Maintenance of contractile force of the hind limb muscles by the somato-lumbar sympathetic reflexes

This study aimed to clarify whether the reflex excitation of muscle sympathetic nerves induced by contractions of the skeletal muscles modulates their contractility. In anesthetized rats, isometric tetanic contractions of the triceps surae muscles were induced by electrical stimulation of the intact tibial nerve before and after transection of the lumbar sympathetic trunk (LST), spinal cord, or dorsal roots. The amplitude of the tetanic force (TF) was reduced by approximately 10% at 20 min after transection of the LST, spinal cord, or dorsal roots. The recorded postganglionic sympathetic nerve activity from the lumbar gray ramus revealed that both spinal and supraspinal reflexes were induced in response to the contractions. Repetitive electrical stimulation of the cut peripheral end of the LST increased the TF amplitude. Our results indicated that the spinal and supraspinal somato-sympathetic nerve reflexes induced by contractions of the skeletal muscles contribute to the maintenance of their own contractile force.

The tissue proteome of dorsal root ganglia in Friedreich ataxia

Dorsal root ganglia (DRG) at all levels of the spinal cord are a prominent target of Friedreich ataxia (FA). The lesions include hypoplasia of neurons, proliferation of satellite cells, infiltration by IBA- 1-reactive monocytes, and formation of residual nodules. Paucity and smallness of DRG neurons account for the lack of large myelinated axons in dorsal roots and sensory peripheral nerves. The lack of myelin in dorsal roots can be attributed to low levels of neuregulin 1 type III (NRG1[III]). Lysates of 13 DRG of genetically confirmed FA patients were analyzed by antibody microarray with 878 different validated antibodies that target structural and signaling proteins, and by Western blots. KIT and mTOR, two proteins involved in cellular proliferation, were significantly upregulated in the DRG of FA. KIT is a transmembrane receptor that dimerizes when it binds two molecules of stem cell factor (SCF) in its extracellular domain and becomes activated as protein tyrosine kinase. Immunohistochemistry with anti-KIT generated reaction product in satellite cells of normal DRG and prominent labeling of these cells in FA that co-localized with SCF on double- label immunofluorescence; SCF was present in S100-positive satellite cells rather than monocytes. Immunohistochemical reaction product of mTOR and other mTOR complex proteins, such as hamartin (TSC1), tuberin (TSC2), raptor (mTOR complex 1) and rictor (mTOR complex 2) was also present in satellite cells of normal DRG and DRG of FA. Antibodies to two downstream proteins that are considered to be indicators of mTOR activity, P70 S6K and 4E-binding protein 1, revealed no reaction product in DRG of FA. TSC1, TSC2, and mTOR are best known from their roles in tuberous sclerosis, but expression of these proteins, and KIT, in DRG may contribute to signaling cascades underlying the proliferation of satellite cells in FA.LEARNING OBJECTIVESThis presentation will enable the learner to: 1.Discuss cellular proliferation in the pathogenesis of the DRG lesion in Friedreich ataxiaCONFLICT OF INTERESTAHK is a consultant to PTC Therapeutics of South Plainfield, NJ USA. SP and CS are majority owners of Kinexus.

Epidural Electrical Stimulation Of The Cervical Dorsal Roots Restores Voluntary Arm Control In Paralyzed Monkeys

Recovering arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control practically limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts, triggered by intracortical signals produced sustained arm movements enabling monkeys with arm paralysis to perform an unconstrained, three-dimensional reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that artificial recruitment of the sensory afferents was synergistically integrated with spared descending inputs and spinal reflexes to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Spinal Reflex Recovery after Dorsal Rhizotomy and Repair with Platelet-Rich Plasma (PRP) Gel Combined with Bioengineered Human Embryonic Stem Cells (hESCs)

Dorsal root rhizotomy (DRZ) is currently considered an untreatable injury, resulting in the loss of sensitive function and usually leading to neuropathic pain. In this context, we recently proposed a new surgical approach to treat DRZ that uses platelet-rich plasma (PRP) gel to restore the spinal reflex. Success was correlated with the reentry of primary afferents into the spinal cord. Here, aiming to enhance previous results, cell therapy with bioengineered human embryonic stem cells (hESCs) to overexpress fibroblast growth factor 2 (FGF2) was combined with PRP. For these experiments, adult female rats were submitted to a unilateral rhizotomy of the lumbar spinal dorsal roots, which was followed by root repair with PRP gel with or without bioengineered hESCs. One week after DRZ, the spinal cords were processed to evaluate changes in the glial response (GFAP and Iba-1) and excitatory synaptic circuits (VGLUT1) by immunofluorescence. Eight weeks postsurgery, the lumbar intumescences were processed for analysis of the repaired microenvironment by transmission electron microscopy. Spinal reflex recovery was evaluated by the electronic Von Frey method for eight weeks. The transcript levels for human FGF2 were over 37-fold higher in the induced hESCs than in the noninduced and the wildtype counterparts. Altogether, the results indicate that the combination of hESCs with PRP gel promoted substantial and prominent axonal regeneration processes after DRZ. Thus, the repair of dorsal roots, if done appropriately, may be considered an approach to regain sensory-motor function after dorsal root axotomy.

Neonatal Mice Spinal Cord Interneurons Sending Axons in Dorsal Roots

Background: Spinal cord interneurons send their axons in the dorsal root. Their antidromic fire could modulate peripheral receptors. Thus, it could control pain, other sensorial modality, or muscle spindle activity. In this study, we assessed a staining technique to analyze whether interneurons send axons in the neonate mouse’s dorsal roots. We conducted experiments in 10 Swiss-Webster mice, which ranged in age from 2 to 13 postnatal days. We dissected the spinal cord and studied it in vitro. Results: We observed interneurons in the spinal cord dorsal horn sending axons through dorsal roots. A mix of fluorochromes applied in dorsal roots marked these interneurons. They have a different morphology than motoneurons. Primary afferent depolarization in afferent terminals produces antidromic action potentials (dorsal root reflex; DRR). These reflexes appeared by stimulation of adjacent dorsal roots. We found that in the presence of bicuculline, DRR recorded in the L4 dorsal root evoked by L5 dorsal root stimulation was reduced. Simultaneously, the monosynaptic reflex (MR) in the L5 ventral root was not affected; nevertheless, a long-lasting after discharge appeared. The addition of 2-amino-5 phosphonovalric acid (AP5), an antagonist of NMDA receptors, abolished the MR without changing the after discharge. Action potentials persisted in dorsal roots even in low Ca2+ concentration. Conclusions: Thus, firing interneurons could send their axons by dorsal roots. Antidromic potentials may be characteristics of the neonatal mouse, probably disappearing in adulthood.

Transplantation of Cultured Olfactory Bulb Cells Prevents Abnormal Sensory Responses during Recovery from Dorsal Root Avulsion in the Rat

The central branches of the C7 and C8 dorsal roots were avulsed close to their entry point into the spinal cord in adult rats. The forepaw responses to heat and cold stimuli were tested at 1, 2, and 3 weeks after injury. Over this period, the paws were sensitive to both stimuli at 1-2 weeks and returned toward normal at 3 weeks. Immunohistology showed no evidence of axonal regeneration into the spinal cord in a control group of rats with avulsion only, implying that adjacent dorsal roots and their corresponding dermatomes were involved in the recovery. In a further group of rats, a mixture of bulbar olfactory ensheathing cells and olfactory nerve fibroblasts were transplanted into the gap between the avulsed roots and the spinal cord at the time of avulsion. These rats showed no evidence of either loss of sensation or exaggerated responses to stimuli at any of the time points from 1 to 3 weeks. Immunohistology showed that the transplanted cells formed a complete bridge, and the central branches of the dorsal root fibers had regenerated into the dorsal horn of the spinal cord. These regenerating axons, including Tuj1 and CGRP immunoreactive fibers, were ensheathed by the olfactory ensheathing cells. This confirms our previous demonstration of central regeneration by these transplants and suggests that such transplants may provide a useful means to prevent the development of abnormal sensations such as allodynia after spinal root lesions.