Synaptic Currents Generated by Neuronal Acetylcholine Receptors Sensitive to α-Bungarotoxin

AbstractNicotinic acetylcholine receptors are widely distributed throughout the nervous system, but their functions remain largely unknown. One of the most abundant is a class of receptors that contains the α7 gene product, has a high relative permeability to calcium, and binds α-bungarotoxin. Here, we report that receptors sensitive to α-bungarotoxin, though concentrated in perisynaptic clusters on neurons, can generate a large amount of the synaptic current. Residual currents through other nicotinic receptors are sufficient to elicit action potentials, but with slower rise times. This demonstrates a postsynaptic response for α-bungarotoxin-sensitive receptors on neurons and suggests that the functional domain of the postsynaptic membrane is broader than previously recognized

Proposed evolutionary changes in the role of myelin

© 2013 Stiefel, Torben-Nielsen and Coggan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these termsMyelin is the multi-layered lipid sheet periodically wrapped around neuronal axons. It is most frequently found in vertebrates. Myelin allows for saltatory action potential (AP) conduction along axons. During this form of conduction, the AP travels passively along the myelin-covered part of the axon, and is recharged at the intermittent nodes of Ranvier. Thus, myelin can reduce the energy load needed and/or increase the speed of AP conduction. Myelin first evolved during the Ordovician period. We hypothesize that myelin's first role was mainly energy conservation. During the later "Mesozoic marine revolution," marine ecosystems changed toward an increase in marine predation pressure. We hypothesize that the main purpose of myelin changed from energy conservation to conduction speed increase during this Mesozoic marine revolution. To test this hypothesis, we optimized models of myelinated axons for a combination of AP conduction velocity and energy efficiency. We demonstrate that there is a trade-off between these objectives. We then compared the simulation results to empirical data and conclude that while the data are consistent with the theory, additional measurements are necessary for a complete evaluation of the proposed hypothesis.Peer reviewedFinal Published versio

A Process for Digitizing and Simulating Biologically Realistic Oligocellular Networks Demonstrated for the Neuro-Glio-Vascular Ensemble

One will not understand the brain without an integrated exploration of structure and function, these attributes being two sides of the same coin: together they form the currency of biological computation. Accordingly, biologically realistic models require the re-creation of the architecture of the cellular components in which biochemical reactions are contained. We describe here a process of reconstructing a functional oligocellular assembly that is responsible for energy supply management in the brain and creating a computational model of the associated biochemical and biophysical processes. The reactions that underwrite thought are both constrained by and take advantage of brain morphologies pertaining to neurons, astrocytes and the blood vessels that deliver oxygen, glucose and other nutrients. Each component of this neuro-glio-vasculature ensemble (NGV) carries-out delegated tasks, as the dynamics of this system provide for each cell-type its own energy requirements while including mechanisms that allow cooperative energy transfers. Our process for recreating the ultrastructure of cellular components and modeling the reactions that describe energy flow uses an amalgam of state-of the-art techniques, including digital reconstructions of electron micrographs, advanced data analysis tools, computational simulations and in silico visualization software. While we demonstrate this process with the NGV, it is equally well adapted to any cellular system for integrating multimodal cellular data in a coherent framework

Cooperativity between remote sites of ectopic spiking allows afterdischarge to be initiated and maintained at different locations

Many symptoms of nerve damage arise from ectopic spiking caused by hyperexcitability. Ectopic spiking can originate at the site of axonal damage and elsewhere within affected neurons. This raises the question of whether localized damage elicits cell-wide changes in excitability and/or if localized changes in excitability can drive abnormal spiking at remote locations. Computer modeling revealed an example of the latter involving afterdischarge (AD)--stimulus-evoked spiking that outlasts stimulation. We found that AD originating in a hyperexcitable region of axon could shift to the soma where it was maintained. This repositioning of ectopic spike initiation was independent of distance between the two sites but relied on the rate and number of ectopic spikes originating from the first site. Nonlinear dynamical analysis of a reduced model demonstrated that properties which rendered the axonal site prone to initiating AD discouraged it from maintaining AD, whereas the soma had the inverse properties thus enabling the two sites to interact cooperatively. A first phase of AD originating in the axon could, by providing sufficient drive to trigger somatic AD, give way to a second phase of AD originating in the soma such that spiking continued when axonal AD failed. Ectopic spikes originating from the soma during phase 2 AD propagated successfully through the defunct site of axonal spike initiation. This novel mechanism whereby ectopic spiking at one site facilitates ectopic spiking at another site is likely to contribute to the chronification of hyperexcitability in conditions such as neuropathic pain

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-gliavasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging

Excitation states of metabolic networks predict dose-response fingerprinting and ligand pulse phase signalling

With a computational model of energy metabolism in an astrocyte, we show how a system of enzymes in a cascade can act as a functional unit of interdependent reactions, rather than merely a series of independent reactions. These systems may exist in multiple states, depending on the level of stimulation, and the effects of substrates at any point will depend on those states. Response trajectories of metabolites downstream from cAMP-stimulated glycogenolysis exhibit a host of non-linear dynamical response characteristics including hysteresis and response envelopes. Dose-dependent phase transitions predict a novel intracellular signalling mechanism and suggest a theoretical framework that could be relevant to single cell information processing, drug discovery or synthetic biology. Ligands may produce unique dose-response fingerprints depending on the state of the system, allowing selective output tuning. We conclude with the observation that state- and dose-dependent phase transitions, what we dub "ligand pulses" (LPs), may carry information and resemble action potentials (APs) generated from excitatory postsynaptic potentials. In our model, the relevant information from a cAMP-dependent glycolytic cascade in astrocytes could reflect the level of neuromodulatory input that signals an energy demand threshold. We propose that both APs and LPs represent specialized cases of molecular phase signalling with a common evolutionary root. (C) 2019 The Authors. Published by Elsevier Ltd