Poster session and reception
Tuesday, February 13, 2018 - 4:00pm - 5:30pm
- The Elusive Channel Driving Ischemic Spreading Depolarization
R. David Andrew (Queen's University)
Our brain`s immediate response to lost blood flow caused by trauma, stroke or cardiac arrest is a spreading depolarization (SD) which acutely injures neurons within minutes. SD can then recur over many hours, expanding brain injury. SD evoked by oxygen/glucose deprivation (OGD) involves a profound inward current, but the conducting channel(s) remains unidentified. In our experiments, the usual suspected channel candidates are blocked with a mix of antagonists yet SD persists. So there is a channel(s) mediating the SD current that has eluded previous investigation. The Na+/K+ ATPase is the transporter whose failure during ischemia evokes SD. Nanomolar amounts of the marine poison palytoxin (PLTX) specifically converts this pump into an open channel that drives an SD-like event that we routinely imaged in live neocortical slices. We hypothesize that in a PLTX fashion, ischemia converts the Na+/K+ pump into an open channel that drives SD initiation and propagation. The gold standard for characterizing a channel`s properties is membrane patch recording. We use cell-attached and outside-out patch configurations taken from adult rat pyramidal neurons to demonstrate that a similar channel is opened by PLTX or by OGD during pharmacological blockade of glutamate receptors, sodium channels, and several other channel candidates. Channel opening frequency increases during OGD and slows with return to regular saline. Understanding the basis of SD generation will lead to more accurate modeling of SD, as well as reveal new pharmacological targets for reducing ischemic injury to the higher brain.
- waveCSD: A method for estimating transmembrane currents originated from propagating neuronal activity in the neocortex: Application to study cortical spreading depression
Arash Moshkforoush (Florida International University)
Recent years have witnessed an upsurge in the development of methods for estimating current source densities (CSDs) in the neocortical tissue from their recorded local filed potential (LFP) reflections using microelectrode arrays. Among these, methods utilizing linear arrays work under the assumption that CSDs vary as a function of cortical depth; whereas they are constant in the tangential direction, infinitely or in a confined cylinder. This assumption is violated in the analysis of propagating neuronal activation propagates along the neocortical sheet, e.g. propagation of alpha waves or cortical spreading depression associated with migraine aura. In this study, we have developed a novel mathematical method (waveCSD) for CSD analysis of LFPs associated with a planar wave of neocortical neuronal activity propagating at a constant velocity towards a linear probe. Results show that the algorithm is robust to the presence of noise in LFP data and uncertainties in knowledge of propagation velocity. Also, results show high level of accuracy of the method in a wide range of electrode resolutions. Simulations indicate that waveCSD method has a significantly higher reconstruction accuracy compared to the widely-used inverse CSD method (iCSD) in the analysis of CSDs originating from propagation of neuronal activity. Using in vivo experimental recordings from the rat neocortex, we employed the waveCSD method to characterize, for the first time, the transmembrane currents associated with cortical spreading depressions. Co-authors: Pedro A. Valdes-Hernandez, Daniel E. Rivera, Yoichiro Mori, Jorge Riera.
- Revisiting CSD Propagation Characteristics with Microelectrode Arrays: From Field Potentials to Spiking
Daniel Rivera (Florida International University)
Cortical spreading depression (CSD) is a wave of neuronal depolarization that leads to a silencing of spontaneous neuronal activity. Mechanisms underlying CSD genesis/propagation, yet to be fully understood, have been investigated using two electrophysiological recording techniques: I) intracranial potentials with isolated electrodes, and II) membrane potentials with whole-cell/patch approaches. Technological advances in intracranial recording with microelectrode arrays (MEA), however, have still not been used for the analysis of CSD events in vivo. In this study, we used Wistar rats anesthetized by the administration of a mixture of isoflurane and pure oxygen, and obtained CSD-related intracranial potentials from the neocortex of Wistar rats using high-resolution linear/planar MEAs. Firstly, we confirmed the existence of facilitation/adaptation mechanisms in the CSD propagation. Secondly, we found a cortical-depth dependency in the propagation velocity of the CSD. Lastly, laminar spiking in different neuronal populations (i.e., interneurons and pyramidal cells) suggests a short-term (~1 minute) sequencing profile in the neuronal silencing. We conclude that MEAs offer a unique framework for characterization of spatiotemporal profiles of neuronal depolarization in vivo, relevant network connections, and associated differences in putative neuronal firing rates during CSD. Co-authors: Arash Moshkforoush, Darlene Ramos, Yoichiro Mori, Jorge Riera.
- Modeling electrodiffusion in the extracellular space around a morphologically detailed neuron
Andreas Våvang Solbrå (University of Oslo)
Many pathological conditions are linked to abnormal extracellular ion concentrations in the brain. Among these is cortical spreading depression, a phenomenon characterized by a wave of neural hyperactivity, followed by a prolonged period of inhibition. In order to investigate the role of ion-concentration dynamics in such pathological conditions, one must in principle measure the spatial distribution of all ion concentrations over time. This remains challenging experimentally, which makes computational modeling an attractive tool. We have previously introduced the Kirchoff-Nernst-Planck framework, an efficient framework for modeling electrodiffusion. In this study, we introduce a 3-dimensional version of this framework, and use it to model the electrodiffusion of ions surrounding a morphologically detailed neuron. The simulation covered a 1 cubic millimeter cylinder of tissue for over a minute, and was performed in less than a day on a standard desktop computer, demonstrating the frameworks efficiency.
- Electric field confinement and control of spreading depression
Andrew Whalen (The Pennsylvania State University)
Spreading depression or depolarization is a large-scale pathological brain phenomenon related to migraine, stroke, hemorrhage and traumatic brain injury. Once initiated, spreading depression propagates across gray matter extruding potassium and other active molecules, collapsing the resting membrane electro-chemical gradient of cells leading to spike inactivation and cellular swelling, and propagates independently of synaptic transmission. Here we present the suppression and confinement of spreading depression utilizing externally applied transcortical DC electric fields and simultaneous epifluorescence and intrinsic optical imaging in brain slices. We experimentally observe the electric field induced forcing of spreading depression propagation to locations in cortex deeper than the unmodulated propagation path, whereby further propagation is confined and arrested even after field termination. Our experiments also show that the opposite electric field polarity will produce an increase in propagation velocity and a confinement of the wave to the more superficial layers of cortex than the unmodulated propagation path. These field polarities are of opposite sign to the polarity that blocks neuronal spiking and seizures, and are consistent with biophysical models of spreading depression. The results could guide the design of new medical devices targeting sufferers of migraine headaches with a non-invasive and localized enabled method of treatment.
- Expanding the NEURON simulation platform for multiscale modeling
William Lytton (SUNY Downstate Medical Center)
- Towards modelling of the role of glial cells in cerebral interstitial fluid movement
Ada Johanne Ellingsrud (Simula Research Laboratory)
Within the endfoot barrier of astrocytes near the perivascular spaces surrounding the blood vessels, there is a high concentration of the channel membrane protein aquaporin-4. The AQP4 proteins form structures in the astrocytic membranes allowing for highly efficient water transport, and play an important role in mechanisms underlying volume and water homeostasis in the brain. The water transport through AQP4 is driven by osmotic pressure gradients, primarily regulated by movement of ions in the brain tissue. However, our current understanding of these mechanics is far from complete. Several researches have proposed electrodiffusive frameworks for modelling glial membrane dynamics and ion transport. Existing models that additionally address mechanical variables such as microscopic fluid flow and hydrostatic pressure are not well explored numerically, leaving modelling of water glial dynamics and their role in interstitial fluid flow largely open. We aim to design and analyze numerical schemes for electrodiffusive models connecting mechanical and electrochemical variables at cellular level. Furthermore, we will apply the schemes to study the effect of astrocytic water dynamics in flow and transport of metabolic waste within the parenchyma.