1,511 research outputs found
Stochastic models for the in silico simulation of synaptic processes
Background: Research in life sciences is benefiting from a large availability of formal description techniques and analysis methodologies. These allow both the phenomena investigated to be precisely modeled and virtual experiments to be performed in silico. Such experiments may result in easier, faster, and satisfying approximations of their in vitro/vivo
counterparts. A promising approach is represented by the study of biological phenomena as a collection of interactive entities through process calculi equipped with stochastic semantics. These exploit formal grounds developed in the theory of concurrency in computer science, account for the not continuous, nor discrete, nature of many phenomena,
enjoy nice compositional properties and allow for simulations that have been demonstrated to be coherent with data in literature.
Results: Motivated by the need to address some aspects of the functioning of neural synapses, we have developed one such model for synaptic processes in the calyx of Held, which is a glutamatergic synapse in the auditory pathway of the
mammalia. We have developed such a stochastic model starting from existing kinetic models based on ODEs of some sub-components of the synapse, integrating other data from literature and making some assumptions about non-fully understood processes. Experiments have confirmed the coherence of our model with known biological data, also
validating the assumptions made. Our model overcomes some limitations of the kinetic ones and, to our knowledge, represents the first model of synaptic processes based on process calculi. The compositionality of the approach has permitted us to independently focus on tuning the models of the pre- and post- synaptic traits, and then to naturally connect them, by dealing with “interface” issues. Furthermore, we have improved the expressiveness of the model, e.g. by embedding easy control of element concentration time courses. Sensitivity analysis over several parameters of the
model has provided results that may help clarify the dynamics of synaptic transmission, while experiments with the model
of the complete synapse seem worth explaining short-term plasticity mechanisms.
Conclusions: Specific presynaptic and postsynaptic mechanisms can be further analysed under various conditions, for instance by studying the presynaptic behaviour under repeated activations. The level of details of the description can be refined, for instance by further specifying the neurotransmitter generation and release steps. Taking advantage of the
compositionality of the approach, an enhanced model could then be composed with other neural models, designed within the same framework, in order to obtain a more detailed and comprehensive model. In the long term, we are interested, in particular, in addressing models of synaptic plasticity, i.e. activity dependent mechanisms, which are the bases of
memory and learning processes.
More on the computer science side, we plan to follow some directions to improve the underlying computational model
and the linguistic primitives it provides as suggested by the experiments carried out, e.g. by introducing a suitable notion of (spatial) locality
Disentangling astroglial physiology with a realistic cell model in silico
Electrically non-excitable astroglia take up neurotransmitters, buffer extracellular K+ and generate Ca2+ signals that release molecular regulators of neural circuitry. The underlying machinery remains enigmatic, mainly because the sponge-like astrocyte morphology has been difficult to access experimentally or explore theoretically. Here, we systematically incorporate multi-scale, tri-dimensional astroglial architecture into a realistic multi-compartmental cell model, which we constrain by empirical tests and integrate into the NEURON computational biophysical environment. This approach is implemented as a flexible astrocyte-model builder ASTRO. As a proof-of-concept, we explore an in silico astrocyte to evaluate basic cell physiology features inaccessible experimentally. Our simulations suggest that currents generated by glutamate transporters or K+ channels have negligible distant effects on membrane voltage and that individual astrocytes can successfully handle extracellular K+ hotspots. We show how intracellular Ca2+ buffers affect Ca2+ waves and why the classical Ca2+ sparks-and-puffs mechanism is theoretically compatible with common readouts of astroglial Ca2+ imaging
Detailed simulations of cell biology with Smoldyn 2.1.
Most cellular processes depend on intracellular locations and random collisions of individual protein molecules. To model these processes, we developed algorithms to simulate the diffusion, membrane interactions, and reactions of individual molecules, and implemented these in the Smoldyn program. Compared to the popular MCell and ChemCell simulators, we found that Smoldyn was in many cases more accurate, more computationally efficient, and easier to use. Using Smoldyn, we modeled pheromone response system signaling among yeast cells of opposite mating type. This model showed that secreted Bar1 protease might help a cell identify the fittest mating partner by sharpening the pheromone concentration gradient. This model involved about 200,000 protein molecules, about 7000 cubic microns of volume, and about 75 minutes of simulated time; it took about 10 hours to run. Over the next several years, as faster computers become available, Smoldyn will allow researchers to model and explore systems the size of entire bacterial and smaller eukaryotic cells
Deterministic networks for probabilistic computing
Neural-network models of high-level brain functions such as memory recall and
reasoning often rely on the presence of stochasticity. The majority of these
models assumes that each neuron in the functional network is equipped with its
own private source of randomness, often in the form of uncorrelated external
noise. However, both in vivo and in silico, the number of noise sources is
limited due to space and bandwidth constraints. Hence, neurons in large
networks usually need to share noise sources. Here, we show that the resulting
shared-noise correlations can significantly impair the performance of
stochastic network models. We demonstrate that this problem can be overcome by
using deterministic recurrent neural networks as sources of uncorrelated noise,
exploiting the decorrelating effect of inhibitory feedback. Consequently, even
a single recurrent network of a few hundred neurons can serve as a natural
noise source for large ensembles of functional networks, each comprising
thousands of units. We successfully apply the proposed framework to a diverse
set of binary-unit networks with different dimensionalities and entropies, as
well as to a network reproducing handwritten digits with distinct predefined
frequencies. Finally, we show that the same design transfers to functional
networks of spiking neurons.Comment: 22 pages, 11 figure
3D mesh processing using GAMer 2 to enable reaction-diffusion simulations in realistic cellular geometries
Recent advances in electron microscopy have enabled the imaging of single
cells in 3D at nanometer length scale resolutions. An uncharted frontier for in
silico biology is the ability to simulate cellular processes using these
observed geometries. Enabling such simulations requires watertight meshing of
electron micrograph images into 3D volume meshes, which can then form the basis
of computer simulations of such processes using numerical techniques such as
the Finite Element Method. In this paper, we describe the use of our recently
rewritten mesh processing software, GAMer 2, to bridge the gap between poorly
conditioned meshes generated from segmented micrographs and boundary marked
tetrahedral meshes which are compatible with simulation. We demonstrate the
application of a workflow using GAMer 2 to a series of electron micrographs of
neuronal dendrite morphology explored at three different length scales and show
that the resulting meshes are suitable for finite element simulations. This
work is an important step towards making physical simulations of biological
processes in realistic geometries routine. Innovations in algorithms to
reconstruct and simulate cellular length scale phenomena based on emerging
structural data will enable realistic physical models and advance discovery at
the interface of geometry and cellular processes. We posit that a new frontier
at the intersection of computational technologies and single cell biology is
now open.Comment: 39 pages, 14 figures. High resolution figures and supplemental movies
available upon reques
Stochasticity from function -- why the Bayesian brain may need no noise
An increasing body of evidence suggests that the trial-to-trial variability
of spiking activity in the brain is not mere noise, but rather the reflection
of a sampling-based encoding scheme for probabilistic computing. Since the
precise statistical properties of neural activity are important in this
context, many models assume an ad-hoc source of well-behaved, explicit noise,
either on the input or on the output side of single neuron dynamics, most often
assuming an independent Poisson process in either case. However, these
assumptions are somewhat problematic: neighboring neurons tend to share
receptive fields, rendering both their input and their output correlated; at
the same time, neurons are known to behave largely deterministically, as a
function of their membrane potential and conductance. We suggest that spiking
neural networks may, in fact, have no need for noise to perform sampling-based
Bayesian inference. We study analytically the effect of auto- and
cross-correlations in functionally Bayesian spiking networks and demonstrate
how their effect translates to synaptic interaction strengths, rendering them
controllable through synaptic plasticity. This allows even small ensembles of
interconnected deterministic spiking networks to simultaneously and
co-dependently shape their output activity through learning, enabling them to
perform complex Bayesian computation without any need for noise, which we
demonstrate in silico, both in classical simulation and in neuromorphic
emulation. These results close a gap between the abstract models and the
biology of functionally Bayesian spiking networks, effectively reducing the
architectural constraints imposed on physical neural substrates required to
perform probabilistic computing, be they biological or artificial
Structural Analysis and Stochastic Modelling Suggest a Mechanism for Calmodulin Trapping by CaMKII
Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as “calmodulin trapping”. It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively. We built structural models of calmodulin bound to both of these sites. Molecular dynamics simulation showed that while binding of calmodulin to the supposed low-affinity binding site on CaMKII is compatible with closing (and hence, inactivation) of the kinase, and could even favour it, binding to the high-affinity site is not. Stochastic simulations of a biochemical model showed that the existence of two such binding sites, one of them accessible only in the active, open conformation, would be sufficient to explain calmodulin trapping by CaMKII. We can explain the effect of CaMKII autophosphorylation at Thr286 on calmodulin trapping: It stabilises the active state and therefore makes the high-affinity binding site accessible. Crucially, a model with only one binding site where calmodulin binding and CaMKII inactivation are strictly mutually exclusive cannot reproduce calmodulin trapping. One of the predictions of our study is that calmodulin binding in itself is not sufficient for CaMKII activation, although high-affinity binding of calmodulin is
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