scholarly journals Adaptive Exponential Integrate-and-Fire Model as an Effective Description of Neuronal Activity

2005 ◽  
Vol 94 (5) ◽  
pp. 3637-3642 ◽  
Author(s):  
Romain Brette ◽  
Wulfram Gerstner
Keyword(s):  
Simple Model ◽  
Expressive Power ◽  
Detailed Model ◽  
Fire Model ◽  
Integrate And Fire ◽  
Conductance States ◽  
Effective Description ◽  
High Conductance

We introduce a two-dimensional integrate-and-fire model that combines an exponential spike mechanism with an adaptation equation, based on recent theoretical findings. We describe a systematic method to estimate its parameters with simple electrophysiological protocols (current-clamp injection of pulses and ramps) and apply it to a detailed conductance-based model of a regular spiking neuron. Our simple model predicts correctly the timing of 96% of the spikes (±2 ms) of the detailed model in response to injection of noisy synaptic conductances. The model is especially reliable in high-conductance states, typical of cortical activity in vivo, in which intrinsic conductances were found to have a reduced role in shaping spike trains. These results are promising because this simple model has enough expressive power to reproduce qualitatively several electrophysiological classes described in vitro.

scholarly journals Generalized Integrate-and-Fire Models of Neuronal Activity Approximate Spike Trains of a Detailed Model to a High Degree of Accuracy

2004 ◽  
Vol 92 (2) ◽  
pp. 959-976 ◽  
Author(s):  
Renaud Jolivet ◽  
Timothy J. Lewis ◽  
Wulfram Gerstner
Keyword(s):  
Cortical Neurons ◽  
Direct Reduction ◽  
Spike Trains ◽  
Model Parameters ◽  
Detailed Model ◽  
Fire Model ◽  
Integrate And Fire ◽  
Fire Models ◽  
Wide Range ◽  
Simple Models

We demonstrate that single-variable integrate-and-fire models can quantitatively capture the dynamics of a physiologically detailed model for fast-spiking cortical neurons. Through a systematic set of approximations, we reduce the conductance-based model to 2 variants of integrate-and-fire models. In the first variant (nonlinear integrate-and-fire model), parameters depend on the instantaneous membrane potential, whereas in the second variant, they depend on the time elapsed since the last spike [Spike Response Model (SRM)]. The direct reduction links features of the simple models to biophysical features of the full conductance-based model. To quantitatively test the predictive power of the SRM and of the nonlinear integrate-and-fire model, we compare spike trains in the simple models to those in the full conductance-based model when the models are subjected to identical randomly fluctuating input. For random current input, the simple models reproduce 70–80 percent of the spikes in the full model (with temporal precision of ±2 ms) over a wide range of firing frequencies. For random conductance injection, up to 73 percent of spikes are coincident. We also present a technique for numerically optimizing parameters in the SRM and the nonlinear integrate-and-fire model based on spike trains in the full conductance-based model. This technique can be used to tune simple models to reproduce spike trains of real neurons.

scholarly journals Simple Model for Testing Drugs against Nonreplicating Mycobacterium tuberculosis

2010 ◽  
Vol 54 (10) ◽  
pp. 4150-4158 ◽  
Author(s):  
Claudia Sala ◽  
Neeraj Dhar ◽  
Ruben C. Hartkoorn ◽  
Ming Zhang ◽  
Young Hwan Ha ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Simple Model ◽  
High Throughput Screening ◽  
Phenotypic Resistance ◽  
Experimental Drugs ◽  
Dormant Cells ◽  
Potency Ranking ◽  
Increased Susceptibility

ABSTRACT Nonreplicating or dormant cells of Mycobacterium tuberculosis constitute a challenge to tuberculosis (TB) therapy because of their tolerance or phenotypic resistance to most drugs. Here, we propose a simple model for testing drugs against nongrowing cells that exploits the 18b strain of M. tuberculosis, a streptomycin (STR)-dependent mutant. Optimal conditions were established that allowed 18b cells to replicate in the presence of STR and to survive, but not multiply, following withdrawal of STR. In the presence of the antibiotic, M. tuberculosis 18b was susceptible to the currently approved TB drugs, isoniazid (INH) and rifampin (RIF), and to the experimental drugs TMC207, PA-824, meropenem (MER), benzothiazinone (BTZ), and moxifloxacin (MOXI). After STR depletion, the strain displayed greatly reduced susceptibility to the cell wall inhibitors INH and BTZ but showed increased susceptibility to RIF and PA-824, while MOXI and MER appeared equipotent under both conditions. The same potency ranking was found against nonreplicating M. tuberculosis 18b after in vivo treatment of chronically infected mice with five of these drugs. Despite the growth arrest, strain 18b retains significant metabolic activity in vitro, remaining positive in the resazurin reduction assay. Upon adaption to a 96-well format, this assay was shown to be suitable for high-throughput screening with strain 18b to find new inhibitors of dormant M. tuberculosis.

High-conductance states and A-type K+ channels are potential regulators of the conductance-current balance triggered by HCN channels

2015 ◽  
Vol 113 (1) ◽  
pp. 23-43 ◽  
Author(s):  
Poonam Mishra ◽  
Rishikesh Narayanan
Keyword(s):  
Dominant Role ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Voltage Response ◽  
Hcn Channels ◽  
Type K ◽  
Conductance States ◽  
The Impact ◽  
High Conductance

An increase in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel conductance reduces input resistance, whereas the consequent increase in the inward h current depolarizes the membrane. This results in a delicate and unique conductance-current balance triggered by the expression of HCN channels. In this study, we employ experimentally constrained, morphologically realistic, conductance-based models of hippocampal neurons to explore certain aspects of this conductance-current balance. First, we found that the inclusion of an experimentally determined gradient in A-type K+ conductance, but not in M-type K+ conductance, tilts the HCN conductance-current balance heavily in favor of conductance, thereby exerting an overall restorative influence on neural excitability. Next, motivated by the well-established modulation of neuronal excitability by synaptically driven high-conductance states observed under in vivo conditions, we inserted thousands of excitatory and inhibitory synapses with different somatodendritic distributions. We measured the efficacy of HCN channels, independently and in conjunction with other channels, in altering resting membrane potential (RMP) and input resistance ( Rin) when the neuron received randomized or rhythmic synaptic bombardments through variable numbers of synaptic inputs. We found that the impact of HCN channels on average RMP, Rin, firing frequency, and peak-to-peak voltage response was severely weakened under high-conductance states, with the impinging synaptic drive playing a dominant role in regulating these measurements. Our results suggest that the debate on the role of HCN channels in altering excitability should encompass physiological and pathophysiological neuronal states under in vivo conditions and the spatiotemporal interactions of HCN channels with other channels.

scholarly journals Predicting spike timing in highly synchronous auditory neurons at different sound levels

2013 ◽  
Vol 110 (7) ◽  
pp. 1672-1688 ◽  
Author(s):  
Bertrand Fontaine ◽  
Victor Benichoux ◽  
Philip X. Joris ◽  
Romain Brette
Keyword(s):  
Temporal Structure ◽  
Spike Trains ◽  
Sound Level ◽  
Spike Timing ◽  
Spike Threshold ◽  
Integrate And Fire ◽  
Fire Models ◽  
Wide Range

A challenge for sensory systems is to encode natural signals that vary in amplitude by orders of magnitude. The spike trains of neurons in the auditory system must represent the fine temporal structure of sounds despite a tremendous variation in sound level in natural environments. It has been shown in vitro that the transformation from dynamic signals into precise spike trains can be accurately captured by simple integrate-and-fire models. In this work, we show that the in vivo responses of cochlear nucleus bushy cells to sounds across a wide range of levels can be precisely predicted by deterministic integrate-and-fire models with adaptive spike threshold. Our model can predict both the spike timings and the firing rate in response to novel sounds, across a large input level range. A noisy version of the model accounts for the statistical structure of spike trains, including the reliability and temporal precision of responses. Spike threshold adaptation was critical to ensure that predictions remain accurate at different levels. These results confirm that simple integrate-and-fire models provide an accurate phenomenological account of spike train statistics and emphasize the functional relevance of spike threshold adaptation.

scholarly journals The tomosyn homologue, Sro7, is a direct effector of the Rab GTPase, Sec4, in post-Golgi vesicle tethering

2018 ◽  
Vol 29 (12) ◽  
pp. 1476-1486 ◽  
Author(s):  
Guendalina Rossi ◽  
Kelly Watson ◽  
Wade Kennedy ◽  
Patrick Brennwald
Keyword(s):  
Plasma Membrane ◽  
Simple Model ◽  
Genetic Analysis ◽  
Rab Gtpase ◽  
Vesicle Tethering ◽  
Effector Pathways ◽  
Rab Effector

The tomosyn/Sro7 family is thought to play an important role in cell surface trafficking both as an effector of Rab family GTPases and as a regulator of plasma-membrane SNARE function. Recent work has determined the binding site of GTP-bound Sec4 on Sro7. Here we examine the effect of mutations in Sro7 that block Sec4 binding in determining the role of this interaction in Sro7 function. Using an in vitro vesicle:vesicle tethering assay, we find that most of Sro7’s ability to tether vesicles is blocked by mutations that disrupt binding to Sec4-GTP. Similarly, genetic analysis demonstrates that the interaction with Sec4 is important for most of Sro7’s functions in vivo. The interaction of Sro7 with Sec4 appears to be particularly important when exocyst function is compromised. This provides strong evidence that Sro7 and the exocyst act as dual effector pathways downstream of Sec4. We also demonstrate that Sro7 tethering requires the presence of Sec4 on both opposing membranes and that homo-oligomerization of Sro7 occurs during vesicle tethering. This suggests a simple model for Sro7 function as a Rab effector in tethering post-Golgi vesicles to the plasma membrane in a pathway parallel to that of the exocyst complex.

scholarly journals Thalamocortical synapses in the cat visual system in vivo are weak and unreliable

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Madineh Sedigh-Sarvestani ◽  
Larry A Palmer ◽  
Diego Contreras
Keyword(s):  
Visual System ◽  
Dynamic Properties ◽  
Short Term Plasticity ◽  
V1 Neurons ◽  
Membrane Fluctuations ◽  
Conductance States ◽  
Constrained Models ◽  
High Conductance

The thalamocortical synapse of the visual system has been central to our understanding of sensory computations in the cortex. Although we have a fair understanding of the functional properties of the pre and post-synaptic populations, little is known about their synaptic properties, particularly in vivo. We used simultaneous recordings in LGN and V1 in cat in vivo to characterize the dynamic properties of thalamocortical synaptic transmission in monosynaptically connected LGN-V1 neurons. We found that thalamocortical synapses in vivo are unreliable, highly variable and exhibit short-term plasticity. Using biologically constrained models, we found that variable and unreliable synapses serve to increase cortical firing by means of increasing membrane fluctuations, similar to high conductance states. Thus, synaptic variability and unreliability, rather than acting as system noise, do serve a computational function. Our characterization of LGN-V1 synaptic properties constrains existing mathematical models, and mechanistic hypotheses, of a fundamental circuit in computational neuroscience.

scholarly journals From Subthreshold to Firing-Rate Resonance

2003 ◽  
Vol 89 (5) ◽  
pp. 2538-2554 ◽  
Author(s):  
Magnus J. E. Richardson ◽  
Nicolas Brunel ◽  
Vincent Hakim
Keyword(s):  
Firing Rate ◽  
General Class ◽  
Background Noise ◽  
Low Frequency ◽  
Specific Conductance ◽  
Fire Model ◽  
Integrate And Fire ◽  
Subthreshold Resonance

First published December 27, 2002; 10.1152/jn.00955.2002. Many types of neurons exhibit subthreshold resonance. However, little is known about whether this frequency preference influences spike emission. Here, the link between subthreshold resonance and firing rate is examined in the framework of conductance-based models. A classification of the subthreshold properties of a general class of neurons is first provided. In particular, a class of neurons is identified in which the input impedance exhibits a suppression at a nonzero low frequency as well as a peak at higher frequency. The analysis is then extended to the effect of subthreshold resonance on the dynamics of the firing rate. The considered input current comprises a background noise term, mimicking the massive synaptic bombardment in vivo. Of interest is the modulatory effect an additional weak oscillating current has on the instantaneous firing rate. When the noise is weak and firing regular, the frequency most preferentially modulated is the firing rate itself. Conversely, when the noise is strong and firing irregular, the modulation is strongest at the subthreshold resonance frequency. These results are demonstrated for two specific conductance-based models and for a generalization of the integrate-and-fire model that captures subthreshold resonance. They suggest that resonant neurons are able to communicate their frequency preference to postsynaptic targets when the level of noise is comparable to that prevailing in vivo.

Comparison of discharge variability in vitro and in vivo in cat visual cortex neurons

1996 ◽  
Vol 75 (5) ◽  
pp. 1806-1814 ◽  
Author(s):  
G. R. Holt ◽  
W. R. Softky ◽  
C. Koch ◽  
R. J. Douglas
Keyword(s):  
Visual Cortex ◽  
Background Activity ◽  
Visual Stimuli ◽  
Constant Current ◽  
Interspike Intervals ◽  
Integrate And Fire ◽  
A New Technique ◽  
Visual Cortex Neurons

1. In neocortical slices, the majority of neurons fire quite regularly in response to constant current injections. But neurons in the intact animal fire irregularly in response to constant current injection as well as to visual stimuli. 2. To quantify this observation, we developed a new measure of variability, which compares only adjacent interspike intervals and is therefore less sensitive to rate variations than existing measures such as the coefficient of variation of interspike intervals. 3. We find that the variability of firing is much higher in cells of primary visual cortex in the anesthetized cat than in slice. The response to current injected from an intracellular electrode in vivo is also variable, but slightly more regular and less bursty than in response to visual stimuli. 4. Using a new technique for analyzing the variability of integrate-and-fire neurons, we prove that this behavior is consistent with a simple integrate-and-fire model receiving a large amount of synaptic background activity, but not with a noisy spiking mechanism.

The genetics of cell migration in Drosophila melanogaster and Caenorhabditis elegans development

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3035-3046 ◽  
Author(s):  
D.J. Montell
Keyword(s):  
Cell Migration ◽  
Caenorhabditis Elegans ◽  
Simple Model ◽  
Molecular Mechanisms ◽  
Small Gtpases ◽  
Model Systems ◽  
Model Organisms ◽  
Cell Movements

Cell migrations are found throughout the animal kingdom and are among the most dramatic and complex of cellular behaviors. Historically, the mechanics of cell migration have been studied primarily in vitro, where cells can be readily viewed and manipulated. However, genetic approaches in relatively simple model organisms are yielding additional insights into the molecular mechanisms underlying cell movements and their regulation during development. This review will focus on these simple model systems where we understand some of the signaling and receptor molecules that stimulate and guide cell movements. The chemotactic guidance factor encoded by the Caenorhabditis elegans unc-6 locus, whose mammalian homolog is Netrin, is perhaps the best known of the cell migration guidance factors. In addition, receptor tyrosine kinases (RTKs), and FGF receptors in particular, have emerged as key mediators of cell migration in vivo, confirming the importance of molecules that were initially identified and studied in cell culture. Somewhat surprisingly, screens for mutations that affect primordial germ cell migration in Drosophila have revealed that enzymes involved in lipid metabolism play a role in guiding cell migration in vivo, possibly by producing and/or degrading lipid chemoattractants or chemorepellents. Cell adhesion molecules, such as integrins, have been extensively characterized with respect to their contribution to cell migration in vitro and genetic evidence now supports a role for these receptors in certain instances in vivo as well. The role for non-muscle myosin in cell motility was controversial, but has now been demonstrated genetically, at least in some cell types. Currently the best characterized link between membrane receptor signaling and regulation of the actin cytoskeleton is that provided by the Rho family of small GTPases. Members of this family are clearly essential for the migrations of some cells; however, key questions remain concerning how chemoattractant and chemorepellent signals are integrated within the cell and transduced to the cytoskeleton to produce directed cell migration. New types of genetic screens promise to fill in some of these gaps in the near future.

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