First Node Of Ranvier Research Articles

Dental pulp stem cells-derived schwann cells for peripheral nerve injury regeneration.

The peripheral nervous system (PNS) has an intrinsic ability for repair and regeneration even after severe injury. Peripheral nerve injury is followed by the normal rapid progression of Wallerian degeneration (anterograde or orthograde degeneration). During this process, the distal detached nerve segment degenerates, and the surrounding myelin breaks down. Simultaneously, the proximal segment of the axon undergoes degeneration that extends proximally only as far as the first node of Ranvier. The proximal segment can undergo a chromatolytic reaction; the Nissl bodies dissolve; and the nucleus migrates towards the periphery of the cell and the size of the nucleolus, nucleus and neuronal cell body increases, initiating a process of protein synthesis in an attempt to regenerate. Schwann cells play a major role in PNS axon regeneration. They are able to dedifferentiate, reenter the cell cycle and promote axonal regrowth by phagocytosis of the axonal and myelin debris, recruiting macrophages to the injury site, secreting several neurotrophic and key transcription factors and forming a unique column of cells called bands of Bungner within their endoneurial tubes for guiding the axonal sprouts from the proximal stumps (Burnett and Zager, 2004) (Figure 1).

Targeting Retinoblastoma Protein Offers Therapeutic Opportunities For Peripheral Nerve Injury

Peripheral nerve injury is common. Severed peripheral axons that fail to reconnect to their targets are associated with temporary or permanent functional impairment. Fortunately, the higher intrinsic capacity of axons in the PNS to regrow compared with their counterparts in the CNS justifies exploring strategies to ramp up effi cient regeneration. Peripheral nerve injury, or axotomy, triggers a cascade of events: a degenerative phase that involves breakdown of axons and myelin within the distal stump, dying back of axons in the proximal stump up to the first node of Ranvier, clearance of myelin debris by Schwann cells (SCs) and macrophages, a regenerative phase involving upregulation of regeneration-associated genes in neurons and SCs, reconstruction of the endoneurial assembly including repopulation of cytoskeletol molecules in axons and finally reconnec tion to targets [1]. Unfortunately, the active regenerative phase is circumscribed, peaking at 7 days postaxotomy whereas failure to generate an effective regenerative milieu within this span of time may leave behind the axons with poor regenerative and sprouting capacity. Misdirected growth of axons to nonspecific targets also compli cates successful regrowth. Therapies aimed at inactivating the inhibitory molecules that dampen the intrinsic growth response of neurons within the microenvironment may be an efficient and feasible strategy to improve regeneration in the PNS. For example, targeting the inhibitory molecule RHOA has a striking impact in enhancing the regenerative capacity of peripheral axons [2]. Tumor suppressors are a class of molecules possessing growth inhibitory properties. Their presence in the injured nerves can be compared with deracinated trees, in the path of axon regeneration, with numerous and divergent signaling branches targeted for growth inhibition. Relieving the growth inhibition posed by such inhibitors, for example, targeting the central growth ‘brake’ PTEN, has proven remarkably effective in increasing the extent by which peripheral axons regenerate [3]. Having experience with this approach in our laboratory, we have recently identified another tumor suppressor, retinoblastoma protein (Rb1), as a novel target for improving PNS regeneration [4].

The intrinsic and synaptic responsiveness of a new realistic Purkinje cell model

The latest discoveries on Purkinje cell (PC) physiology suggest that the mechanisms of PCs intrinsic excitability have to be revisited. Starting from available models [1], we have constructed a new PC model in Python-NEURON, which explicitly accounts for the Axon Initial Segment (AIS) [2-4] and a part of the axon including the first node of Ranvier (RVN). The fast Na+ channels are located in AIS, soma with initial dendrite and RVN [4]. The K+ delayed rectifier channels are located only in the soma. The Ca2+ and Ca2+-dependent K+ channels, including SK2, as well as intracellular Ca2+ dynamics have been updated [5]. The new model configuration now generates simple spike (SS) firing reproducing the experimental input-output curve[6]. SSs initiate in AIS and then back-propagate into the soma decaying sharply inside the dendritic tree. Activation of parallel fiber (pf) generates a short burst followed by a pause caused by Stellate cells. Following a complex spike (CS), SS activity is interrupted independently of the inhibitory synaptic input. Interestingly, the model can shift its state from silent to autorhythmic (configuring a bistable behavior) upon transient current injection or activation of CFs. The pf and granule cell ascending axon (aa) synapses have been modeled using a stochastic release mechanism activating AMPA synaptic receptors. The facilitation and depression profiles of pf and aa synapses faithfully reproduce the experimental data. This model provides a valuable tool to further investigate the Purkinje cell function in cerebellar network models.

First Node of Ranvier Facilitates High-Frequency Burst Encoding

In central neurons the first node of Ranvier is located at the first axonal branchpoint, ∼ 100 μm from the axon initial segment where synaptic inputs are integrated and converted into action potentials (APs). Whether the first node contributes to this signal transformation is not well understood. Here it was found that in neocortical layer 5 axons, the first branchpoint is required for intrinsic high-frequency (≥ 100 Hz) AP bursts. Furthermore, block of nodal Na(+) channels or axotomy of the first node in intrinsically bursting neurons depolarized the somatic AP voltage threshold (∼ 5 mV) and eliminated APs selectively within a high-frequency cluster in response to steady currents or simulated synaptic inputs. These results indicate that nodal persistent Na(+) current exerts an anterograde influence on AP initiation in the axon initial segment, revealing a computational role of the first node of Ranvier beyond conduction of the propagating AP.

The Nodal Origin of Intrinsic Bursting

The output of cortical neurons in the form of bursts of action potentials was thought to be controlled solely by the dendrites. In this issue of Neuron, Maarten Kole reveals that axonal sodium channels at the first node of Ranvier are essential for neuronal burst firing.

Na+ imaging reveals little difference in action potential–evoked Na+ influx between axon and soma

In cortical pyramidal neurons, the axon initial segment (AIS) is pivotal in synaptic integration. It has been asserted that this is because there is a high density of Na(+) channels in the AIS. However, we found that action potential-associated Na(+) flux, as measured by high-speed fluorescence Na(+) imaging, was about threefold larger in the rat AIS than in the soma. Spike-evoked Na(+) flux in the AIS and the first node of Ranvier was similar and was eightfold lower in basal dendrites. At near-threshold voltages, persistent Na(+) conductance was almost entirely axonal. On a time scale of seconds, passive diffusion, and not pumping, was responsible for maintaining transmembrane Na(+) gradients in thin axons during high-frequency action potential firing. In computer simulations, these data were consistent with the known features of action potential generation in these neurons.

Subthalamic firing without an end, but now with a beginning

Subthalamic firing without an end, but now with a beginning

Axonal Speeding: Shaping Synaptic Potentials in Small Neurons by the Axonal Membrane Compartment

The role of the axonal membrane compartment in synaptic integration is usually neglected. We show here that in interneurons of the cerebellar molecular layer, where dendrites are so short that the somatodendritic domain can be considered isopotential, the axonal membrane contributes a significant part of the cell input capacitance. We examine the impact of axonal membrane on synaptic integration by cutting the axon with two-photon illumination. We find that the axonal compartment acts as a sink for signals generated at fast conductance synapses, thus increasing the initial decay rate of corresponding synaptic potentials over the value predicted from the resistance-capacitance (RC) product of the cell membrane; signals generated at slower synapses are much less affected. This mechanism sharpens the spike firing precision of fast glutamatergic inputs without resorting to multisynaptic pathways.

Modulation of motoneuronal firing behavior after spinal cord injury using intraspinal microstimulation current pulses: a modeling study

We simulated the effects of delivering focal electrical stimuli to the central nervous system to modulate the firing rate of neurons and alleviate motor disorders. Application of these stimuli to the spinal cord to reduce the increased excitability of motoneurons and resulting spasticity after spinal cord injury (SCI) was examined by means of a morphologically detailed computer model of a spinal motoneuron. High-frequency sinusoidal and rectangular pulses as well as biphasic charge-balanced and charge-imbalanced pulses were examined. Our results suggest that suprathreshold high-frequency sinusoidal or rectangular current pulses could inactivate the Na+ channels in the soma and initial segment, and block action potentials from propagating through the axon. Subthreshold biphasic charge-imbalanced pulses reduced the motoneuronal firing rate significantly (up to approximately 25% reduction). The reduction in firing rate was achieved through stimulation-induced hyperpolarization generated in the first node of Ranvier. Because of their low net DC current, these pulses could be tolerated safely by the tissue. To deliver charge-imbalanced pulses with the lowest net DC current and induce the largest reduction in motoneuronal firing rate, we studied the effect of various charge-imbalanced pulse parameters. Short pulse durations were found to induce the largest reduction in firing rate for the same net DC level. Subthreshold high-frequency sinusoidal and rectangular current pulses and low-frequency biphasic charge-balanced pulses, on the other hand, were ineffective in reducing the motoneuronal firing rate. In conclusion, the proposed electrical stimulation paradigms could provide potential rehabilitation interventions for suppressing the excitability of neurons to reduce the severity of motor disorders after injury to the central nervous system.

Passive Soma Facilitates Submillisecond Coincidence Detection in the Owl's Auditory System

Neurons of the avian nucleus laminaris (NL) compute the interaural time difference (ITD) by detecting coincident arrivals of binaural signals with submillisecond accuracy. The cellular mechanisms for this temporal precision have long been studied theoretically and experimentally. The myelinated axon initial segment in the owl's NL neuron and small somatic spikes observed in auditory coincidence detector neurons of various animals suggest that spikes in the NL neuron are generated at the first node of Ranvier and that the soma passively receives back-propagating spikes. To investigate the significance of the "passive soma" structure, we constructed a two-compartment NL neuron model, consisting of a cell body and a first node, and systematically changed the excitability of each compartment. Here, we show that a neuron with a less active soma achieves higher ITD sensitivity and higher noise tolerance with lower energy costs. We also investigate the biophysical mechanism of the computational advantage of the "passive soma" structure by performing sub- and suprathreshold analyses. Setting a spike initiation site with high sodium conductance, not in the large soma but in the small node, serves to amplify high-frequency input signals and to reduce the impact and the energy cost of spike generation. Our results indicate that the owl's NL neuron uses a "passive soma" design for computational and metabolic reasons.

Relative contributions of axonal and somatic Na channels to action potential initiation in cerebellar Purkinje neurons.

Neuronal excitability is likely to be regulated by the site of action potential initiation, the location on a neuron that crosses threshold first. Although initiation is axonal in many neurons, in Purkinje cells, somatic conductances can generate spontaneous action potentials, suggesting that the perisomatic region (soma and/or initial segment) contributes to spike initiation and may regulate firing. To identify directly the cellular regions at which Na channel modulation significantly influences firing, we measured spontaneous and evoked action potentials in Purkinje cells in cerebellar slices from postnatal day 14-28 mice while applying drugs locally to either the soma/initial segment or the first node of Ranvier. Na currents were decreased by tetrodotoxin (TTX) or increased by beta-pompilidotoxin (beta-PMTX). Dual somatic and axonal recordings indicated that spike thresholds and input-output curves were sensitive to TTX or beta-PMTX at the perisomatic region but were unchanged by either drug at the first node. When perisomatic Na channel availability was reduced with subsaturating TTX, however, the input-output curve became shallower during additional TTX block of nodal channels, revealing a latent role for nodal Na channels in facilitating firing. In perisomatic TTX, axons failed to generate spontaneous or evoked spike trains. In contrast, choline block of the initial segment alone altered normal input-output curves. The data suggest that, although the first node reliably follows action potentials, spike initiation in Purkinje neurons occurs in the initial segment. Moreover, Purkinje cell output depends on the density, availability, and kinetics of perisomatic Na channels, a characteristic that may distinguish spontaneously firing from quiescent neurons.

Site of Action Potential Initiation in Layer 5 Pyramidal Neurons

Fundamental to an understanding of how neurons integrate synaptic input is the knowledge of where within a neuron this information is converted into an output signal, the action potential. Although it has been known for some time that action potential initiation occurs within the axon of neurons, the precise location has remained elusive. Here, we provide direct evidence using voltage-sensitive dyes that the site of action potential initiation in cortical layer 5 pyramidal neurons is approximately 35 microm from the axon hillock. This was the case during action potential generation under a variety of conditions, after axonal inhibition, and at different stages of development. Once initiated action potentials propagated down the axon in a saltatory manner. Experiments using local application of low-sodium solution and TTX, as well as an investigation of the influence of axonal length on action potential properties, provided evidence that the initial 40 microm of the axon is essential for action potential generation. To morphologically identify the relationship between the site of action potential initiation and axonal myelination, we labeled oligodendrocytes supplying processes to the proximal region of the axon. These experiments indicated that the axon initial segment was approximately 40 mcirom in length, and the first node of Ranvier was approximately 90 microm from the axon hillock. Experiments targeting the first node of Ranvier suggested it was not involved in action potential initiation. In conclusion, these results indicate that, in layer 5 pyramidal neurons, action potentials are generated in the distal region of the axon initial segment.

The site of action potential initiation in cerebellar Purkinje neurons

Knowledge of the site of action potential initiation is essential for understanding how synaptic input is converted into neuronal output. Previous studies have shown that the lowest-threshold site for initiation of action potentials is in the axon. Here we use recordings from visualized rat cerebellar Purkinje cell axons to localize the site of initiation to a well-defined anatomical structure: the first node of Ranvier, which normally forms at the first axonal branch point.

Reflections on the carotid nerve sensory discharge and coupling between glomus cells.

In most sensory receptors of vertebrates, the action potentials of myelinated fibers originate from the first node of Ranvier, closest to the nerve terminals (Loewenstein & Rathkamp, 1958). The spike origin is not established in receptors innervated by unmyelinated (C) fibers, but probably occurs in the fiber at some distance from the endings (Edwards & Ottoson, 1958; Ringham, 1971). The carotid body glomus cells are innervated by myelinated (A) and unmyelinated (C) fibers from the carotid nerve (Fidone & Sato, 1969), although it is not known where the action potentials originate in either type of fiber. These uncertainties are due to a large extent to the complex morphology of the carotid body innervation. A single carotid nerve fiber divides extensively to innervate up to 20 glomus cells (Eyzaguirre & Gallego, 1975; Kondo, 1976) forming what is, presumably, the sensory unit. Moreover, glomus cells may be innervated more than once by the same fiber, and some cells are innervated by more than one carotid nerve fiber (De Castro, 1940; 1951). Figure 1 is a composite drawing from De Castro’s original microscope slides examined by Eyzaguirre & Gallego (1975). Axon 1 innervates glomeruli A and C. Cells marked by dots in glomerulus A are innervated by branches from axons 1 and 2. As shown below, this complex innervation pattern has to be considered when analyzing the origin of the sensory discharge.KeywordsNerve TerminalCarotid BodyTransmitter ReleaseGlomus CellNodose GanglionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Immunocytochemical evidence for the retrograde transport of intraaxonal cathepsin D: possible relevance to the dying-back process

Immunocytochemical localization of cathepsin D was studied in rat nerves using an antibody to cathepsin D (CD). In normal or control nerves, immunoreactive CD was present in the cytoplasm of Schwann cells but not in axons. In ligated or transected nerves, intraaxonal CD appeared as granular or elongated particles increasing with time at the cut end of the distal stump. In the proximal stump of transected nerves, CD was detected in the nascent axon tips, as well as in a length of axon extending up to the first node of Ranvier. In swollen axons induced by 2, 5-hexanedione (HD), CD was associated with granular particles in areas where bidirectional organelle movement was impaired. This study represents the first documentation of intraaxonal CD and provides evidence that immunoreactive CD originates at the nerve terminal in conjunction with the anterograde-to-retrograde (A-R) conversion process of axoplasmic transport. When the A-R conversion process is induced at more proximal sites in the nerve by transection, CD can be observed. In circumstances where axoplasmic transport is impaired, such as nerves exposed to 2, 5-HD or ligated and transected nerves, CD-positive granular particles were seen in association with retrogradely moving organelles and their accumulation was related to sites of preferential axonal degeneration.

Ultrastructural findings of the macaque monkey vestibular ganglion cells.

The fine structure of macaque monkey vestibular ganglion cell was studied under the electron microscope. Over 400 serial sections enabled us to observe the entire surface of 114 ganglion cells. Eight ganglion cells were characterized by loose myelin layers. The compact myelin sheath was not demonstrated around any area of the perikaryon in these eight cells. The rest of the cells exhibited both compact and loose myelin layers around one perikaryon. All ganglion cells were bipolar in this study. The initial dendritic process was generally thinner and shorter than the initial axonal process. Both compact and loose myelin sheaths were demonstrated around the initial axonal and dendritic segment as far as the first node of Ranvier, after which all processes became thickly myelinated. This study demonstrated two types of cells: myelinated and unmyelinated. However, there is no obvious size or histological difference between the perikarya of different types of ganglion cells.

Ultrastructural Findings of the Macaque Monkey Vestibular Ganglion Cells

The fine structure of the macaque monkey vestibular ganglion cell was studied under the electron microscope. Over 400 serial sections enabled us to observe the entire surface of 114 ganglion cells. Eight ganglion cells were characterized by loose myelin layers. The compact myelin sheath was not demonstrated around any area of the perikaryon in these eight cells. The rest of the cells exhibited both compact and loose myelin layers around one perikaryon. All ganglion cells were bipolar in this study. The initial dendritic process was generally thinner and shorter than the initial axonal process. Both compact and loose myelin sheaths were demonstrated around the initial axonal and dendritic segment as far as the first node of Ranvier, after which all processes became thickly myelinated. This study demonstrated two types of cells: myelinated and unmyelinated. However, there is no obvious size or histological difference between the perikarya of different types of ganglion cells.

Latency of gustatory neural impulses initiated in frog tongue

Latencies of gustatory neural impulses evoked by stimulation of the bullfrog tongue with the 4 basic taste substances (NaCl, acetic acid, quinine-HCl (Q-HCl), sucrose), CaCl 2 and water were studied by recording antidromic impulses conducted to the fungiform papillae. Mean latencies of the impulses ranged from 58 to 107 ms when very strong stimuli, such as 2 M NaCl, 0.1 M acetic acid, 0.1 M Q-HCl, 2 M sucrose and 1 M CaCl 2, were applied. Mean latency in response to water was 2.41 s. The time required for arrival of an applied taste stimulus on the taste receptor membrane was a mean of 20.1 ms. The time required for antidromic conduction from the impulse initiation site to the recording site was a mean of 2.4 ms. Electrical stimulation of the fungiform papilla with a strong intensity produced the impulse with a long and fluctuating latency. The mean minimum latency of the fluctuating impulse, from which the conduction time was substracted, was 5.3 ms. Mechanical destruction of the taste disk situated at the top of the fungiform papilla resulted in a disappearance of the fluctuating impulse, suggesting that this was initiated synaptically via a depolarization of taste cells by electrical current. The minimum 5.3-ms latency was likely to be the time required from the onset of taste cell depolarization to the initiation of an impulse at the first node of Ranvier of myelinated gustatory fiber. These results indicate that the latencies of 58–107 ms by strong taste stimulation were composed of the 30- to 79-ms latency of taste cell receptor potential and the remaining 28 ms latency, which was the sum of the time of the stimulant diffusion, the time from taste cell depolarization to the first impulse and the time of impulse conduction.

Morphometry and ultrastructure of the squirrel monkey (Saimiri sciureus) vestibular nerve.

Vestibular nerves of squirrel monkeys (Saimiri sciureus) embedded in plastics and epoxies were examined with light microscopy (LM) and transmission electron microscopy (TEM), and computerized measures were obtained and analyzed statistically. An average of 12,412 perikarya and 12,005 myelinated nerve fibers was obtained. Approximately 0.7% of the perikarya appeared unmyelinated under LM. About 500 unmyelinated fibers were counted. The cross-sectional area of 1,864 perikarya was 200-650 micron 2. The cross-sectional area of 1,346 nerve fibers was 3-11 micron 2 for the axoplasm and 11-12 micron 2 for the myelin sheath of the same fiber. Myelin thickness was directly proportional to the axoplasm cross-sectional area of the nerve fibers. The cross-sectional area of central axons and peripheral dendrites differed significantly (p less than 0.001). The initial segments of peripheral dendrites were usually smaller, but longer than the initial segments of the central axons. Both initial segments increased in diameter after the first node of Ranvier. Schmidt-Lantermann incisures were more abundant in thick and heavily myelinated fibers than in thin and lightly myelinated fibers. Larger perikarya usually had larger fibers and vice versa, within the first 100-200 micron from the first node of Ranvier. No major ultrastructural differences were found between myelinated and unmyelinated perikarya, except at the hillock region. The Nissl substance was preferentially located in the peripheral cytoplasm.

Initiation site of gustatory neural impulse in frog tongue.

The taste organ in the frog tongue is situated at the summit of the fungiform papilla. Morphologically, the frog taste organ is usually called the taste disk rather than taste bud. It comprises many taste cells which respond to various taste stimuli with depolarizing receptor potentials. There are many axon terminals at the base of the taste cell layer in the frog, and it has been found that there exists a chemical synapse between a frog taste cell and a gustatory axon terminal. It is considered that a depolarizing receptor potential in a taste cell elicited by a taste stimulus may release a transmitter from the cell, and then the postsynaptic potential in the axon terminal membrane evoked by the transmitter may trigger an initiation of gustatory neural impulses.Although it has been supposed that gustatory neural impulses may be initiated at the first node of Ranvier on the gustatory nerve fiber, obvious evidence has not been obtained until recently. In order to clarify the initiation site of gustatory neural impulse, it is important to examine the course of single gustatory nerve fibers within the fungiform papilla as giving attention to the spatial position of nodes of Ranvier.The purpose of the present experiment was to examine histologically the sensory innervation of the frog taste disk and to determine electrophysiologically the initiation site of gustatory neural impulses.