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Poster presentation: Background To test the importance of synchronous neuronal firing for information processing in the brain, one has to investigate if synchronous firing strength is correlated to the experimental subjects. This requires a tool that can compare the strength of the synchronous firing across different conditions, while at the same time it should correct for other features of neuronal firing such as spike rate modulation or the auto-structure of the spike trains that might co-occur with synchronous firing. Here we present the bi- and multivariate extension of previously developed method NeuroXidence [1,2], which allows for comparing the amount of synchronous firing between different conditions. ...
Poster presentation: Introduction The ability of neurons to emit different firing patterns is considered relevant for neuronal information processing. In dopaminergic neurons, prominent patterns include highly regular pacemakers with separate spikes and stereotyped intervals, processes with repetitive bursts and partial regularity, and irregular spike trains with nonstationary properties. In order to model and quantify these processes and the variability of their patterns with respect to pharmacological and cellular properties, we aim to describe the two dimensions of burstiness and regularity in a single model framework. Methods We present a stochastic spike train model in which the degree of burstiness and the regularity of the oscillation are described independently and with two simple parameters. In this model, a background oscillation with independent and normally distributed intervals gives rise to Poissonian spike packets with a Gaussian firing intensity. The variability of inter-burst intervals and the average number of spikes in each burst indicate regularity and burstiness, respectively. These parameters can be estimated by fitting the model to the autocorrelograms. This allows to assign every spike train a position in the two-dimensional space described by regularity and burstiness and thus, to investigate the dependence of the firing patterns on different experimental conditions. Finally, burst detection in single spike trains is possible within the model because the parameter estimates determine the appropriate bandwidth that should be used for burst identification. Results and Discussion We applied the model to a sample data set obtained from dopaminergic substantia nigra and ventral tegmental area neurons recorded extracellularly in vivo and studied differences between the firing activity of dopaminergic neurons in wildtype and K-ATP channel knock-out mice. The model is able to represent a variety of discharge patterns and to describe changes induced pharmacologically. It provides a simple and objective classification scheme for the observed spike trains into pacemaker, irregular and bursty processes. In addition to the simple classification, changes in the parameters can be studied quantitatively, also including the properties related to bursting behavior. Interestingly, the proposed algorithm for burst detection may be applicable also to spike trains with nonstationary firing rates if the remaining parameters are unaffected. Thus, the proposed model and its burst detection algorithm can be useful for the description and investigation of neuronal firing patterns and their variability with cellular and experimental conditions.
Poster presentation: Coordinated neuronal activity across many neurons, i.e. synchronous or spatiotemporal pattern, had been believed to be a major component of neuronal activity. However, the discussion if coordinated activity really exists remained heated and controversial. A major uncertainty was that many analysis approaches either ignored the auto-structure of the spiking activity, assumed a very simplified model (poissonian firing), or changed the auto-structure by spike jittering. We studied whether a statistical inference that tests whether coordinated activity is occurring beyond chance can be made false if one ignores or changes the real auto-structure of recorded data. To this end, we investigated the distribution of coincident spikes in mutually independent spike-trains modeled as renewal processes. We considered Gamma processes with different shape parameters as well as renewal processes in which the ISI distribution is log-normal. For Gamma processes of integer order, we calculated the mean number of coincident spikes, as well as the Fano factor of the coincidences, analytically. We determined how these measures depend on the bin width and also investigated how they depend on the firing rate, and on rate difference between the neurons. We used Monte-Carlo simulations to estimate the whole distribution for these parameters and also for other values of gamma. Moreover, we considered the effect of dithering for both of these processes and saw that while dithering does not change the average number of coincidences, it does change the shape of the coincidence distribution. Our major findings are: 1) the width of the coincidence count distribution depends very critically and in a non-trivial way on the detailed properties of the inter-spike interval distribution, 2) the dependencies of the Fano factor on the coefficient of variation of the ISI distribution are complex and mostly non-monotonic. Moreover, the Fano factor depends on the very detailed properties of the individual point processes, and cannot be predicted by the CV alone. Hence, given a recorded data set, the estimated value of CV of the ISI distribution is not sufficient to predict the Fano factor of the coincidence count distribution, and 3) spike jittering, even if it is as small as a fraction of the expected ISI, can falsify the inference on coordinated firing. In most of the tested cases and especially for complex synchronous and spatiotemporal pattern across many neurons, spike jittering increased the likelihood of false positive finding very strongly. Last, we discuss a procedure [1] that considers the complete auto-structure of each individual spike-train for testing whether synchrony firing occurs at chance and therefore overcomes the danger of an increased level of false positives.
Knodel, Markus Michael ; Bucher, Daniel ; Queisser, Sean Gillian ; Schuster, Christoph M. ; Wittum, Gabriel
Poster presentation: An important challenge in neuroscience is understanding how networks of neurons go about processing information. Synapses are thought to play an essential role in cellular information processing however quantitative and mathematical models of the underlying physiologic processes that occur at synaptic active zones are lacking. We are generating mathematical models of synaptic vesicle dynamics at a well-characterized model synapse, the Drosophila larval neuromuscular junction. This synapse's simplicity, accessibility to various electrophysiological recording and imaging techniques, and the genetic malleability intrinsic to Drosophila system make it ideal for computational and mathematical studies. We have employed a reductionist approach and started by modeling single presynaptic boutons. Synaptic vesicles can be divided into different pools; however, a quantitative understanding of their dynamics at the Drosophila neuromuscular junction is lacking [4]. We performed biologically realistic simulations of high and low release probability boutons [3] using partial differential equations (PDE) taking into account not only the evolution in time but also the spatial structure in two dimensions (the extension to three dimensions will be implemented soon). PDEs are solved using UG, a program library for the calculation of multi-dimensional PDEs solved using a finite volume approach and implicit time stepping methods leading to extended linear equation systems be solvedwith multi-grid methods [3,4]. Numerical calculations are done on multi-processor computers for fast calculations using different parameters in order to asses the biological feasibility of different models. In preliminary simulations, we modeled vesicle dynamics as a diffusion process describing exocytosis as Neumann streams at synaptic active zones. The initial results obtained with these models are consistent with experimental data. However, this should be regarded as a work in progress. Further refinements will be implemented, including simulations using morphologically realistic geometries which were generated from confocal scans of the neuromuscular junction using NeuRA (a Neuron Reconstruction Algorithm). Other parameters such as glutamate diffusion and reuptake dynamics, as well as postsynaptic receptor kinetics will be incorporated as well.
Poster presentation: Characterizing neuronal encoding is essential for understanding information processing in the brain. Three methods are commonly used to characterize the relationship between neural spiking activity and the features of putative stimuli. These methods include: Wiener-Volterra kernel methods (WVK), the spike-triggered average (STA), and more recently, the point process generalized linear model (GLM). We compared the performance of these three approaches in estimating receptive field properties and orientation tuning of 251 V1 neurons recorded from 2 monkeys during a fixation period in response to a moving bar. The GLM consisted of two formulations of the conditional intensity function for a point process characterization of the spiking activity: one with a stimulus only component and one with the stimulus and spike history. We fit the GLMs by maximum likelihood using GLMfit in Matlab. Goodness-of-fit was assessed using cross-validation with Kolmogorov-Smirnov (KS) tests based on the time-rescaling theorem to evaluate the accuracy with which each model predicts the spiking activity of individual neurons and for each movement direction (4016 models in total, for 251 neurons and 16 different directions). The GLMs that considered spike history of up to 35 ms, accurately predicted neuronal spiking activity (95% confidence intervals for KS test) with a performance of 97.0% (3895/4016) for the training data, and 96.5% (3876/4016) for the test data. If spike history was not considered, performance dropped to 73,1% in the training and 71.3% in the testing data. In contrast, the WVF and the STA predicted spiking accurately for 24.2% and 44.5% of the test data examples respectively. The receptive field size estimates obtained from the GLM (with and without history), WVF and STA were comparable. Relative to the GLM orientation tuning was underestimated on average by a factor of 0.45 by the WVF and the STA. The main reason for using the STA and WVF approaches is their apparent simplicity. However, our analyses suggest that more accurate spike prediction as well as more credible estimates of receptive field size and orientation tuning can be computed easily using GLMs implemented in Matlab with standard functions such as GLMfit.
Poster presentation: Introduction Rhythmic synchronization of neural activity in the gamma-frequency range (30–100 Hz) was observed in many brain regions; see the review in [1]. The functional relevance of these oscillations remains to be clarified, a task that requires modeling of the relevant aspects of information processing. The temporal correlation hypothesis, reviewed in [2], proposes that the temporal correlation of neural units provides a means to group the neural units into so-called neural assemblies that are supposed to represent mental objects. Here, we approach the modeling of the temporal grouping of neural units from the perspective of oscillatory neural network systems based on phase model oscillators. Patterns are assumed to be stored in the network based on Hebbian memory and assemblies are identified with phase-locked subset of these patterns. Going beyond foregoing discussions, we demonstrate the combination of two recently discussed mechanisms, referred to as "acceleration" [3] and "pooling" [4]. The combination realizes in a complementary manner a competition for activity on a local scale, while providing a competition for coherence among different assemblies on a non-local scale. ...
Poster presentation: Introduction Adequate anesthesia is crucial to the success of surgical interventions and subsequent recovery. Neuroscientists, surgeons, and engineers have sought to understand the impact of anesthetics on the information processing in the brain and to properly assess the level of anesthesia in an non-invasive manner. Studies have indicated a more reliable depth of anesthesia (DOA) detection if multiple parameters are employed. Indeed, commercial DOA monitors (BIS, Narcotrend, M-Entropy and A-line ARX) use more than one feature extraction method. Here, we propose TESPAR (Time Encoded Signal Processing And Recognition) a time domain signal processing technique novel to EEG DOA assessment that could enhance existing monitoring devices. ...
Poster presentation: Functional connectivity of the brain describes the network of correlated activities of different brain areas. However, correlation does not imply causality and most synchronization measures do not distinguish causal and non-causal interactions among remote brain areas, i.e. determine the effective connectivity [1]. Identification of causal interactions in brain networks is fundamental to understanding the processing of information. Attempts at unveiling signs of functional or effective connectivity from non-invasive Magneto-/Electroencephalographic (M/EEG) recordings at the sensor level are hampered by volume conduction leading to correlated sensor signals without the presence of effective connectivity. Here, we make use of the transfer entropy (TE) concept to establish effective connectivity. The formalism of TE has been proposed as a rigorous quantification of the information flow among systems in interaction and is a natural generalization of mutual information [2]. In contrast to Granger causality, TE is a non-linear measure and not influenced by volume conduction. ...
Poster presentation: Our work deals with the self-organization [1] of a memory structure that includes multiple hierarchical levels with massive recurrent communication within and between them. Such structure has to provide a representational basis for the relevant objects to be stored and recalled in a rapid and efficient way. Assuming that the object patterns consist of many spatially distributed local features, a problem of parts-based learning is posed. We speculate on the neural mechanisms governing the process of the structure formation and demonstrate their functionality on the task of human face recognition. The model we propose is based on two consecutive layers of distributed cortical modules, which in turn contain subunits receiving common afferents and bounded by common lateral inhibition (Figure 1). In the initial state, the connectivity between and within the layers is homogeneous, all types of synapses – bottom-up, lateral and top-down – being plastic. During the iterative learning, the lower layer of the system is exposed to the Gabor filter banks extracted from local points on the face images. Facing an unsupervised learning problem, the system is able to develop synaptic structure capturing local features and their relations on the lower level, as well as the global identity of the person at the higher level of processing, improving gradually its recognition performance with learning time. ...
Poster presentation: Introduction We study the problem of object recognition invariant to transformations, such as translation, rotation and scale. A system is underdetermined if its degrees of freedom (number of possible transformations and potential objects) exceed the available information (image size). The regularization theory solves this problem by adding constraints [1]. It is unclear what constraints biological systems use. We suggest that rather than seeking constraints, an underdetermined system can make decisions based on available information by grouping its variables. We propose a dynamical system as a minimum system for invariant recognition to demonstrate this strategy. ...
Poster presentation: Introduction Dopaminergic neurons in the midbrain show a variety of firing patterns, ranging from very regular firing pacemaker cells to bursty and irregular neurons. The effects of different experimental conditions (like pharmacological treatment or genetical manipulations) on these neuronal discharge patterns may be subtle. Applying a stochastic model is a quantitative approach to reveal these changes. ...
NeuroXidence: reliable and efficient analysis of an excess or deficiency of joint-spike events
(2009)
Poster presentation: We present a non-parametric and computationally-efficient method named NeuroXidence (see http://www.NeuroXidence.com ) that detects coordinated firing within a group of two or more neurons and tests whether the observed level of coordinated firing is significantly different from that expected by chance. NeuroXidence [1] considers the full auto-structure of the data, including the changes in the rate responses and the history dependencies in the spiking activity. We demonstrate that NeuroXidence can identify epochs with significant spike synchronisation even if these coincide with strong and fast rate modulations. We also show, that the method accounts for trial-by-trial variability in the rate responses and their latencies, and that it can be applied to short data windows lasting only tens of milliseconds. Based on simulated data we compare the performance of NeuroXidence with the UE-method [2,3] and the cross-correlation analysis. An application of NeuroXidence to 42 single-units (SU) recorded in area 17 of an anesthetized cat revealed significant coincident events of high complexities, involving firing of up to 8 SUs simultaneously (5 ms window). The results were highly consistent with those obtained by traditional pair-wise measures based on cross-correlation: Neuronal synchrony was strongest in stimulation conditions in which the orientation of the sinusoidal grating matched the preferred orientation of most of the SUs included in the analysis, and was the weakest when the neurons were stimulated least optimally. Interestingly, events of higher complexities showed stronger stimulus-specific modulation than pair-wise interactions. The results suggest strong evidence for stimulus specific synchronous firing and, therefore, support the temporal coding hypothesis in visual cortex. ...
Poster presentation: Introduction We here focus on constructing a hierarchical neural system for position-invariant recognition, which is one of the most fundamental invariant recognition achieved in visual processing [1,2]. The invariant recognition have been hypothesized to be done by matching a sensory image of a particular object stimulated on the retina to the most suitable representation stored in memory of the higher visual cortical area. Here arises a general problem: In such a visual processing, the position of the object image on the retina must be initially uncertain. Furthermore, the retinal activities possessing sensory information are being far from the ones in the higher area with a loss of the sensory object information. Nevertheless, with such recognition ambiguity, the particular object can effortlessly and easily be recognized. Our aim in this work is an attempt to resolve such a general recognition problem. ...
Poster presentation: Introduction We here address the problem of integrating information about multiple objects and their positions on the visual scene. A primate visual system has little difficulty in rapidly achieving integration, given only a few objects. Unfortunately, computer vision still has great difficultly achieving comparable performance. It has been hypothesized that temporal binding or temporal separation could serve as a crucial mechanism to deal with information about objects and their positions in parallel to each other. Elaborating on this idea, we propose a neurally plausible mechanism for reaching local decision-making for "what" and "where" information to the global multi-object recognition. ...
Poster presentation: Introduction The brain is a highly interconnected network of constantly interacting units. Understanding the collective behavior of these units requires a multi-dimensional approach. The results of such analyses are hard to visualize and interpret. Hence tools capable of dealing with such tasks become imperative. ....
Poster presentation: NO-sensitive guanylyl cyclases (sGCs) are cytosolic receptors for nitric oxide (NO) catalyzing the conversion of GTP to cGMP. sGCs are obligate heterodimers composed of one alpha and beta subunit each. The allosteric mechanism of sGC activation via NO is well understood, however, our knowledge about alternative mechanisms such as protein-protein interactions regulating activity, availability, translocation and expression of sGC is rather limited. In a search by the yeast two-hybrid system using the catalytic domain of the alpha1 subunit as the bait, we have identified two structurally related proteins AGAP1 [1] and MRIP2 as novel sGC interacting proteins. MRIP2 is a multi-domain protein of 75 kDa comprising a single PH and ArfGAP domain each and two ankyrin repeats. Co-immunoprecipitation experiments using COS1 cells overexpressing both proteins demonstrated the interaction of MRIP2 with both subunits of the sGC alpha1beta1. Confocal microscopical analysis showed a prominent plasma membrane staining of MRIP2. This membrane association is mediated through an N-terminal myristoylation site and through binding of its PH domain to phospholipids such as phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). We hypothesize that MRIP2 may represent an acceptor protein for sGC that mediates recruitment of cytosolic sGC to the plasma membrane or other subcellular compartments.
Poster presentation: NO-sensitive guanylyl cyclases (GC) are the principal receptors for nitric oxide (NO) and convert GTP into the second messenger cGMP. We showed that GC is prone to tyrosine phosphorylation in COS1 cells overexpressing the human holoenzyme. Similar results were obtained in PC12 cells and in rat aortic tissue slices. The major phosphorylation site was mapped to position 192 in the regulatory domain of the beta1 subunit. Tyrosine phosphorylation of GC was reduced in the presence of the inhibitors PP1 and PP2 indicating that Src-like kinases are critically involved in phosphorylation. Moreover, co-immunoprecipitation experiments revealed an interaction between Src and GC. To further analyse the relevance of this posttranslational modification we generated a phospho-specific antibody raised against pTyr192. This antibody clearly distinguishes between phosphorylated and non-phosphorylated GC and may be a powerful tool to analyse the subcellular localisation of the phosphorylated enzyme.
Poster presentation NO-sensitive guanylyl cyclases (soluble guanylyl cyclase, sGC) are among the key regulators of intracellular cGMP concentration. The mechanisms underlying NO-mediated activation of sGC are quite well understood, however, little is known about the fine-tuning of sGC activity through alternative mechanisms such as protein phosphorylation. Several reports have demonstrated the reversible phosphorylation of sGC on serine/threonine residues, and it has been speculated, though not experimentally proven, that sGC might also be phosphorylated on tyrosine residues. Using broad-spectrum phosphatase inhibitors we were able to demonstrate tyrosine phosphorylation at Tyr192 of the beta 1 subunit of human sGC in COS1 cells. This residue forms part of a sequence segment (YEDL) representing a preferential binding site for SH2 domains of Src-like kinases. Pull-down assays and co-immunoprecipitation experiments showed that Src can indeed bind via its SH2 domain to pTyr192 of beta 1 indicating that tyrosine phosphorylation of sGC may be followed by recruitment of Src-like kinases to the phosphorylated beta 1 subunit. In support of this hypothesis, immunofluorescence studies showed a colocalization of overexpressed sGC and Src at the plasma membrane of COS1 and Hela cells. Together, our results point to an unexpected crosstalk between tyrosine kinase pathway(s) and the NO/cGMP signalling cascade which may result in translocation of the predominantly cytosolic sGC to the cytosolic face of the plasma membrane.