Speed Of Action Potential Propagation Research Articles

Secretome analysis of oligodendrocytes and precursors reveals their roles as contributors to the extracellular matrix and potential regulators of inflammation.

Oligodendrocytes form myelin that ensheaths axons and accelerates the speed of action potential propagation. Oligodendrocyte progenitor cells (OPCs) proliferate and replenish oligodendrocytes. While the myelin-forming role of oligodendrocytes and OPCs is well-established, potential additional roles of these cells are yet to be fully explored. Here, we analyzed the secreted proteome of oligodendrocytes and OPCs in vitro to determine whether these cell types are major sources of secreted proteins in the central nervous system (CNS). Interestingly, we found that both oligodendrocytes and OPCs secret various extracellular matrix proteins. Considering the critical role of neuroinflammation in neurological disorders, we evaluated the responses and potential contributions of oligodendrocytes and OPCs to this process. By characterizing the secreted proteomes of these cells after pro-inflammatory cytokine treatment, we discovered the secretion of immunoregulators such as C2 and B2m. This finding sheds new light on the hitherto underappreciated role of oligodendrocytes and OPCs in actively modulating neuroinflammation. Our study provides a comprehensive and unbiased proteomic dataset of proteins secreted by oligodendrocyte and OPC under both physiological and inflammatory conditions. It revealed the potential of these cells to secrete matrix and signaling molecules, highlighting their multifaceted function beyond their conventional myelin-forming roles.

Propagation speeds of action potentials in the human retina compensate for traveling distances

Propagation speeds of action potentials in the human retina compensate for traveling distances

3-photon fluorescence and third-harmonic generation imaging of myelin sheaths in mouse digital skin in vivo: A comparative study

Myelin sheaths wrapping axons are key structures that help maintain the propagation speed of action potentials in both central and peripheral nervous systems (CNS and PNS). However, noninvasive, deep imaging technologies visualizing myelin sheaths in the digital skin in vivo are lacking in animal models. 3-photon fluorescence (3PF) imaging excited at the 1700-nm window enables deep imaging of myelin sheaths, but necessitates labeling by exogenous fluorescent dyes. Since myelin sheaths are lipid-rich structures which generate strong third-harmonic signals, in this paper, we perform a detailed comparative experimental study of both third-harmonic generation (THG) and 3PF imaging in the mouse digital skin in vivo. Our results show that THG imaging also enables visualization of myelin sheaths deep in the mouse digital skin, which shows colocalization with 3PF signals from labeled myelin sheaths. Besides its superior label-free advantage, THG does not suffer from photobleaching due to its 3PF property.

Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed.

Print Page SummaryIntroductionAstrocytes support neuronal function throughout the central nervous system. In the grey matter they regulate synapse number during development, remove synaptically-released neurotransmitters to terminate their action and prevent excitotoxicity, control the extracellular potassium concentration to prevent hyperexcitability, regulate blood flow to ensure an adequate energy supply, provide lactate to neurons for energy, and respond to rises of intracellular calcium concentration ([Ca2+]i) by releasing ATP and other gliotransmitters that act on neuronal receptors to modulate information processing. However, their role is unclear in the white matter, which transmits information rapidly between grey matter areas using axons wrapped with capacitance-reducing myelin, although they have been suggested to regulate myelination during development and during normal function.RationaleRecently it has been suggested that learning and memory may reflect, not only changes of synaptic function in the grey matter, but also changes of white matter function. In particular, neural circuit function might be regulated by changes in the conduction speed of myelinated axons that result in an altered arrival time of action potentials at a distant neuron. These speed changes might be brought about by alterations of the properties of the passively conducting myelinated internodes, or of the intervening excitable nodes of Ranvier where the action potential is generated. We applied immunohistochemistry to assess how astrocytes interact with myelinated axons, used neuronal stimulation and light evoked calcium uncaging in astrocytes to evoke Ca2+-dependent release of gliotransmitters, and employed electrophysiology and pharmacology to characterise how astrocyte-released substances might affect the axon initial segment (AIS) and nodes of Ranvier of myelinated neurons. Measurements of conduction velocity and computer modelling allowed us to interpret the results.ResultsAstrocytes closely approach the axons of myelinated neurons in layer V of the cerebral cortex. Uncaging Ca2+ within astrocytes, or stimulating spike trains in neurons, evoked a rise of astrocyte [Ca2+]i that triggered the release of ATP-containing vesicles from these cells. This evoked an inward current in the AIS and nodes of Ranvier of the pyramidal neurons. Pharmacology showed that this was mediated by the activation of Gs-linked adenosine A2a receptors, implying that the released ATP was converted to adenosine by extracellular enzymes. The A2a receptors raise the intracellular concentration of cyclic AMP, which activates HCN channels mediating the inward hyperpolarization-activated current Ih, and thus depolarizes the cell. In the AIS the activation of A2a receptors alters excitability and hence action potential generation, while in the nodes of Ranvier it decreases the conduction speed of the action potential along the axon.ConclusionAs in the grey matter, astrocyte [Ca2+]i regulates the release of ATP into the extracellular space in the white matter. After conversion to adenosine, this regulates the excitability and conduction speed of myelinated axons. The changes in excitability at the AIS will lead to changes in the relationship between the synaptic input and action potential output of the cell. The altered conduction speed of the myelinated axon may change neural circuit function by changing the action potential arrival time at the cell’s output synapses, thus altering the integration of signals in postsynaptic neurons. Variations in astrocyte-derived adenosine level can occur between wake and sleep states, and the extracellular adenosine concentration rises during energy deprivation conditions. These changes of adenosine level could thus control white matter information flow and neural circuit function.Astrocytes regulate myelinated axon excitability and conduction speed.For cortical neurons with myelinated axons crossing the corpus callosum (left), astrocytes regulate axon initial segment (AIS) excitability and axonal conduction speed (middle). Increases of astrocyte [Ca2+]i release ATP which, after conversion to adenosine (Ado) extracellularly, activates A2a receptors that raise the intracellular cyclic AMP concentration, and thus generate an inward current via HCN2 channels in the AIS and nodes of Ranvier (right). Created with BioRender.com.In the brain’s grey matter, astrocytes regulate synapse properties, but their role is unclear for the white matter where myelinated axons rapidly transmit information between grey matter areas. We found that, in rodents, neuronal activity raised [Ca2+]i in astrocyte processes located near action potential generating sites in the axon initial segment (AIS) and nodes of Ranvier of myelinated axons. This released ATP which was converted extracellularly to adenosine and thus, via A2a receptors, activated HCN2-containing cation channels that regulate two aspects of myelinated axon function: excitability of the AIS and speed of action potential propagation. Variations in astrocyte-derived adenosine level, between wake and sleep states or during energy deprivation, could thus control white matter information flow and neural circuit function.

Conduction Velocity Along the Local Axons of Parvalbumin Interneurons Correlates With the Degree of Axonal Myelination.

Parvalbumin-containing (PV+) basket cells in mammalian neocortex are fast-spiking interneurons that regulate the activity of local neuronal circuits in multiple ways. Even though PV+ basket cells are locally projecting interneurons, their axons are myelinated. Can this myelination contribute in any significant way to the speed of action potential propagation along such short axons? We used dual whole cell recordings of synaptically connected PV+ interneurons and their postsynaptic target in acutely prepared neocortical slices from adult mice to measure the amplitude and latency of single presynaptic action potential-evoked inhibitory postsynaptic currents. These same neurons were then imaged with immunofluorescent array tomography, the synapses between them identified and a precise map of the connections was generated, with the exact axonal length and extent of myelin coverage. Our results support that myelination of PV+ basket cells significantly increases conduction velocity, and does so to a degree that can be physiologically relevant.

Genetic Variation in CNS Myelination and Functional Brain Connectivity in Recombinant Inbred Mice

Myelination greatly increases the speed of action potential propagation of neurons, thereby enhancing the efficacy of inter-neuronal communication and hence, potentially, optimizing the brain’s signal processing capability. The impact of genetic variation on the extent of axonal myelination and its consequences for brain functioning remain to be determined. Here we investigated this question using a genetic reference panel (GRP) of mouse BXD recombinant inbred (RI) strains, which partly model genetic diversity as observed in human populations, and which show substantial genetic differences in a variety of behaviors, including learning, memory and anxiety. We found coherent differences in the expression of myelin genes in brain tissue of RI strains of the BXD panel, with the largest differences in the hippocampus. The parental C57BL/6J (C57) and DBA/2J (DBA) strains were on opposite ends of the expression spectrum, with C57 showing higher myelin transcript expression compared with DBA. Our experiments showed accompanying differences between C57 and DBA in myelin protein composition, total myelin content, and white matter conduction velocity. Finally, the hippocampal myelin gene expression of the BXD strains correlated significantly with behavioral traits involving anxiety and/or activity. Taken together, our data indicate that genetic variation in myelin gene expression translates to differences observed in myelination, axonal conduction speed, and possibly in anxiety/activity related behaviors.

Differential development of myelin in zebra finch song nuclei.

Songbirds learn vocalizations by hearing and practicing songs. As song develops, the tempo becomes faster and more precise. In the songbird brain, discrete nuclei form interconnected myelinated circuits that control song acquisition and production. The myelin sheath increases the speed of action potential propagation by insulating the axons of neurons and by reducing membrane capacitance. As the brain develops, myelin increases in density, but the time course of myelin development across discrete song nuclei has not been systematically studied in a quantitative fashion. We tested the hypothesis that myelination develops differentially across time and song nuclei. We examined myelin development in the brains of the zebra finch (Taeniopygia guttata) from chick at posthatch day (d) 8 to adult (up to 147 d) in five major song nuclei: HVC (proper name), robust nucleus of the arcopallium (RA), Area X, lateral magnocellular nucleus of the anterior nidopallium, and medial portion of the dorsolateral thalamic nucleus (DLM). All of these nuclei showed an increase in the density of myelination during development but at different rates and to different final degrees. Exponential curve fits revealed that DLM showed earlier myelination than other nuclei, and HVC showed the slowest myelination of song nuclei. Together, these data show differential maturation of myelination in different portions of the song system. Such differential maturation would be well placed to play a role in regulating the development of learned song.

On time and space in the brain: A relativistic pseudo-diffusion framework

Considering that the propagation speed of action potentials in the brain connectome has a finite limit and that present is ill-defined in the brain we apply concepts borrowed from the theories of special and general relativity to introduce the view that time and space are tightly blended in the brain. It is shown that the brain functional and structural features can be unified through a combined brain “spacetime”. This 4-dimensional brain spacetime presents a functional curvature generated by brain activity, in a similar way gravitational masses give our 4-dimensional Universe spacetime its curvature. After laying its foundations and developing this framework using a relativistic pseudo-diffusion model of neural propagation, we explore how this whole-brain framework may shed light on brain functional features and dysfunction phenotypes (clinical expression of diseases) observed in some neuropsychiatric and consciousness disorders. Statement of SignificanceBecause action potentials in the brain connectome propagate with a finite velocity limit, simultaneity across brain nodes is only relative. A new concept is emerging where time and space in the brain, as in the Universe, are tightly mingled through a combined “spacetime”. This 4-dimensional spacetime merging brain structure and function presents a curvature generated by brain activity, in a similar way gravitational masses give our Universe spacetime its curvature, driving activity flow within the brain.

Intramuscular fibre conduction velocity and muscle fascicle length in human vastus lateralis.

Muscle fascicle length and muscle fibre conduction velocity (MFCV) are thought to be important parameters for power performance. It might be expected that faster muscle fibre conduction velocities would compensate for longer fascicle lengths to increase the speed of action potential propagation along the elongated fibres. However, the relationship between muscle fascicle length and MFCV remains unknown. The aim of the present study was to explore the relationship between average vastus lateralis MFCV and average fascicle length. In 17 moderately trained, healthy, male, physical education students (age, 23.4 ± 3.1 years; body height, 178 ± 5.5 cm; body mass, 82.7 ± 6.9 kg; body mass index, 24.6 ± 1.5 kg·m-2) resting MFCV was measured with intramuscular microelectrodes while muscle architecture was evaluated with ultrasonography. Fascicle length was highly correlated with total MFCV (r = 0.923, p = 0.000), maximum MFCV (r = 0.949, p = 0.000), and MFCV of the fastest (r = 0.709, p = 0.001), but not of the slowest fibres (r = 0.131, p = 0.616). No significant correlations were also found between vastus lateralis thickness or fascicle angle with any of MFCV parameters (r = 0.145-0.430; R2 < 0.130; p > 0.05). These data indicate that average MFCV is associated with average fascicle length in vastus lateralis muscle in different individuals. It seems that participants with longer fascicle lengths have also higher MFCVs.

Robust stabilization of delayed neural fields with partial measurement and actuation

Neural fields are integro-differential equations describing spatiotemporal activity of neuronal populations. When considering finite propagation speed of action potentials, neural fields are affected by space-dependent delays. In this paper, we provide conditions under which such dynamics can be robustly stabilized by a proportional feedback acting only on a portion of the neuronal population and by relying on measurements of this subpopulation only. To that aim, in line with recent works, we extend the concept of input-to-state stability (ISS) to generic nonlinear delayed spatiotemporal dynamics and provide a small-gain result relying on Lyapunov–Krasovskii functionals. Exploiting the robustness properties induced by ISS, we provide conditions under which a uniform control signal can be used for the whole controlled subpopulation and we analyze the robustness of the proposed strategy to measurement and actuation delays. These theoretical findings are compared to simulation results in a model of pathological oscillations generation in Parkinson’s disease.

Modelling in vivo action potential propagation along a giant axon

A partial differential equation model for the three-dimensional current flow in an excitable, unmyelinated axon is considered. Where the axon radius is significantly below a critical value R(crit) (that depends upon intra- and extra-cellular conductivity and ion channel conductance) the resistance of the intracellular space is significantly higher than that of the extracellular space, such that the potential outside the axon is uniformly small whilst the intracellular potential is approximated by the transmembrane potential. In turn, since the current flow is predominantly axial, it can be shown that the transmembrane potential is approximated by a solution to the one-dimensional cable equation. It is noted that the radius of the squid giant axon, investigated by (Hodgkin and Huxley 1952e), lies close to R(crit). This motivates us to apply the three-dimensional model to the squid giant axon and compare the results thus found to those obtained using the cable equation. In the context of the in vitro experiments conducted in (Hodgkin and Huxley 1952e) we find only a small difference between the wave profiles determined using these two different approaches and little difference between the speeds of action potential propagation predicted. This suggests that the cable equation approximation is accurate in this scenario. However when applied to the it in vivo setting, in which the conductivity of the surrounding tissue is considerably lower than that of the axoplasm, there are marked differences in both wave profile and speed of action potential propagation calculated using the two approaches. In particular, the cable equation significantly over predicts the increase in the velocity of propagation as axon radius increases. The consequences of these results are discussed in terms of the evolutionary costs associated with increasing the speed of action potential propagation by increasing axon radius.

Signaling through ERK1/2 Controls Myelin Thickness during Myelin Repair in the Adult Central Nervous System

Oligodendrocytes, the myelin-forming cells of the CNS, exquisitely tailor the thickness of individual myelin sheaths to the diameter of their target axons to maximize the speed of action potential propagation, thus ensuring proper neuronal connectivity and function. Following demyelinating injuries to the adult CNS, newly formed oligodendrocytes frequently generate new myelin sheaths. Following episodes of demyelination such as those that occur in patients with multiple sclerosis, however, the matching of myelin thickness to axon diameter fails leaving remyelinated axons with thin myelin sheaths potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes determine the appropriate thickness of myelin for an axon of defined size during repair is unknown and identifying the signals that regulate myelin thickness has obvious therapeutic implications. Here, we show that sustained activation of extracellular-regulated kinases 1 and 2 (ERK1/2) in oligodendrocyte lineage cells results in accelerated myelin repair after injury, and is sufficient for the generation of thick myelin sheaths around remyelinated axons in the adult mouse spinal cord. Our findings suggest a model where ERK1/2 MAP kinase signaling acts as a myelin thickness rheostat that instructs oligodendrocytes to generate axon-appropriate quantities of myelin.

Effect of clustered ion channels along an unmyelinated axon

In most unmyelinated axons, ion channels are distributed uniformly along the axon to facilitate stable propagation of action potentials. In this case, the conduction in the axon is continuous, and the excitability along the membrane is constant. Some experimental papers show that ion channels also locate in clusters in some unmyelinated axons. In this paper, we investigate theoretically the effect of clustered ion channels along unmyelinated axon. We mainly focused on two aspects: the propagation efficiency and the propagation speed. Our results show that localization of potassium ion channels is beneficial for increasing propagation efficiency and propagation speed of action potentials; however, localization of sodium ion channels is advantageous to the propagation efficiency only when axonal parameters are in a specific range.

Simulation analysis of intermodal sodium channel function

Although most sodium ion channels clustered in nodes of Ranvier provide the physiological basis for saltatory conduction, sodium ion channels cannot be excluded from internodal regions completely. The density of internodal sodium ion channels is of the order of 10/microm2. The function of internodal sodium ion channels has been neglected for a long time; however, experimental and theoretical results show that internodal sodium ion channels play an important role in action potential propagation. In this paper, based on the compartment model, we investigate the function of internodal sodium ion channels. We find that internodal sodium ion channels can promote action potential propagation, enlarge the maximal internodal distance guaranteeing stable action potential propagation, and increase the propagation speed of action potentials. In this paper, we find an optimal conductance of internodal sodium ion channels (4-5 mS/cm2), which accords with the active internodal sodium ion conductance in a real myelinated axon. With the optimal conductance, the average sodium ion channel conductance of the axon is minimal, and the metabolic energy consumption due to ion channels is also minimal.

Solitary waves in soybean induced by localized thermal stress

Action potentials in higher plants are believed to be the information carriers in intercellular and intracellular communication in the presence of an environmental stressor. Plant electrophysiologists have recorded long distance electrical signaling in higher plants during the last two hundred years. Reproducing the duration, speed of propagation, and the shape of the action potential is challenging. Early measurements revealed that the speed of action potential propagation in plants is extremely slow – from 0.1 mm/s to 20 cm/s, although many faster plant responses to stress have been recorded as well. We hypothesized that this discrepancy is most likely due to the artifacts of aliasing from slow registration systems. In this study, we employ real time measurements using modern data acquisition techniques to detect ultra fast action potentials in green plants induced by localized heat stress. Thermal shock or heat stress is the most common environmental stress. Based on more sophisticated measuring techniques, we show that plants transmit solitary waves and that the speed of action potential propagation in green plants is similar to the speed of action potentials in mammalians, varying from a few meters per second up to 105 m/s. Possible pathways for electrical signal propagation in vascular plants are discussed.

Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport.

The COOH-terminal tail of mammalian neurofilament heavy subunit (NF-H), the largest neurofilament subunit, contains 44-51 lysine–serine–proline repeats that are nearly stoichiometrically phosphorylated after assembly into neurofilaments in axons. Phosphorylation of these repeats has been implicated in promotion of radial growth of axons, control of nearest neighbor distances between neurofilaments or from neurofilaments to other structural components in axons, and as a determinant of slow axonal transport. These roles have now been tested through analysis of mice in which the NF-H gene was replaced by one deleted in the NF-H tail. Loss of the NF-H tail and all of its phosphorylation sites does not affect the number of neurofilaments, alter the ratios of the three neurofilament subunits, or affect the number of microtubules in axons. Additionally, it does not reduce interfilament spacing of most neurofilaments, the speed of action potential propagation, or mature cross-sectional areas of large motor or sensory axons, although its absence slows the speed of acquisition of normal diameters. Most surprisingly, at least in optic nerve axons, loss of the NF-H tail does not affect the rate of transport of neurofilament subunits.

Insect-induced biolectrochemical signals in potato plants

Action potentials and resting potentials were measured in potato plants ( Solanum tuberosum L.) under different physiological conditions. External stimuli (e.g. changing temperature, wounding or exposing plant leaves or soil to certain chemical compounds) cause an action potential to be generated and change the restingpotential from the original steady state level. The amplitude, polarity and the speed of action potential propagation depend onthe type of external stimuli or stress. The kinetics and amplitude of the resting potential also change depending on the nature of the external stimuli. For example, in the presence of leaf-feeding larvae of the Colorado potato beetle ( Leptinortsa decemlineata (Say); Coleoptera; Chrysomelidae), the speed at which insect-induced action potentials moved downward through the stem was about 0.05 cm s −1. The action potentials propagated downwards from the damaged leaf along the stem. When the upper leaves of potato plants were sprayed with 0.3 ml of 1 mM aqueous solution of pentachlorophenol, the effect was almost identical to that induced by Colorado potato beetle. To our knowledge, this is the first demonstration of action potential generation in plants induced by insect damage or chemical injury.