true-blue and Disease-Models--Animal

The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.

Topics: Adenoviridae; Analysis of Variance; Animals; Benzofurans; Cell Movement; Disease Models, Animal; Gene Expression Regulation; Genetic Vectors; Macrophages; Mice; Mice, Transgenic; Microfluidic Analytical Techniques; Microscopy, Electron, Transmission; Motor Neurons; Myelin Sheath; Nerve Regeneration; Proto-Oncogene Proteins c-jun; Schwann Cells; Sciatic Neuropathy; Spinal Cord

We sought to determine whether electrical stimulation (ES) with subthreshold, continuous, low-frequency impulses is a viable clinical method for improving functional recovery after facial nerve crush injury. In 10 rabbits, bilateral crush injuries were made on the facial nerve by compression for 30 s with mosquito forceps, causing complete facial paralysis. Subthreshold continuous direct current ES with 20-Hz square-wave pulses was applied to the proximal stump on one side for 4 weeks. Vibrissae movement returned significantly earlier on the ES side, with a less variable recovery time. Electrophysiologically, the stimulated side had a significantly shorter latency, longer duration, and faster conduction velocity. Light and transmission electron microscopy revealed that the electrical stimulation also markedly decreased Wallerian degeneration. The average numbers of fluorescent, double-labeled nerve cells were significantly different between the ES and non-ES sides. This study shows that subthreshold, continuous, low-frequency ES immediately after a crush injury of the facial nerve results in earlier recovery of facial function and shorter overall recovery time.

Topics: Action Potentials; Animals; Benzofurans; Biophysics; Dextrans; Disease Models, Animal; Electric Stimulation Therapy; Electrophysiology; Facial Nerve; Facial Nerve Injuries; Functional Laterality; Male; Microscopy, Electron, Transmission; Movement; Muscle, Skeletal; Neural Conduction; Rabbits; Recovery of Function; Rhodamines; Statistics, Nonparametric; Vibrissae

In neurons, cytoplasmic dynein functions as a molecular motor responsible for retrograde axonal transport. An impairment of axonal transport is thought to play a key role in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis, the most frequent motor neuron disease in the elderly. In this regard, previous studies described two heterozygous mouse strains bearing missense point mutations in the dynein heavy chain 1 gene that were reported to display late-onset progressive motor neuron degeneration. Here we show, however, that one of these mutant strains, the so-called Cra mice does not suffer from motor neuron loss, even in aged animals. Consistently, we did not observe electrophysiological or biochemical signs of muscle denervation, indicative of motor neuron disease. The "hindlimb clasping" phenotype of Cra mice could rather be due to the prominent degeneration of sensory neurons associated with a loss of muscle spindles. Altogether, these findings show that dynein heavy chain mutation triggers sensory neuropathy rather than motor neuron disease.

Topics: Age Factors; Analysis of Variance; Animals; Benzofurans; Choline O-Acetyltransferase; Cytoplasmic Dyneins; Disease Models, Animal; Dyneins; Electromyography; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Motor Neuron Disease; Motor Neurons; Muscle Denervation; Muscle, Skeletal; Mutation; Neuromuscular Junction; Sensation Disorders; Spinal Nerve Roots; Superoxide Dismutase; Superoxide Dismutase-1

The neural mechanisms of low back pain (LBP) are still enigmatic. Presently, low back muscles are being discussed as an important source of LBP. Here, the neuroanatomical pathway of the nociceptive information from the caudal multifidus muscle (MF) was studied. True blue was injected into the MF at the level L5 to visualize the dorsal root ganglion (DRG) cells that supply this muscle. The distribution of the stained cells had a maximum in the DRG L3, not in L5. Injection of 5% formalin into the MF at levels L4 and L5 induced a significant increase in the number of c-Fos-immunoreactive (-ir) nuclei in the dorsal horn in many lumbar segments. Cells expressing c-Fos were particularly numerous in the most lateral part of the ipsilateral laminae I-II. The number of c-Fos-ir nuclei in the dorsal horn of segment L3 was significantly higher than that in segment L5. To visualize supraspinal projections, fluorogold (FG) was injected into the contralateral ventrolateral periaqueductal gray (vlPAG) 6 days prior to formalin or saline injection into the MF. The number of double-labeled dorsal horn neurons (FG-positive plus c-Fos-ir) in all lumbar segments was significantly higher in the formalin group than in the saline group. These results show that (1) the origin of the sensory supply of the MF is shifted two segments cranially relative to the location of the muscle, (2) the spinal cells processing nociceptive input from the caudal MF are widely distributed, and (3) the vlPAG is a supraspinal center of nociception from the MF.

Topics: Afferent Pathways; Animals; Benzofurans; Biomarkers; Brain; Disease Models, Animal; Efferent Pathways; Fluorescent Dyes; Ganglia, Spinal; Low Back Pain; Male; Muscle, Skeletal; Neurons, Afferent; Nociceptors; Periaqueductal Gray; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Stilbamidines

Loss of dorsal root ganglion neuron, or injury to dorsal roots, induces permanent somatosensory defect without therapeutic option. We explored an approach to restoring hind limb somatosensory innervation after elimination of L4, L5 and L6 dorsal root ganglion neurons in rats. Somatosensory pathways were reconstructed by connecting L4, L5 and L6 lumbar dorsal roots to T10, T11 and T12 intercostal nerves, respectively, thus allowing elongation of thoracic ganglion neuron peripheral axons into the sciatic nerve. Connection of thoracic dorsal root ganglion neurons to peripheral tissues was documented 4 and 7 months after injury. Myelinated and unmyelinated fibers regrew in the sciatic nerve. Nerve terminations expressing calcitonin-gene-related-peptide colonized the footpad skin. Retrograde tracing showed that T10, T11 and T12 dorsal root ganglion neurons expressing calcitonin-gene-related-peptide or the neurofilament RT97 projected axons to the sciatic nerve and the footpad skin. Recording of somatosensory evoked potentials in the upper spinal cord indicated connection between the sciatic nerve and the central nervous system. Hind limb retraction in response to nociceptive stimulation of the reinnervated footpads and reversion of skin lesions suggested partial recovery of sensory function. Proprioceptive defects persisted. Delayed somatosensory reinnervation of the hind limb after destruction of lumbar dorsal root neurons in rats indicates potential approaches to reduce chronic disability after severe injury to somatosensory pathways.

Topics: Amidines; Animals; Benzofurans; Calcitonin Gene-Related Peptide; Cell Count; Disease Models, Animal; Electric Stimulation; Electromyography; Evoked Potentials, Somatosensory; Ganglia, Spinal; Immunohistochemistry; Lectins; Lower Extremity; Male; Microscopy, Electron, Transmission; Nerve Degeneration; Nerve Regeneration; Neurofilament Proteins; Neurons; Pain Measurement; Phosphopyruvate Hydratase; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Rhizotomy; Time Factors