The Secrets of a Functional Synapse – From a Computational and Experimental Viewpoint

BACKGROUND: Neuronal communication is tightly regulated in time and in space. The neuronal transmission takes place in the nerve terminal, at a specialized structure called the synapse. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle and diffusion of the released NT in the synaptic cleft; the NT then binds to the appropriate receptor, and as a result, a potential change at the target cell membrane is induced. The entire process lasts for only a fraction of a millisecond. An essential property of the synapse is its capacity to undergo biochemical and morphological changes, a phenomenon that is referred to as synaptic plasticity. RESULTS: In this survey, we consider the mammalian brain synapse as our model. We take a cell biological and a molecular perspective to present fundamental properties of the synapse:(i) the accurate and efficient delivery of organelles and material to and from the synapse; (ii) the coordination of gene expression that underlies a particular NT phenotype; (iii) the induction of local protein expression in a subset of stimulated synapses. We describe the computational facet and the formulation of the problem for each of these topics. CONCLUSION: Predicting the behavior of a synapse under changing conditions must incorporate genomics and proteomics information with new approaches in computational biology

Potential and Challenges of Analog Reconfigurable Computation in Modern and Future CMOS

In this work, the feasibility of the floating-gate technology in analog computing platforms in a scaled down general-purpose CMOS technology is considered. When the technology is scaled down the performance of analog circuits tends to get worse because the process parameters are optimized for digital transistors and the scaling involves the reduction of supply voltages. Generally, the challenge in analog circuit design is that all salient design metrics such as power, area, bandwidth and accuracy are interrelated. Furthermore, poor flexibility, i.e. lack of reconfigurability, the reuse of IP etc., can be considered the most severe weakness of analog hardware. On this account, digital calibration schemes are often required for improved performance or yield enhancement, whereas high flexibility/reconfigurability can not be easily achieved. Here, it is discussed whether it is possible to work around these obstacles by using floating-gate transistors (FGTs), and analyze problems associated with the practical implementation. FGT technology is attractive because it is electrically programmable and also features a charge-based built-in non-volatile memory. Apart from being ideal for canceling the circuit non-idealities due to process variations, the FGTs can also be used as computational or adaptive elements in analog circuits. The nominal gate oxide thickness in the deep sub-micron (DSM) processes is too thin to support robust charge retention and consequently the FGT becomes leaky. In principle, non-leaky FGTs can be implemented in a scaled down process without any special masks by using “double”-oxide transistors intended for providing devices that operate with higher supply voltages than general purpose devices. However, in practice the technology scaling poses several challenges which are addressed in this thesis. To provide a sufficiently wide-ranging survey, six prototype chips with varying complexity were implemented in four different DSM process nodes and investigated from this perspective. The focus is on non-leaky FGTs, but the presented autozeroing floating-gate amplifier (AFGA) demonstrates that leaky FGTs may also find a use. The simplest test structures contain only a few transistors, whereas the most complex experimental chip is an implementation of a spiking neural network (SNN) which comprises thousands of active and passive devices. More precisely, it is a fully connected (256 FGT synapses) two-layer spiking neural network (SNN), where the adaptive properties of FGT are taken advantage of. A compact realization of Spike Timing Dependent Plasticity (STDP) within the SNN is one of the key contributions of this thesis. Finally, the considerations in this thesis extend beyond CMOS to emerging nanodevices. To this end, one promising emerging nanoscale circuit element - memristor - is reviewed and its applicability for analog processing is considered. Furthermore, it is discussed how the FGT technology can be used to prototype computation paradigms compatible with these emerging two-terminal nanoscale devices in a mature and widely available CMOS technology.Siirretty Doriast

BenchMarks 2010, July 2

BenchMarks. Friday, July 2, 2010 The community newsletter of The Rockefeller University BenchMarks is published monthly and is distributed on the campus of The Rockefeller University. It produced by the Office of Communications and Public Affairshttps://digitalcommons.rockefeller.edu/benchmarks_2010/1002/thumbnail.jp

Neural architecture for echo suppression during sound source localization based on spiking neural cell models

Zusammenfassung Diese Arbeit untersucht die biologischen Ursachen des psycho-akustischen Präzedenz Effektes, der Menschen in die Lage versetzt, akustische Echos während der Lokalisation von Schallquellen zu unterdrücken. Sie enthält ein Modell zur Echo-Unterdrückung während der Schallquellenlokalisation, welches in technischen Systemen zur Mensch-Maschine Interaktion eingesetzt werden kann. Die Grundlagen dieses Modells wurden aus eigenen elektrophysiologischen Experimenten an der Mongolischen Wüstenrennmaus gewonnen. Die dabei erstmalig an der Wüstenrennmaus erzielten Ergebnisse, zeigen ein besonderes Verhalten spezifischer Zellen im Dorsalen Kern des Lateral Lemniscus, einer dedizierten Region des auditorischen Hirnstammes. Die dort sichtbare Langzeithemmung scheint die Grundlage für die Echounterdrückung in höheren auditorischen Zentren zu sein. Das entwickelte Model war in der Lage dieses Verhalten nachzubilden, und legt die Vermutung nahe, dass eine starke und zeitlich präzise Hyperpolarisation der zugrundeliegende physiologische Mechanismus dieses Verhaltens ist. Die entwickelte Neuronale Modellarchitektur modelliert das Innenohr und fünf wesentliche Kerne des auditorischen Hirnstammes in ihrer Verbindungsstruktur und internen Dynamik. Sie stellt einen neuen Typus neuronaler Modellierung dar, der als Spike-Interaktionsmodell (SIM) bezeichnet wird. SIM nutzen die präzise räumlich-zeitliche Interaktion einzelner Aktionspotentiale (Spikes) für die Kodierung und Verarbeitung neuronaler Informationen. Die Basis dafür bilden Integrate-and-Fire Neuronenmodelle sowie Hebb'sche Synapsen, welche um speziell entwickelte dynamische Kernfunktionen erweitert wurden. Das Modell ist in der Lage, Zeitdifferenzen von 10 mykrosekunden zu detektieren und basiert auf den Prinzipien der zeitlichen und räumlichen Koinzidenz sowie der präzisen lokalen Inhibition. Es besteht ausschließlich aus Elementen einer eigens entwickelten Neuronalen Basisbibliothek (NBL) die speziell für die Modellierung verschiedenster Spike- Interaktionsmodelle entworfen wurde. Diese Bibliothek erweitert die kommerziell verfügbare dynamische Simulationsumgebung von MATLAB/SIMULINK um verschiedene Modelle von Neuronen und Synapsen, welche die intrinsischen dynamischen Eigenschaften von Nervenzellen nachbilden. Die Nutzung dieser Bibliothek versetzt sowohl den Ingenieur als auch den Biologen in die Lage, eigene, biologisch plausible, Modelle der neuronalen Informationsverarbeitung ohne detaillierte Programmierkenntnisse zu entwickeln. Die grafische Oberfläche ermöglicht strukturelle sowie parametrische Modifikationen und ist in der Lage, den Zeitverlauf mikroskopischer Zellpotentiale aber auch makroskopischer Spikemuster während und nach der Simulation darzustellen. Zwei grundlegende Elemente der Neuronalen Basisbibliothek wurden zur Implementierung als spezielle analog-digitale Schaltungen vorbereitet. Erste Silizium Implementierungen durch das Team des DFG Graduiertenkollegs GRK 164 konnten die Möglichkeit einer vollparallelen on line Verarbeitung von Schallsignalen nachweisen. Durch Zuhilfenahme des im GRK entwickelten automatisierten Layout Generators wird es möglich, spezielle Prozessoren zur Anwendung biologischer Verarbeitungsprinzipien in technischen Systemen zu entwickeln. Diese Prozessoren unterscheiden sich grundlegend von den klassischen von Neumann Prozessoren indem sie räumlich und zeitlich verteilte Spikemuster, anstatt sequentieller binärer Werte zur Informationsrepräsentation nutzen. Sie erweitern das digitale Kodierungsprinzip durch die Dimensionen des Raumes (2 dimensionale Nachbarschaft) der Zeit (Frequenz, Phase und Amplitude) sowie der zeitlichen Dynamik analoger Potentialverläufe. Diese Dissertation besteht aus sieben Kapiteln, welche den verschiedenen Bereichen der Computational Neuroscience gewidmet sind. Kapitel 1 beschreibt die Motivation dieser Arbeit welche aus der Absicht rühren, biologische Prinzipien der Schallverarbeitung zu erforschen und für technische Systeme während der Interaktion mit dem Menschen nutzbar zu machen. Zusätzlich werden fünf Gründe für die Nutzung von Spike-Interaktionsmodellen angeführt sowie deren neuartiger Charakter beschrieben. Kapitel 2 führt die biologischen Prinzipien der Schallquellenlokalisation und den psychoakustischen Präzedenz Effekt ein. Aktuelle Hypothesen zur Entstehung dieses Effektes werden anhand ausgewählter experimenteller Ergebnisse verschiedener Forschungsgruppen diskutiert. Kapitel 3 beschreibt die entwickelte Neuronale Basisbibliothek und führt die einzelnen neuronalen Simulationselemente ein. Es erklärt die zugrundeliegenden mathematischen Funktionen der dynamischen Komponenten und beschreibt deren generelle Einsetzbarkeit zur dynamischen Simulation spikebasierter Neuronaler Netzwerke. Kapitel 4 enthält ein speziell entworfenes Modell des auditorischen Hirnstammes beginnend mit den Filterkaskaden zur Simulation des Innenohres, sich fortsetzend über mehr als 200 Zellen und 400 Synapsen in 5 auditorischen Kernen bis zum Richtungssensor im Bereich des auditorischen Mittelhirns. Es stellt die verwendeten Strukturen und Parameter vor und enthält grundlegende Hinweise zur Nutzung der Simulationsumgebung. Kapitel 5 besteht aus drei Abschnitten, wobei der erste Abschnitt die Experimentalbedingungen und Ergebnisse der eigens durchgeführten Tierversuche beschreibt. Der zweite Abschnitt stellt die Ergebnisse von 104 Modellversuchen zur Simulationen psycho-akustischer Effekte dar, welche u.a. die Fähigkeit des Modells zur Nachbildung des Präzedenz Effektes testen. Schließlich beschreibt der letzte Abschnitt die Ergebnisse der 54 unter realen Umweltbedingungen durchgeführten Experimente. Dabei kamen Signale zur Anwendung, welche in normalen sowie besonders stark verhallten Räumen aufgezeichnet wurden. Kapitel 6 vergleicht diese Ergebnisse mit anderen biologisch motivierten und technischen Verfahren zur Echounterdrückung und Schallquellenlokalisation und führt den aktuellen Status der Hardwareimplementierung ein. Kapitel 7 enthält schließlich eine kurze Zusammenfassung und einen Ausblick auf weitere Forschungsobjekte und geplante Aktivitäten. Diese Arbeit möchte zur Entwicklung der Computational Neuroscience beitragen, indem sie versucht, in einem speziellen Anwendungsfeld die Lücke zwischen biologischen Erkenntnissen, rechentechnischen Modellen und Hardware Engineering zu schließen. Sie empfiehlt ein neues räumlich-zeitliches Paradigma der dynamischen Informationsverarbeitung zur Erschließung biologischer Prinzipien der Informationsverarbeitung für technische Anwendungen.This thesis investigates the biological background of the psycho-acoustical precedence effect, enabling humans to suppress echoes during the localization of sound sources. It provides a technically feasible and biologically plausible model for sound source localization under echoic conditions, ready to be used by technical systems during man-machine interactions. The model is based upon own electro-physiological experiments in the mongolian gerbil. The first time in gerbils obtained results reveal a special behavior of specific cells of the dorsal nucleus of the lateral lemniscus (DNLL) - a distinct region in the auditory brainstem. The explored persistent inhibition effect of these cells seems to account for the base of echo suppression at higher auditory centers. The developed model proved capable to duplicate this behavior and suggests, that a strong and timely precise hyperpolarization is the basic mechanism behind this cell behavior. The developed neural architecture models the inner ear as well as five major nuclei of the auditory brainstem in their connectivity and intrinsic dynamics. It represents a new type of neural modeling described as Spike Interaction Models (SIM). SIM use the precise spatio-temporal interaction of single spike events for coding and processing of neural information. Their basic elements are Integrate-and-Fire Neurons and Hebbian synapses, which have been extended by specially designed dynamic transfer functions. The model is capable to detect time differences as small as 10 mircrosecondes and employs the principles of coincidence detection and precise local inhibition for auditory processing. It consists exclusively of elements of a specifically designed Neural Base Library (NBL), which has been developed for multi purpose modeling of Spike Interaction Models. This library extends the commercially available dynamic simulation environment of MATLAB/SIMULINK by different models of neurons and synapses simulating the intrinsic dynamic properties of neural cells. The usage of this library enables engineers as well as biologists to design their own, biologically plausible models of neural information processing without the need for detailed programming skills. Its graphical interface provides access to structural as well as parametric changes and is capable to display the time course of microscopic cell parameters as well as macroscopic firing pattern during simulations and thereafter. Two basic elements of the Neural Base Library have been prepared for implementation by specialized mixed analog-digital circuitry. First silicon implementations were realized by the team of the DFG Graduiertenkolleg GRK 164 and proved the possibility of fully parallel on line processing of sounds. By using the automated layout processor under development in the Graduiertenkolleg, it will be possible to design specific processors in order to apply theprinciples of distributed biological information processing to technical systems. These processors differ from classical von Neumann processors by the use of spatio temporal spike pattern instead of sequential binary values. They will extend the digital coding principle by the dimensions of space (spatial neighborhood), time (frequency, phase and amplitude) as well as the dynamics of analog potentials and introduce a new type of information processing. This thesis consists of seven chapters, dedicated to the different areas of computational neuroscience. Chapter 1: provides the motivation of this study arising from the attempt to investigate the biological principles of sound processing and make them available to technical systems interacting with humans under real world conditions. Furthermore, five reasons to use spike interaction models are given and their novel characteristics are discussed. Chapter 2: introduces the biological principles of sound source localization and the precedence effect. Current hypothesis on echo suppression and the underlying principles of the precedence effect are discussed by reference to a small selection of physiological and psycho-acoustical experiments. Chapter 3: describes the developed neural base library and introduces each of the designed neural simulation elements. It also explains the developed mathematical functions of the dynamic compartments and describes their general usage for dynamic simulation of spiking neural networks. Chapter 4: introduces the developed specific model of the auditory brainstem, starting from the filtering cascade in the inner ear via more than 200 cells and 400 synapses in five auditory regions up to the directional sensor at the level of the auditory midbrain. It displays the employed parameter sets and contains basic hints for the set up and configuration of the simulation environment. Chapter 5: consists of three sections, whereas the first one describes the set up and results of the own electro-physiological experiments. The second describes the results of 104 model simulations, performed to test the models ability to duplicate psycho-acoustical effects like the precedence effect. Finally, the last section of this chapter contains the results of 54 real world experiments using natural sound signals, recorded under normal as well as highly reverberating conditions. Chapter 6: compares the achieved results to other biologically motivated and technical models for echo suppression and sound source localization and introduces the current status of silicon implementation. Chapter 7: finally provides a short summary and an outlook toward future research subjects and areas of investigation. This thesis aims to contribute to the field of computational neuroscience by bridging the gap between biological investigation, computational modeling and silicon engineering in a specific field of application. It suggests a new spatio-temporal paradigm of information processing in order to access the capabilities of biological systems for technical applications

THE INFLUENCE OF Ca2+ REGULATION IN SYNAPTIC FACILITATION OF MOTOR NERVE TERMINALS IN CRAYFISH AND \u3ci\u3eDROSOPHILA\u3c/i\u3e AS WELL AS IN THE PHYSIOLOGICAL REGULATION OF LARVAL \u3ci\u3eDROSOPHILA\u3c/i\u3e HEART

Intracellular Ca2+ ions are highly regulated in animal cells for them to function normally. Since the tight regulation of [Ca2+]i is so ubiquitous among cells, it is not surprising that altered function in [Ca2+]i regulation is associated with a myriad of disease states in humans. This is particularly evident in pacing myocytes and nerve terminals related to synaptic transmission. A common thread through this dissertation is on the role of three regulators proteins that are common to many cell types. These are the plasmalemmal Na+/Ca2+ exchanger (NCX), the Ca2+-ATPase (PMCA) and the SERCA on the endoplasmic reticulum. In chapter 1 a historical overview is provided on how the understanding in the importance of Ca2+ came about. In Chapter 2, I address indirectly the function of residual [Ca2+]i on the efficacy of synaptic transmission by quantal analysis but also develop novel means of assessing quantal analysis to assign a n and p value to particular synapses. Chapters 3 and 4 address the role of the three Ca2+ regulator proteins in short bursts of synaptic transmission related to short-term facilitation or depression depending on the type of neuromuscular junction (NMJ). Two key model NMJs I used were the crayfish (Chapter 3) and the larval Drosophila (Chapter 4). For comparative purposes in investigating the role of the three proteins in [Ca2+]i regulation, I used the Drosophila larval heart preparation (Chapter 5). Throughout these studies, I used various pharmacological and ionic approaches to compromise the function of these Ca2+ channels. The results were unexpected in some cases due to non-specific effects of the pharmacological agent or ionic manipulations. In addition, a mutational line of Drosophila was used to asses SERCA function, but the results at the NMJ were not as expected. However, results with the mutation on the function of the heart were promising. The significance of these studies stresses that multiple approaches to compromise channels is warranted and the findings should be beneficial for future investigators to advance in mechanistic studies

Consciousness in the Universe is Scale Invariant and Implies an Event Horizon of the Human Brain

Our brain is not a "stand alone" information processing organ: it acts as a central part of our integral nervous system with recurrent information exchange with the entire organism and the cosmos. In this study, the brain is conceived to be embedded in a holographic structured field that interacts with resonant sensitive structures in the various cell types in our body. In order to explain earlier reported ultra-rapid brain responses and effective operation of the meta-stable neural system, a field-receptive mental workspace is proposed to be communicating with the brain. Our integral nervous system is seen as a dedicated neural transmission and multi-cavity network that, in a non-dual manner, interacts with the proposed supervening meta-cognitive domain. Among others, it is integrating discrete patterns of eigen-frequencies of photonic/solitonic waves, thereby continuously updating a time-symmetric global memory space of the individual. Its toroidal organization allows the coupling of gravitational, dark energy, zero-point energy field (ZPE) as well as earth magnetic fields energies and transmits wave information into brain tissue, that thereby is instrumental in high speed conscious and sub-conscious information processing. We propose that the supposed field-receptive workspace, in a mutual interaction with the whole nervous system, generates self-consciousness and is conceived as operating from a 4th spatial dimension (hyper-sphere). Its functional structure is adequately defined by the geometry of the torus, that is envisioned as a basic unit (operator) of space-time. The latter is instrumental in collecting the pattern of discrete soliton frequencies that provided an algorithm for coherent life processes, as earlier identified by us. It is postulated that consciousness in the entire universe arises through, scale invariant, nested toroidal coupling of various energy fields, that may include quantum error correction. In the brain of the human species, this takes the form of the proposed holographic workspace, that collects active information in a "brain event horizon", representing an internal and fully integral model of the self. This brain-supervening workspace is equipped to convert integrated coherent wave energies into attractor type/standing waves that guide the related cortical template to a higher coordination of reflection and action as well as network synchronicity, as required for conscious states. In relation to its scale-invariant global character, we find support for a universal information matrix, that was extensively described earlier, as a supposed implicate order as well as in a spectrum of space-time theories in current physics. The presence of a field-receptive resonant workspace, associated with, but not reducible to, our brain, may provide an interpretation framework for widely reported, but poorly understood transpersonal conscious states and algorithmic origin of life. It also points out the deep connection of mankind with the cosmos and our major responsibility for the future of our planet.</p

Virtual screening and in vitro evaluation of putative positive allosteric modulators of the GABAB receptor

-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system (CNS). GABA exhibits its function by binding to either the ionotropic GABAA receptor or the metabotropic GABAB receptor, causing a decrease in activity in the nervous system. Disruption in the GABAergic system has been associated with various neurological conditions, including Alzheimer’s disease, anxiety, depressive disorders, and epilepsy. Currently, there is only one marketed drug that work on the GABAB – receptor, on the orthosteric site to be more specific. The discovery of allosteric modulators for the G-protein coupled receptors provides a promising new strategy with potential for developing novel treatments for a variety of CNS disorders, as they allow for increased drug selectivity and potentially decreased adverse side effects. Homology models of the GABAB receptor were built due to the lack of an experimentally solved three-dimensional structure, and they were used to screen for potentially new allosteric modulators using a combination of structure-based and ligand based virtual screening (in silico) with compounds from the Molport database and DrugBank. 16 compounds were purchased for testing – 8 from each database, and were further investigated and evaluated by experimental in vitro testing. Our results indicate that we have four hits, two from each database (DrugBank: I-4 = Mefloquine and I-10 = Rivaroxaban, Molport: I-23 and I-24) where it seems like I-4, I-23 and I-24 acts like PAMs whereas I-10 acts like a NAM/antagonist. The compounds from DrugBank, especially Mefloquine is of interest due to its well-known adverse effect profile which may be linked to the GABAergic system. Further investigation and confirmation of activity at the GABAB receptor could potentially lead to development of novel drugs as well as important tools for studying the structure and function of the GABAB receptor. And at the same time be used to explain the side effects seen when using Mefloquine