We consider a multistate extension of the Poissontype channel, originally introduced by Kabanov, in which the channel is a continuous-time Markov chain with transition rates modulated by the input signal. There exist many physical examples of such channels, from optical communication to biological signal transduction: for example, biological systems often transmit information by inducing conformational changes in proteins through varying intensities of light, voltage, or concentration of signaling molecules. Going beyond Kabanov, the multistate extension is crucial for understanding these systems. We focus on the case where the channel is fully observable, i.e., the output is the channel state, and only one state transition is sensitive to the input. Under stationarity, we derive a one-dimensional variational formula for the Shannon capacity. The structural information of the channel is encoded through the invariant measure of an associated Markov chain, and we numerically demonstrate the effect of the underlying graphical structure on the channel's communication capability.

Information theory has been successfully applied to biology with interesting results and applications, ranging from scientific discovery, to system modeling, and engineering. Novel concepts such as semantic and useful information have been proposed to address the peculiarity of biological systems in contrast to Shannon's classical theory. In this paper, the concept of subjective information, previously observed as an emergent property in a simulated biological system with determinate characteristics, is further explored through the proposal of a novel metric for its quantification. This measure is based on a biological system's ability to dynamically sense and react to environmental signals to achieve a goal. The novel metric is validated through the simulation of a computational model that enables its correlation with different strategies for information acquisition from the environment and processing. The obtained results indicate that the proposed measure of subjective information is reliable in quantifying the effectiveness of a biological system's strategy in using information from the environment for its growth and survival.

Similar activity patterns may arise from model neural networks with distinct coupling properties and individual unit dynamics. These similar patterns may, however, respond differently to parameter variations and specifically to tuning of inputs that represent control signals. In this work, we analyze the responses resulting from modulation of a localized input in each of three classes of model neural networks that have been recognized in the literature for their capacity to produce robust three-phase rhythms: coupled fast-slow oscillators, near-heteroclinic oscillators, and threshold-linear networks. Triphasic rhythms, in which each phase consists of a prolonged activation of a corresponding subgroup of neurons followed by a fast transition to another phase, represent a fundamental activity pattern observed across a range of central pattern generators underlying behaviors critical to survival, including respiration, locomotion, and feeding. To perform our analysis, we extend the recently developed local timing response curve (lTRC), which allows us to characterize the timing effects due to perturbations, and we complement our lTRC approach with model-specific dynamical systems analysis. Interestingly, we observe disparate effects of similar perturbations across distinct model classes. Thus, this work provides an analytical framework for studying control of oscillations in nonlinear dynamical systems and may help guide model selection in future efforts to study systems exhibiting triphasic rhythmic activity.

The COVID-19 pandemic has resulted in one of the major challenges for humanity in the 21st century. The impact of these challenges has led to a tremendous loss of life, impact on long-term health, well-being as well as personal psychology, and negative societal changes and not to mention its impact on the global economy. Since this is a health issue, similar to other forms of diseases and pandemics, society has largely relied on the fields of medical, virology, immunology, biotechnology, and pharmaceutical science to develop novel therapeutic solutions for treatments. This has resulted in vaccines that have been rolled out to elevate immunity levels that will hopefully allow the majority of the population to reach herd immunity. However, given the technological advancements that we have reached in the 21st century, questions have also risen as to how other disciplines can play a role in solving and obtaining new knowledge of communicable disease pandemics.

The evolutionary consequences of quorum sensing in regulating bacterial cooperation are not fully understood. In this study, we reveal unexpected effects of regulating public good production through quorum sensing on bacterial population dynamics, showing that quorum sensing can be a collectively harmful alternative to unregulated production. We analyze a birth-death model of bacterial population dynamics accounting for public good production and the presence of non-producing cheaters. Our model demonstrates that when demographic noise is a factor, the consequences of controlling public good production according to quorum sensing depend on the cost of public good production and the growth rate of populations in the absence of public goods. When public good production is inexpensive, quorum sensing is a destructive alternative to unconditional production, in terms of the mean population extinction time. When costs are higher, quorum sensing becomes a constructive strategy for the producing strain, both stabilizing cooperation and decreasing the risk of population extinction.

Fox and Lu introduced a Langevin framework for discrete-time stochastic models of randomly gated ion channels such as the Hodgkin-Huxley (HH) system. They derived a Fokker-Planck equation with state-dependent diffusion tensor [Formula: see text] and suggested a Langevin formulation with noise coefficient matrix [Formula: see text] such that SS[Formula: see text]. Subsequently, several authors introduced a variety of Langevin equations for the HH system. In this article, we present a natural 14-dimensional dynamics for the HH system in which each directed edge in the ion channel state transition graph acts as an independent noise source, leading to a 14 [Formula: see text] 28 noise coefficient matrix [Formula: see text]. We show that (1) the corresponding 14D system of ordinary differential equations is consistent with the classical 4D representation of the HH system; (2) the 14D representation leads to a noise coefficient matrix [Formula: see text] that can be obtained cheaply on each time step, without requiring a matrix decomposition; (3) sample trajectories of the 14D representation are pathwise equivalent to trajectories of Fox and Lu's system, as well as trajectories of several existing Langevin models; (4) our 14D representation (and those equivalent to it) gives the most accurate interspike interval distribution, not only with respect to moments but under both the [Formula: see text] and [Formula: see text] metric-space norms; and (5) the 14D representation gives an approximation to exact Markov chain simulations that are as fast and as efficient as all equivalent models. Our approach goes beyond existing models, in that it supports a stochastic shielding decomposition that dramatically simplifies [Formula: see text] with minimal loss of accuracy under both voltage- and current-clamp conditions.

Biochemical signal transduction, a form of molecular communication, can be modeled using graphical Markov channels with input-modulated transition rates. Such channel models are strongly non-Gaussian. In this paper we use a linear noise approximation to construct a novel class of Gaussian additive white noise channels that capture essential features of fully- and partially-observed intensity- driven signal transduction. When channel state transitions that are sensitive to the input signal are directly observable, high-frequency information is transduced more efficiently than low-frequency information, and the mutual information rate per bandwidth (spectral efficiency) is significantly greater than when sensitive transitions and observable transitions are disjoint. When both observable and hidden transitions are input-sensitive, we observe a superadditive increase in spectral efficiency.

In this paper, we consider the energy cost of communicating using molecular communication. In a simplified scenario, we show that the energy bound in Landauer's principle can be achieved, implying that molecular communication can approach fundamental thermodynamic limits.

Nerve cells produce electrical impulses ("spikes") through the coordinated opening and closing of ion channels. Markov processes with voltage-dependent transition rates capture the stochasticity of spike generation at the cost of complex, time-consuming simulations. Schmandt and Galán introduced a novel method, based on the stochastic shielding approximation, as a fast, accurate method for generating approximate sample paths with excellent first and second moment agreement to exact stochastic simulations. We previously analyzed the mathematical basis for the method's remarkable accuracy, and showed that for models with a Gaussian noise approximation, the stationary variance of the occupancy at each vertex in the ion channel state graph could be written as a sum of distinct contributions from each edge in the graph. We extend this analysis to arbitrary discrete population models with first-order kinetics. The resulting decomposition allows us to rank the "importance" of each edge's contribution to the variance of the current under stationary conditions. In most cases, transitions between open (conducting) and closed (non-conducting) states make the greatest contributions to the variance, but there are exceptions. In a 5-state model of the nicotinic acetylcholine receptor, at low agonist concentration, a pair of "hidden" transitions (between two closed states) makes a greater contribution to the variance than any of the open-closed transitions. We exhaustively investigate this "edge importance reversal" phenomenon in simplified 3-state models, and obtain an exact formula for the contribution of each edge to the variance of the open state. Two conditions contribute to reversals: the opening rate should be faster than all other rates in the system, and the closed state leading to the opening rate should be sparsely occupied. When edge importance reversal occurs, current fluctuations are dominated by a slow noise component arising from the hidden transitions.

Information theory provides powerful tools for understanding communication systems. This analysis can be applied to intercellular signal transduction, which is a means of chemical communication among cells and microbes. We discuss how to apply information-theoretic analysis to ligand-receptor systems, which form the signal carrier and receiver in intercellular signal transduction channels. We also discuss the applications of these results to neuroscience.

Cyclic adenosine monophosphate (cAMP) is considered a model system for signal transduction, the mechanism by which cells exchange chemical messages. Our previous work calculated the Shannon capacity of a single cAMP receptor; however, a typical cell may have thousands of receptors operating in parallel. In this paper, we calculate the capacity of a cAMP signal transduction system with an arbitrary number of independent, indistinguishable receptors. By leveraging prior results on feedback capacity for a single receptor, we show (somewhat unexpectedly) that the capacity is achieved by an IID input distribution, and that the capacity for n receptors is n times the capacity for a single receptor.

We model biochemical signal transduction, based on a ligand-receptor binding mechanism, as a discrete-time finite-state Markov channel, which we call the binding in discrete time channel. We show how to obtain the capacity of this channel, for the case of binary output, binary channel state, and arbitrary finite input alphabets. We show that the capacity-achieving input distribution is identically and independently distributed. Furthermore, we show that feedback does not increase the capacity of this channel. We show how the capacity of the discrete-time channel approaches the capacity of Kabanov's Poisson channel, in the limit of short time steps and rapid ligand release.

We model the ligand-receptor molecular communication channel with a discrete-time Markov model, and show how to obtain the capacity of this channel. We show that the capacity-achieving input distribution is iid; further, unusually for a channel with memory, we show that feedback does not increase the capacity of this channel.

The response of a neuron to repeated somatic fluctuating current injections in vitro can elicit a reliable and precisely timed sequence of action potentials. The set of responses obtained across trials can also be interpreted as the response of an ensemble of similar neurons receiving the same input, with the precise spike times representing synchronous volleys that would be effective in driving postsynaptic neurons. To study the reproducibility of the output spike times for different conditions that might occur in vivo, we somatically injected aperiodic current waveforms into cortical neurons in vitro and systematically varied the amplitude and DC offset of the fluctuations. As the amplitude of the fluctuations was increased, reliability increased and the spike times remained stable over a wide range of values. However, at specific values called bifurcation points, large shifts in the spike times were obtained in response to small changes in the stimulus, resulting in multiple spike patterns that were revealed using an unsupervised classification method. Increasing the DC offset, which mimicked an overall increase in network background activity, also revealed bifurcation points and increased the reliability. Furthermore, the spike times shifted earlier with increasing offset. Although the reliability was reduced at bifurcation points, a theoretical analysis showed that the information about the stimulus time course was increased because each of the spike time patterns contained different information about the input.

Neurons in sensory systems convey information about physical stimuli in their spike trains. In vitro, single neurons respond precisely and reliably to the repeated injection of the same fluctuating current, producing regions of elevated firing rate, termed events. Analysis of these spike trains reveals that multiple distinct spike patterns can be identified as trial-to-trial correlations between spike times (Fellous, Tiesinga, Thomas, & Sejnowski, 2004 ). Finding events in data with realistic spiking statistics is challenging because events belonging to different spike patterns may overlap. We propose a method for finding spiking events that uses contextual information to disambiguate which pattern a trial belongs to. The procedure can be applied to spike trains of the same neuron across multiple trials to detect and separate responses obtained during different brain states. The procedure can also be applied to spike trains from multiple simultaneously recorded neurons in order to identify volleys of near-synchronous activity or to distinguish between excitatory and inhibitory neurons. The procedure was tested using artificial data as well as recordings in vitro in response to fluctuating current waveforms.

Chemical reaction networks by which individual cells gather and process information about their chemical environments have been dubbed "signal transduction" networks. Despite this suggestive terminology, there have been few attempts to analyze chemical signaling systems with the quantitative tools of information theory. Gradient sensing in the social amoeba Dictyostelium discoideum is a well characterized signal transduction system in which a cell estimates the direction of a source of diffusing chemoattractant molecules based on the spatiotemporal sequence of ligand-receptor binding events at the cell membrane. Using Monte Carlo techniques (MCell) we construct a simulation in which a collection of individual ligand particles undergoing Brownian diffusion in a three-dimensional volume interact with receptors on the surface of a static amoeboid cell. Adapting a method for estimation of spike train entropies described by Victor (originally due to Kozachenko and Leonenko), we estimate lower bounds on the mutual information between the transmitted signal (direction of ligand source) and the received signal (spatiotemporal pattern of receptor binding/unbinding events). Hence we provide a quantitative framework for addressing the question: how much could the cell know, and when could it know it? We show that the time course of the mutual information between the cell's surface receptors and the (unknown) gradient direction is consistent with experimentally measured cellular response times. We find that the acquisition of directional information depends strongly on the time constant at which the intracellular response is filtered. 1 Introduction: gradient sensing in eukaryotes Biochemical signal transduction networks provide the computational machinery by which neurons, amoebae or other single cells sense and react to their chemical environments. The precision of this chemical sensing is limited by fluctuations inherent in reaction and diffusion processes involving a Current address: Computational Neuroscience Graduate Program, The University of Chicago. Oberlin Center for Computation and Modeling, http://occam.oberlin.edu/. To whom correspondence should be addressed. http://www.case.edu/artsci/math/thomas/thomas.html; Oberlin College Research Associate. finite quantity of molecules [1, 2]. The theory of communication provides a framework that makes explicit the noise dependence of chemical signaling. For example, in any reaction A + B C , we may view the time varying reactant concentrations A(t) and B (t) as input signals to a noisy channel, and the product concentration C (t) as an output signal carrying information about A(t) and B (t). In the present study we show that the mutual information between the (known) state of the cell's surface receptors and the (unknown) gradient direction follows a time course consistent with experimentally measured cellular response times, reinforcing earlier claims that information theory can play a role in understanding biochemical cellular communication [3, 4]. Dictyostelium is a soil dwelling amoeba that aggregates into a multicellular form in order to survive conditions of drought or starvation. During aggregation individual amoebae perform chemotaxis, or chemically guided movement, towards sources of the signaling molecule cAMP, secreted by nearby amoebae. Quantitive studies have shown that Dictyostelium amoebae can sense shallow, static gradients of cAMP over long time scales (30 minutes), and that gradient steepness plays a crucial role in guiding cells [5]. The chemotactic efficiency (CE), the population average of the cosine between the cell displacement directions and the true gradient direction, peaks at a cAMP concentration of 25 nanoMolar, similar to the equilibrium constant for the cAMP receptor (the Keq is the concentration of cAMP at which the receptor has a 50% chance of being bound or unbound, respectively). For smaller or larger concentrations the CE dropped rapidly. Nevertheless over long times cells were able (on average) to detect gradients as small as 2% change in [cAMP] per cell length. At an early stage of development when the pattern of chemotactic centers and spirals is still forming, individual amoebae presumably experience an inchoate barrage of weak, noisy and conflicting directional signals. When cAMP binds receptors on a cell's surface, second messengers trigger a chain of subsequent intracellular events including a rapid spatial reorganization of proteins involved in cell motility. Advances in fluorescence microscopy have revealed that the oriented subcellular response to cAMP stimulation is already well underway within two seconds [6, 7]. In order to understand the fundamental limits to communication in this cell signaling process we abstract the problem faced by a cell to that of rapidly identifying the direction of origin of a stimulus gradient superimposed on an existing mean background concentration. We model gradient sensing as an information channel in which an input signal the direction of a chemical source is noisily transmitted via a gradient of diffusing signaling molecules; and the "received signal" is the spatiotemporal pattern of binding events between cAMP and the cAMP receptors [8]. We neglect downstream intracellular events, which cannot increase the mutual information between the state of the cell and the direction of the imposed extracellular gradient [9]. The analysis of any signal transmission system depends on precise representation of the noise corrupting transmitted signals. We develop a Monte Carlo simulation (MCell, [10, 11]) in which a simulated cell is exposed to a cAMP distribution that evolves from a uniform background to a gradient at low (1 nMol) average concentration. The noise inherent in the communication of a diffusionmediated signal is accurately represented by this method. Our approach bridges both the transient and the steady state regimes and allows us to estimate the amount of stimulus-related information that is in principle available to the cell through its receptors as a function of time after stimulus initiation. Other efforts to address aspects of cell signaling using the conceptual tools of information theory have considered neurotransmitter release [3] and sensing temporal signals [4], but not gradient sensing in eukaryotic cells. A typical natural habitat for social amoebae such as Dictyostelium is the complex anisotropic threedimensional matrix of the forest floor. Under experimental conditions cells typically aggregate on a flat two-dimensional surface. We approach the problem of gradient sensing on a sphere, which is both harder and more natural for the ameoba, while still simple enough for us analytically and numerically. Directional data is naturally described using unit vectors in spherical coordinates, but the ameobae receive signals as binding events involving intramembrane protein complexes, so we have developed a method for projecting the ensemble of receptor bindings onto coordinates in R3 . In loose analogy with the chemotactic efficiency [5], we compare the projected directional estimate with the true gradient direction represented as a unit vector on S2 . Consistent with observed timing of the cell's response to cAMP stimulation, we find that the directional signal converges quickly enough for the cell to make a decision about which direction to move within the first two seconds following stimulus onset. 2 Methods 2.1 Monte Carlo simulations Using MCell and DReAMM [10, 11] we construct a spherical cell (radius R = 7.5m, [12]) centered in a cubic volume (side length L = 30m). N = 980 triangular tiles partition the surface (mesh generated by DOME1 ); each contained one cell surface receptor for cAMP with binding rate k+ = 4.4 107 sec-1 M-1 , first-order cAMP unbinding rate k- = 1.1 sec-1 [12] and Keq = k- /k+ = 25nMol cAMP. We established a baseline concentration of approximately 1nMol by releasing a cAMP bolus at time 0 inside the cube with zero-flux boundary conditions imposed on each wall. At t = 2 seconds we introduced a steady flux at the x = -L/2 wall of 1 molecule of cAMP per square micron per msec, adding signaling molecules from the left. Simultaneously, the x = +L/2 wall of the cube assumes absorbing boundary conditions. The new boundary conditions lead (at equilibrium) to a linear gradient of 2 nMol/30m, ranging from 2.0 nMol at the flux source wall to 0 nMol at the absorbing wall (see Figure 1); the concentration profile approaches this new steady state with time constant of approximately 1.25 msec. Sampling boxes centered along the planes x = 13.5m measured the local concentration, allowing us to validate the expected model behavior. Figure 1: Gradient sensing simulations performed with MCell (a Monte Carlo simulator of cellular microphysiology, http://www.mcell.cnl.salk.edu/) and rendered with DReAMM (Design, Render, and Animate MCell Models, http://www.mcell.psc.edu/). The model cell comprised a sphere triangulated with 980 tiles with one cAMP receptor per tile. Cell radius R = 7.5m; cube side L = 30m. Left: Initial equilibrium condition, before imposition of gradient. [cAMP] 1nMol (c. 15,000 molecules in the volume outside the sphere). Right: Gradient condition after transient (c. 15,000 molecules; see Methods for details).

Many observers see geometric visual hallucinations after taking hallucinogens such as LSD, cannabis, mescaline or psilocybin; on viewing bright flickering lights; on waking up or falling asleep; in "near-death" experiences; and in many other syndromes. Klüver organized the images into four groups called form constants: (I) tunnels and funnels, (II) spirals, (III) lattices, including honeycombs and triangles, and (IV) cobwebs. In most cases, the images are seen in both eyes and move with them. We interpret this to mean that they are generated in the brain. Here, we summarize a theory of their origin in visual cortex (area V1), based on the assumption that the form of the retino-cortical map and the architecture of V1 determine their geometry. (A much longer and more detailed mathematical version has been published in Philosophical Transactions of the Royal Society B, 356 [2001].) We model V1 as the continuum limit of a lattice of interconnected hypercolumns, each comprising a number of interconnected iso-orientation columns. Based on anatomical evidence, we assume that the lateral connectivity between hypercolumns exhibits symmetries, rendering it invariant under the action of the Euclidean group E(2), composed of reflections and translations in the plane, and a (novel) shift-twist action. Using this symmetry, we show that the various patterns of activity that spontaneously emerge when V1's spatially uniform resting state becomes unstable correspond to the form constants when transformed to the visual field using the retino-cortical map. The results are sensitive to the detailed specification of the lateral connectivity and suggest that the cortical mechanisms that generate geometric visual hallucinations are closely related to those used to process edges, contours, surfaces, and textures.