Central nervous system (CNS) axons lose their intrinsic ability to regenerate upon maturity, whereas peripheral nervous system (PNS) axons do not. A key difference between these neuronal types is their ability to transport integrins into axons. Integrins can mediate PNS regeneration, but are excluded from adult CNS axons along with their Rab11 carriers. We reasoned that exclusion of the contents of Rab11 vesicles including integrins might contribute to the intrinsic inability of CNS neurons to regenerate, and investigated this by performing laser axotomy. We identify a novel regulator of selective axon transport and regeneration, the ARF6 guanine-nucleotide-exchange factor (GEF) EFA6 (also known as PSD). EFA6 exerts its effects from a location within the axon initial segment (AIS). EFA6 does not localise at the AIS in dorsal root ganglion (DRG) axons, and in these neurons, ARF6 activation is counteracted by an ARF GTPase-activating protein (GAP), which is absent from the CNS, ACAP1. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances regeneration, whereas overexpressing EFA6 prevents DRG regeneration. Our results demonstrate that ARF6 is an intrinsic regulator of regenerative capacity, implicating EFA6 as a focal molecule linking the AIS, signalling and transport.This article has an associated First Person interview with the first author of the paper.

• Keywords
• Axon initial segment, Axon regeneration, Axon transport, Integrin, Neuronal polarisation, Recycling endosome,
• MeSH
• Integrin alpha Chains genetics   metabolism   MeSH
• Amyloid beta-Protein Precursor genetics   metabolism   MeSH
• Axonal Transport genetics   MeSH
• Dendrites metabolism   ultrastructure   MeSH
• Embryo, Mammalian MeSH
• Axon Initial Segment metabolism   ultrastructure   MeSH
• Rats MeSH
• RNA, Small Interfering genetics   metabolism   MeSH
• Microtubules MeSH
• Cerebral Cortex metabolism   ultrastructure   MeSH
• Neurons metabolism   ultrastructure   MeSH
• Rats, Sprague-Dawley MeSH
• Primary Cell Culture MeSH
• GTPase-Activating Proteins genetics   metabolism   MeSH
• rab GTP-Binding Proteins genetics   metabolism   MeSH
• Signal Transduction MeSH
• Ganglia, Spinal metabolism   ultrastructure   MeSH
• Guanine Nucleotide Exchange Factors antagonists & inhibitors   genetics   metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Integrin alpha Chains MeSH
• Amyloid beta-Protein Precursor MeSH
• RNA, Small Interfering MeSH
• GTPase-Activating Proteins MeSH
• Psd protein, rat MeSH Browser
• rab GTP-Binding Proteins MeSH
• rab11 protein MeSH Browser
• Guanine Nucleotide Exchange Factors MeSH

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENT Restoration of neurologic function after spinal cord injury has yet to be achieved in human patients. To accomplish this, severed nerve fibers must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently, a method for stimulating long-distance axon regeneration of sensory fibers in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration program which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum (ER). The study identifies mechanisms that neurons need to activate to regenerate their nerve fibers.

• Keywords
• autophagy, axon regeneration, integrin, sensory, signaling, spinal cord,
• MeSH
• Axons * physiology   MeSH
• Integrins metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Spinal Cord metabolism   MeSH
• Sensory Receptor Cells physiology   MeSH
• Spinal Cord Injuries * therapy   metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Nerve Regeneration physiology   MeSH
• Ganglia, Spinal metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Integrins MeSH

We investigated how selected electromorphological parameters of myelinated axons influence the preservation of interspike intervals when the propagation of action potentials is corrupted by axonal intrinsic noise. Hereby we tried to determine how the intrinsic axonal noise influences the performance of axons serving as carriers for temporal coding. The strategy of this coding supposes that interspike intervals presented to higher order neurons would minimally be deprived of information included in interspike intervals at the axonal initial segment. Our experiments were conducted using a computer model of the myelinated axon constructed in a software environment GENESIS (GEneral NEural SImulation System). We varied the axonal diameter, myelin sheath thickness, axonal length, stimulation current and channel distribution to determine how these parameters influence the role of noise in spike propagation and hence in preserving the interspike intervals. Our results, expressed as the standard deviation of spike travel times, showed that by stimulating the axons with regular rectangular pulses the interspike intervals were preserved with a microsecond accuracy. Stimulation with pulses imitating postsynaptic currents, greater changes of interspike intervals were found, but the influence of implemented noise on the jitter of interspike intervals was approximately the same.

• MeSH
• Action Potentials physiology   MeSH
• Artifacts MeSH
• Ion Channels physiology   MeSH
• Models, Neurological * MeSH
• Nerve Fibers, Myelinated physiology   MeSH
• Computer Simulation MeSH
• Stochastic Processes MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ion Channels MeSH

We investigated how selected electromorphological parameters of myelinated axons influence the preservation of interspike intervals when the propagation of action potentials is corrupted by axonal intrinsic noise. Hereby we tried to determine how the intrinsic axonal noise influences the performance of axons serving as carriers for temporal coding. The strategy of this coding supposes that interspike intervals presented to higher order neurons would minimally be deprived of information included in interspike intervals at the axonal initial segment. Our experiments were conducted using a computer model of the myelinated axon constructed in a software environment GENESIS (GEneral NEural SImulation System). We varied the axonal diameter, myelin sheath thickness, axonal length, stimulation current and channel distribution to determine how these parameters influence the role of noise in spike propagation and hence in preserving the interspike intervals. Our results, expressed as the standard deviation of spike travel times, showed that by stimulating the axons with regular rectangular pulses the interspike intervals were preserved with a microsecond accuracy. Stimulating the axons with pulses imitating postsynaptic currents, greater changes of interspike intervals were found, but the influence of implemented noise on the jitter of interspike intervals was approximately the same.

• MeSH
• Action Potentials physiology   MeSH
• Artifacts * MeSH
• Models, Neurological * MeSH
• Nerve Fibers, Myelinated physiology   MeSH
• Computer Simulation * MeSH
• Reproducibility of Results MeSH
• Stochastic Processes MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Corrected and Republished Article MeSH

Activity was recorded intracellularly from the bodies of 87 reticulospinal neurones in the cat's gigantocellular nucleus, whose axons had a conduction velocity of 18-148 m.s-1. Slow-conducting neurones (18-45 m.s-1, 23%) were characterized by a wider action potential, higher input resistance (3.8-7.0 M omega) and a lower rheobase (1.0-1.7 nA). They were also very sensitive to changes in membrane polarity and generated regular rhythmic activity. Fast-conducting neurons (45-148 m.s-1) were characterized by a short action potential, low input resistance (0.7-2.9 M omega) and a higher rheobase (1.5-5.2 nA). When depolarizing current pulses were applied, they generated responses with action potentials with a high frequency, especially in the initial phase of depolarization, but their thresholds for the initiation of activity and steady firing were higher than in the case of slow neurones. Slow reticulospinal neurones always responded to stimulation of the spinal funiculi (mainly the dorsal funiculus) by a characteristic large postsynaptic potential on which large numbers of spike potentials were superimposed and which did not occur in fast neurones. The differences observed in membrane properties and in the character of generation of action potentials draw attention to the phasic character of fast, and the tonic character of slow, reticulospinal neurones.

• MeSH
• Action Potentials MeSH
• Axons physiology   MeSH
• Electric Conductivity MeSH
• Electrophysiology MeSH
• Kinetics MeSH
• Cats MeSH
• Spinal Cord physiology   MeSH
• Neurons physiology   MeSH
• Synapses physiology   MeSH
• Animals MeSH
• Check Tag
• Cats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

In the present paper the ultrastructural similarities among the terminal portions of Pacinian corpuscles, the nodes of Ranvier, and the initial segments of primary sensory neurons are pointed out. Our conclusion is based on our observations of cat Pacinian corpuscles and other general knowledge of the node of Ranvier and the initial segment published elsewhere. The morpho-functional similarities of three principal excitable regions of the sensory nerve fibres (the initial segments, the node of Ranvier, and the terminal portions of sensory nerve formations) are illustrated by identical distribution of the enzymes which are associated with ionic transport (alkaline phosphatase, Mg(2+)-ATPase), and non-specific cholinesterase. Furthermore, the polyanionic material revealed by Alcian blue staining in three excitable sites of the sensory axon confirms the supposition that excitable axolemma cannot be considered in the isolation of its surroundings produced by Schwann cells.

• MeSH
• Axons chemistry   ultrastructure   MeSH
• Histocytochemistry MeSH
• Cats MeSH
• Rats MeSH
• Mice MeSH
• Neurons, Afferent chemistry   ultrastructure   MeSH
• Ranvier's Nodes chemistry   ultrastructure   MeSH
• Pacinian Corpuscles chemistry   ultrastructure   MeSH
• Animals MeSH
• Check Tag
• Cats MeSH
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH

Incomplete ischemia of the spinal cord of rabbits was produced by a 40-min occlusion of the abdominal aorta followed by 1 and 4 days of recirculation. Regional evaluation of ATP-induced bioluminescence after 20 min of ischemia revealed ATP depletion mainly in the gray matter of the spinal cord. After 40 min of ischemia, ATP-induced bioluminescence was too faint to expose the photographic film. Within 1 and 4 days of recovery following 40 min of ischemia, restitution of ATP was regionally heterogeneous, reduced predominantly in the anterior horns of gray matter. Polysome profiles remained unaltered during the ischemic period, but a marked disaggregation of polyribosomes occurred after 10 min of recirculation. Protein synthesis in a cell-free system was inhibited by the addition of a postischemic cytosol or protein fraction isolated from cytosols on a DEAE column. The inhibition can be overcome by the addition of each initiation factor 2 (eIF-2), GTP and GDP exchange factor (GEF). Occlusion of abdominal aorta for 40 min results in decrease in monoamine oxidase accumulation in both proximal and distal ligature placed on sciatic nerve. Within 4 days of recovery the transport was progressively depressed to 22 and 21% in the proximal and distal direction, respectively.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Axonal Transport MeSH
• Energy Metabolism * MeSH
• Ischemia metabolism   MeSH
• Rabbits MeSH
• Spinal Cord blood supply   MeSH
• Nerve Tissue Proteins biosynthesis   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Nerve Tissue Proteins MeSH

The site of action of cholinergic, adrenergic, peptidergic and opioid agents was studied in myenteric plexus-longitudinal muscle strips from the guinea pig ileum. A preparation in a special triple bath was drawn through two rubber membranes, dividing the strip into three segments. Neurogenic stimulation of the oral segment, set up nerve action potentials also in the neurones projecting axons up to the aboral segment. These axons, turning into varicose nerve terminals, conducted action potentials aborally across the middle segment, that was up to 10 mm wide. Finally, the nerve terminals, extending into the aboral segment, might be also invaded triggering twitches. Agents were added, either to the oral segment, to affect the genesis and spread of action potentials in the proximal parts of cholinergic neurones (cell bodies, axon hillocks, initial segments and axon preterminals) or they were added to the middle segment to affect propagation of action potentials in varicose nerve terminals. As a result, the amplitude of aboral twitches reflected their effects at each site, quantitatively. Noradrenaline and ethylketocyclazocine were more effective at the site of varicose nerve terminals, whereas substance P, acetylcholine and oxotremorine were more effective at the proximal parts; pilocarpine and nicotine were effective at both sites. Changes in membrane polarization might be the final common effect in the mechanism of action of all the stimulatory agents used.

• MeSH
• Action Potentials drug effects   physiology   MeSH
• Potassium Chloride pharmacology   MeSH
• Ethylketocyclazocine pharmacology   MeSH
• Ileum drug effects   physiology   MeSH
• Guinea Pigs MeSH
• Motor Neurons physiology   MeSH
• Parasympathomimetics pharmacology   MeSH
• Myenteric Plexus drug effects   physiology   MeSH
• Substance P pharmacology   MeSH
• In Vitro Techniques MeSH
• Tetrodotoxin pharmacology   MeSH
• Animals MeSH
• Check Tag
• Guinea Pigs MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Potassium Chloride MeSH
• Ethylketocyclazocine MeSH
• Parasympathomimetics MeSH
• Substance P MeSH
• Tetrodotoxin MeSH

To assess the potential role of IL-6 in sciatic nerve injury-induced activation of a pro-regenerative state in remote dorsal root ganglia (DRG) neurons, we compared protein levels of SCG-10 and activated STAT3, as well as axon regeneration in IL-6 knockout (IL-6ko) mice and their wild-type (WT) counterparts. Unilateral sciatic nerve compression and transection upregulated SCG-10 protein levels and activated STAT3 in DRG neurons not only in lumbar but also in cervical segments of WT mice. A pro-regenerative state induced by prior sciatic nerve lesion in cervical DRG neurons of WT mice was also shown by testing for axon regeneration in crushed ulnar nerve. DRG neurons from IL-6ko mice also displayed bilaterally increased levels of SCG-10 and STAT3 in both lumbar and cervical segments after sciatic nerve lesions. However, levels of SCG-10 protein in lumbar and cervical DRG of IL-6ko mice were significantly lower than those of their WT counterparts. Sciatic nerve injury induced a lower level of SCG-10 in cervical DRG of IL-6ko than WT mice, and this correlates with significantly shorter regeneration of axons distal to the crushed ulnar nerve. These results suggest that IL-6 contributes, at the very least, to initiation of the neuronal regeneration program in remote DRG neurons after unilateral sciatic nerve injury.

• Keywords
• Primary sensory neuron, SCG10, STAT3, Sciatic nerve lesion, Ulnar nerve crush,
• MeSH
• Immunohistochemistry MeSH
• Interleukin-6 analysis   deficiency   metabolism   MeSH
• Intracellular Signaling Peptides and Proteins analysis   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurons chemistry   cytology   metabolism   pathology   MeSH
• Peripheral Nerve Injuries metabolism   pathology   surgery   MeSH
• Calcium-Binding Proteins MeSH
• Nerve Regeneration * MeSH
• Ganglia, Spinal cytology   metabolism   pathology   surgery   MeSH
• Stathmin MeSH
• STAT3 Transcription Factor analysis   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Interleukin-6 MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Calcium-Binding Proteins MeSH
• Stat3 protein, mouse MeSH Browser
• Stathmin MeSH
• Stmn2 protein, mouse MeSH Browser
• STAT3 Transcription Factor MeSH

Peripheral neuropathic pain (PNP) frequently occurs as a consequence of nerve injury and may differ depending upon the type of insult and the individual patient. Progress in our knowledge of PNP induction mechanisms depends upon the utilization of appropriate experimental models in rodents based on various types of peripheral nerve lesions. In this review, we draw attention to current knowledge on basic cellular and molecular events in various experimental models used to induce the PNP symptoms. Spontaneous ectopic activity of axotomized and non-axotomized primary sensory neurons, the bodies of which are located in the dorsal root ganglion (DRG), seems to be a key mechanism of PNP induction. The primary sensory neurons are directly affected by nerve injury or indirectly by activated satellite glial cells and adjoining immune cells that release a variety of molecules changing the microenvironment of the neurons. Recently, it has become clear that molecules produced during Wallerian degeneration play an important role not only in axon-promoting conditions distal to nerve injury but also in initiation of neuropathic pain. The molecules, transported by the blood, influence afferent neurons and their axons not only in DRG associated, but also those not directly associated with the injured nerve (i.e., in the contralateral DRG or at different spinal segments). Generally, all experimental PNP models based on a partial injury of peripheral nerve segments contain mechanisms initiated by signal molecules of Wallerian degeneration.

• MeSH
• Axons physiology   MeSH
• Axotomy MeSH
• Pain physiopathology   MeSH
• Disease Models, Animal MeSH
• Peripheral Nervous System Diseases physiopathology   MeSH
• Neurons physiology   MeSH
• Peripheral Nerves physiopathology   surgery   MeSH
• Blood Flow Velocity MeSH
• Ganglia, Spinal blood supply   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH