Jul 2017
Spinal cord injury in hypertonic newborns after antenatal hypoxia-ischemia in a rabbit model of cerebral palsy.
While antenatal hypoxia-ischemia (H-I) is a well-established cause of brain injury, the effects of H-I on the spinal cord remain undefined. This study examined whether hypertonia in rabbits was accompanied by changes in spinal architecture. Rabbit dams underwent global fetal H-I at embryonic day 25 for 40min. ⋯ Direct damage to the spinal cord was demonstrated in a subset of dams imaged during H-I with a 3T magnetic resonance scanner, where apparent diffusion coefficient in fetal spinal cords acutely decreased during hypoxia. Hypertonic kits showed subsequent decreases in lumbar motoneuron counts and extensive TUNEL- and Fluoro-Jade C-positive labeling was present in the spinal cord 48h after H-I, demonstrating spinal neurodegeneration. We speculate that global H-I causes significant loss of both spinal white and gray matter in hypertonic newborns due to direct H-I injury to the spinal cord as well as due to upstream brain injury and consequent loss of descending projections.
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Experimental neurology · Jul 2017
Bilateral tactile hypersensitivity and neuroimmune responses after spared nerve injury in mice lacking vasoactive intestinal peptide.
Vasoactive intestinal peptide (VIP) is one of the neuropeptides showing the strongest up-regulation in the nociceptive pathway after peripheral nerve injury and has been proposed to support neuropathic pain. Nevertheless, the story may be more complicated considering the known suppressive effects of the peptide on the immune reactivity of microglial cells, which have been heavily implicated in the onset and maintenance of pain after nerve injury. We here used mice deficient in VIP and the model of spared nerve injury, characterized by persistent tactile hypersensitivity. ⋯ The latter was also observed at four weeks after spared nerve injury, a time at which bilateral tactile hypersensitivity persisted in VIP-deficient mice. These data suggest an action of VIP in neuropathic states that is more complicated than previously assumed. Future research is now needed for a deeper understanding of the relative contribution of receptors and fiber populations involved in the VIP-neuropathic pain link.
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Experimental neurology · Jul 2017
Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast.
Due to recent military conflicts and terrorist attacks, blast-induced traumatic brain injury (bTBI) presents a health concern for military and civilian personnel alike. Although secondary blast (penetrating injury) and tertiary blast (inertia-driven brain deformation) are known to be injurious, the effects of primary blast caused by the supersonic shock wave interacting with the skull and brain remain debated. Our group previously reported that in vitro primary blast exposure reduced long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and that primary blast affects key proteins governing LTP. ⋯ Roflumilast treatment (1nM delivered 6h post-injury) significantly increased total AMPA glutamate receptor 1 (GluR1) subunit expression, phosphorylation of the GluR1 subunit at the serine-831 site, and phosphorylation of stargazin at the serine-239/240 site upon LTP induction, measured 24h following injury. Roflumilast treatment significantly increased PSD-95 regardless of LTP induction. These findings indicate that further investigation into the translation of PDE4 inhibition as a therapy following bTBI is warranted.