Mechanisms of lateral-inhibitory feedback from horizontal cells to cone photoreceptors at the first synapse of the retina

Polarization of the horizontal cell (HC) membrane potential causes changes in the synaptic cleft pH that result in inhibitory feedback from HCs to cone photoreceptors (PRs). HCs average signals from many PRs and so negative feedback onto PR terminals from HCs subtracts the average luminance of the visual scene from the light responses of an individual cone. This feedback operates by changing the voltage-dependence and amplitude of the L-type Ca2+ current (ICa) that regulates synaptic release. Feedback regulation of PR Ca2+ channels involves protons but the mechanism by which this pH change occurs is unclear. We investigated three possible sources for protons in the cone synaptic cleft: 1) extracellular carbonic anhydrase (CA), 2) protons released into the cleft upon exocytosis of synaptic vesicles, and 3) sodium-hydrogen exchangers (NHEs). Using electrophysiological measurements of HC to cone feedback, we found that CA and vesicular protons are not major sources of protons for feedback. Feedback was eliminated by removal of extracellular Na+ and significantly inhibited by an NHE antagonist, cariporide, implicating NHEs as a significant source of protons. While NHEs are a major proton source, they are not known to be voltage-sensitive and thus unlikely to be responsible for changes in extracellular proton levels caused by changes in HC membrane potential. Instead we found that removal of bicarbonate and inhibition of bicarbonate transporters with 500 μM DIDS both eliminated feedback, suggesting that HC polarization changes extracellular pH by altering bicarbonate transport. To test whether an ephaptic mechanism is involved in mediating feedback, we used paired whole cell recordings to hyperpolarize the HC while cone ICa was active and then measured the kinetics of feedback-induced changes in the cone membrane current. The time constants of the resulting feedback current were slower than the measurement time resolution and not instantaneous as predicted by an ephaptic mechanism

Cytoelectric coupling: Electric fields sculpt neural activity and "tune" the brain's infrastructure

We propose and present converging evidence for the Cytoelectric Coupling Hypothesis: Electric fields generated by neurons are causal down to the level of the cytoskeleton. This could be achieved via electrodiffusion and mechanotransduction and exchanges between electrical, potential and chemical energy. Ephaptic coupling organizes neural activity, forming neural ensembles at the macroscale level. This information propagates to the neuron level, affecting spiking, and down to molecular level to stabilize the cytoskeleton, "tuning" it to process information more efficiently

Electrodiffusion Phenomena in Neuroscience and the Nernst–Planck–Poisson Equations

This work is aimed to give an electrochemical insight into the ionic transport phenomena in the cellular environment of organized brain tissue. The Nernst–Planck–Poisson (NPP) model is presented, and its applications in the description of electrodiffusion phenomena relevant in nanoscale neurophysiology are reviewed. These phenomena include: the signal propagation in neurons, the liquid junction potential in extracellular space, electrochemical transport in ion channels, the electrical potential distortions invisible to patch-clamp technique, and calcium transport through mitochondrial membrane. The limitations, as well as the extensions of the NPP model that allow us to overcome these limitations, are also discussed. View Full-TextKeywords: electrodiffusion; Nernst–Planck–Poisson; neuroscience; neurons; liquid junction potential; ionic channels; patch-clamp</p

The Ca2+Ca^{2+}-activated Cl−Cl^- current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons

Activation of most primary sensory neurons results in transduction currents that are carried by cations. One notable exception is the vertebrate olfactory receptor neuron (ORN), where the transduction current is carried largely by the anion $Cl^-$. However, it remains unclear why ORNs use an anionic current for signal amplification. We have sought to provide clarification on this topic by studying the so far neglected dynamics of $Na^+$, $Ca^{2+}$, $K^+$ and $Cl^-$ in the small space of olfactory cilia during an odorant response. Using computational modeling and simulations we compared the outcomes of signal amplification based on either $Cl^-$ or $Na^+$ currents. We found that amplification produced by $Na^+$ influx instead of a $Cl^-$ efflux is problematic due to several reasons: First, the $Na^+$ current amplitude varies greatly depending on mucosal ion concentration changes. Second, a $Na^+$ current leads to a large increase in the ciliary $Na^+$ concentration during an odorant response. This increase inhibits and even reverses $Ca^{2+}$ clearance by $Na^+/Ca^{2+}/K^+$ exchange, which is essential for response termination. Finally, a $Na^+$ current increases the ciliary osmotic pressure, which could cause swelling to damage the cilia. By contrast, a transduction pathway based on $Cl^-$ efflux circumvents these problems and renders the odorant response robust and reliable.Comment: 31 pages, 10 figures (including SI

An electrodiffusive neuron-extracellular-glia model for exploring the genesis of slow potentials in the brain

Within the computational neuroscience community, there has been a focus on simulating the electrical activity of neurons, while other components of brain tissue, such as glia cells and the extracellular space, are often neglected. Standard models of extracellular potentials are based on a combination of multicompartmental models describing neural electrodynamics and volume conductor theory. Such models cannot be used to simulate the slow components of extracellular potentials, which depend on ion concentration dynamics, and the effect that this has on extracellular diffusion potentials and glial buffering currents. We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine compartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for action potentials and dendritic calcium spikes in neurons, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. The edNEG model accounts for the concentration-dependent effects on ECS potentials that the standard models neglect. Using the edNEG model, we analyze these effects by splitting the extracellular potential into three components: one due to neural sink/source configurations, one due to glial sink/source configurations, and one due to extracellular diffusive currents. Through a series of simulations, we analyze the roles played by the various components and how they interact in generating the total slow potential. We conclude that the three components are of comparable magnitude and that the stimulus conditions determine which of the components that dominate.publishedVersio

Finite-element modeling of neuromodulation via controlled delivery of potassium ions using conductive polymer-coated microelectrodes

: Objective. The controlled delivery of potassium is an interesting neuromodulation modality, being potassium ions involved in shaping neuron excitability, synaptic transmission, network synchronization, and playing a key role in pathological conditions like epilepsy and spreading depression. Despite many successful examples of pre-clinical devices able to influence the extracellular potassium concentration, computational frameworks capturing the corresponding impact on neuronal activity are still missing.Approach. We present a finite-element model describing a PEDOT:PSS-coated microelectrode (herein, simplyionic actuator) able to release potassium and thus modulate the activity of a cortical neuron in anin-vitro-like setting. The dynamics of ions in the ionic actuator, the neural membrane, and the cellular fluids are solved self-consistently.Main results. We showcase the capability of the model to describe on a physical basis the modulation of the intrinsic excitability of the cell and of the synaptic transmission following the electro-ionic stimulation produced by the actuator. We consider three case studies for the ionic actuator with different levels of selectivity to potassium: ideal selectivity, no selectivity, and selectivity achieved by embedding ionophores in the polymer.Significance. This work is the first step toward a comprehensive computational framework aimed to investigate novel neuromodulation devices targeting specific ionic species, as well as to optimize their design and performance, in terms of the induced modulation of neural activity

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Mechanisms of rod photoreceptor motility in development and following transplantation

To establish the mature neuroepithelial tissue architecture, newborn neurons often migrate from their place of birth, usually at the apical neuroepithelial limit, towards their target destination. Even before neurons are born, the nucleus of the mitotic neuronal progenitor cell migrates within the apico-basal cellular extent in synchrony with the cell cycle (interkinetic nuclear migration or IKNM) – a migratory pattern so far only observed in mitotic epithelial progenitor cells. Rod photoreceptors, too, are born at the apical limit of the retinal neuroepithelium. They then populate a layer directly adjacent (outer nuclear layer or ONL), but not the more basal retinal layers. How rod photoreceptors become enriched specifically within the ONL is presently ill-defined. Here, it was identified that rod photoreceptor somata of the developing mouse retina are constantly pushed basally (presumably caused by proximal progenitor IKNM events). To become enriched apically within the (presumptive) ONL despite this, the post-mitotic rod photoreceptors utilised an IKNM-like migratory behaviour more typically associated with dividing cells: rod somata actively migrated apically, driven by microtubule-associated dynein I motors. Another microtubule-associated motor protein, KIF1A, acts as a molecular brake during basal displacement, preventing ectopic basal positions. Rod somata oscillate between apical and basal motions at least from P1 up until ~P10. Whether this involves a component of glial-guided migration could not be established beyond reasonable doubt. Nonetheless, this is the first report of an oscillatory, IKNM-like migration behaviour occurring within a post-mitotic neuronal cell population. Rod photoreceptors have also been assumed to migrate into the adult neural retina following sub-retinal transplantation for cell-replacement therapeutic purposes, although this has not been directly observed. Here, time-lapse footage for the first time showed rod photoreceptors migrating from the sub-retinal space into the host retina. This supports the notion that photoreceptor cell replacement therapy could become a clinically viable treatment option

Use of Serial Block Face-Scanning Electron Microscopy to Study the Ultrastructure of Vertebrate and Invertebrate Biology

PhD ThesisThe development of Serial Block Face Scanning Electron Microscopy (SBF-SEM) allows for acquisition of serially sectioned, imaged data of ultrastructure at high resolution. In this project, optimisation of both SBF-SEM methodology and 3-D image segmentation analysis was applied to the ultrastructural examination of two types of biological tissues, each requiring a different experimental approach. The first project was a connectomic based study, to determine the relationship between the neurons that synapse upon the Lobula Giant Movement Detector 2 (LGMD 2) neuron, within the optic lobe of the locust. A substantial portion of the LGMD 2 neuron was reconstructed along with the afferent neurons, enabling the discovery of retinotopic mapping from the photoreceptors of the eye onto the LGMD 2 neuron. A sub-class of afferent neurons was also found, most likely vital in the process of signal integration across the large LGMD 2 neuron. For the second project, two types of skeletal muscle (psoas and soleus) obtained from fetal and adult guinea pigs were analysed to assess tissue-specific changes in mitochondrial morphology with muscle maturation. Distinct mitochondrial shapes were found across both muscles and age groups and a classification system was developed. It was found that, in both muscles, by late fetal gestation the mitochondrial network is well developed and akin to that found in the adult. Quantitative and qualitative differences in mitochondria morphology and complexity were found between the two muscles in the adult group. These differences are likely to be related to functional specialisation. All data collected during the experiments have also been made available online on Zenodo, roughly 240GB, which can be used for further studies. Overall SBF-SEM was proven to be a robust method of gaining new insights into the ultrastructure in both models and has wide ranging capabilities for a variety of experimental objectives