Cellular Sensory Mechanisms for Detecting Specific Fold-Changes in Extracellular Cues

Cellular sensory systems often respond not to the absolute levels of inputs but to the fold-changes in inputs. Such a property is called fold-change detection (FCD) and is important for accurately sensing dynamic changes in environmental signals in the presence of fluctuations in their absolute levels. Previous studies defined FCD as input-scale invariance and proposed several biochemical models that achieve such a condition. Here, we prove that the previous FCD models can be approximated by a log-differentiator. Although the log-differentiator satisfies the input-scale invariance requirement, its response amplitude and response duration strongly depend on the input timescale. This creates limitations in the specificity and repeatability of detecting fold-changes in inputs. Nevertheless, FCD with specificity and repeatability by cells has been reported in the context of Drosophila wing development. Motivated by this fact and by extending previous FCD models, we here propose two possible mechanisms to achieve FCD with specificity and repeatability. One is the integrate-and-fire type: a system integrates the rate of temporal change in input and makes a response when the integrated value reaches a constant threshold, and this is followed by the reset of the integrated value. The other is the dynamic threshold type: a system response occurs when the input level reaches a threshold, whose value is multiplied by a certain constant after each response. These two mechanisms can be implemented biochemically by appropriately combining feed-forward and feedback loops. The main difference between the two models is their memory of input history; we discuss possible ways to distinguish between the two models experimentally.     

Cellular Sensory Mechanisms for Detecting Specific Fold-Changes in Extracellular Cues

Cellular sensory systems often respond not to the absolute levels of inputs but to the fold-changes in inputs. Such a property is called fold-change detection (FCD) and is important for accurately sensing dynamic changes in environmental signals in the presence of fluctuations in their absolute levels. Previous studies defined FCD as input-scale invariance and proposed several biochemical models that achieve such a condition. Here, we prove that the previous FCD models can be approximated by a log-differentiator. Although the log-differentiator satisfies the input-scale invariance requirement, its response amplitude and response duration strongly depend on the input timescale. This creates limitations in the specificity and repeatability of detecting fold-changes in inputs. Nevertheless, FCD with specificity and repeatability by cells has been reported in the context of Drosophila wing development. Motivated by this fact and by extending previous FCD models, we here propose two possible mechanisms to achieve FCD with specificity and repeatability. One is the integrate-and-fire type: a system integrates the rate of temporal change in input and makes a response when the integrated value reaches a constant threshold, and this is followed by the reset of the integrated value. The other is the dynamic threshold type: a system response occurs when the input level reaches a threshold, whose value is multiplied by a certain constant after each response. These two mechanisms can be implemented biochemically by appropriately combining feed-forward and feedback loops. The main difference between the two models is their memory of input history; we discuss possible ways to distinguish between the two models experimentally.     

Logarithmic and Power Law Input-Output Relations in Sensory Systems with Fold-Change Detection

Two central biophysical laws describe sensory responses to input signals. One is a logarithmic relationship between input and output, and the other is a power law relationship. These laws are sometimes called the Weber-Fechner law and the Stevens power law, respectively. The two laws are found in a wide variety of human sensory systems including hearing, vision, taste, and weight perception; they also occur in the responses of cells to stimuli. However the mechanistic origin of these laws is not fully understood. To address this, we consider a class of biological circuits exhibiting a property called fold-change detection (FCD). In these circuits the response dynamics depend only on the relative change in input signal and not its absolute level, a property which applies to many physiological and cellular sensory systems. We show analytically that by changing a single parameter in the FCD circuits, both logarithmic and power-law relationships emerge; these laws are modified versions of the Weber-Fechner and Stevens laws. The parameter that determines which law is found is the steepness (effective Hill coefficient) of the effect of the internal variable on the output. This finding applies to major circuit architectures found in biological systems, including the incoherent feed-forward loop and nonlinear integral feedback loops. Therefore, if one measures the response to different fold changes in input signal and observes a logarithmic or power law, the present theory can be used to rule out certain FCD mechanisms, and to predict their cooperativity parameter. We demonstrate this approach using data from eukaryotic chemotaxis signaling.     

Fold-Change Detection in a Whole-Pathway Model of Escherichia coli chemotaxis

There has been recent interest in sensory systems that are able to display a response which is proportional to a fold change in stimulus concentration, a feature referred to as fold-change detection (FCD). Here, we demonstrate FCD in a recent whole-pathway mathematical model of Escherichia coli chemotaxis. FCD is shown to hold for each protein in the signalling cascade and to be robust to kinetic rate and protein concentration variation. Using a sensitivity analysis, we find that only variations in the number of receptors within a signalling team lead to the model not exhibiting FCD. We also discuss the ability of a cell with multiple receptor types to display FCD and explain how a particular receptor configuration may be used to elucidate the two experimentally determined regimes of FCD behaviour. All findings are discussed in respect of the experimental literature.     

The responses of auditory ventral-cord neurons ofLocusta migratoria to vibration stimuli

Summary Most of the auditory neurons in the ventral nerve cord ofLocusta migratoria carry information not only from the tympanal organs but also from the subgenual organs (vibration sensors). Six of the eight neuron types studied electrophysiologically respond to at least these two modalities. Artificial sounds (white noise and pure tones varying in frequency and intensity) and sinusoidal vibration (200 Hz with an acceleration of 15.8 cm/s₂ or 2000 Hz and 87 cm/s₂) were used as stimuli.Complex excitatory and/or inhibitory interactions of the signals from both tympanal organs form the discharge patterns of auditory ventral-cord neurons in response to stimulation with air-borne sound. Normally the input of the ipsilateral sense organ dominates. The response patterns of these same neurons elicited by vibration stimuli are formed differently, as follows: (1) the sensory inputs of all subgenual organs are integrated in the responses of the ventral-cord neurons; in a single neuron they have either excitatory or inhibitory effects, but not both. (2) The more legs vibrated, the larger is the response. (3) The subgenual organs in the middle legs are most effective, those in the hind legs least so. (4) Ipsilateral vibration has more effect than contralateral.The six auditory neurons react to vibration combined with air-borne sound in different ways. The B neuron is the only one inhibited by vibration stimuli. The G neuron has been studied more intensively; because its anatomical arrangement and the location of the endings of the subgenual receptor fibers are known, it could be inferred from effects of transection of the connectives that interneurons are interposed between receptor cells and the G neuron.Part of the program Sonderforschungsbereich 114 (Bionach) Bochum, under the auspices of the Deutsche Forschungsgemeinschaft, with the support of the Slovenic Research Society (RSS)     

Carrier frequency-sensitive primary auditory neurons in crickets and their anatomical projection to the central nervous system

The tympanal organ of the cricket Scapsipedus marginatus contains receptor neurons that are tuned to the dominant frequency of the species-specific calling song (F₁ units), as demonstrated by single unit recordings. F₁ units have simple threshold curves with just one characteristic frequency, and they can be characterized by their latency and adaptation rate. The pattern with which these units respond to song indicates that they are a principal source of peripheral input to the CNS for song reception. The tympanal nerve sends its sensory arborizations to the ventromedial neuropile of the prothoracic ganglion. Fibers of the tympanal nerve do not cross the midline; nor do they project to other ganglia, insofar as can be demonstrated with cobalt chloride iontophoresis.     

Mechanism Analysis of Acid Tolerance Response of Bifidobacterium longum subsp. longum BBMN 68 by Gene Expression Profile Using RNA-Sequencing

To analyze the mechanism of the acid tolerance response (ATR) in Bifidobacterium longum subsp. longum BBMN68, we optimized the acid-adaptation condition to stimulate ATR effectively and analyzed the change of gene expression profile after acid-adaptation using high-throughput RNA-Seq. After acid-adaptation at pH 4.5 for 2 hours, the survival rate of BBMN68 at lethal pH 3.5 for 120 min was increased by 70 fold and the expression of 293 genes were upregulated by more than 2 fold, and 245 genes were downregulated by more than 2 fold. Gene expression profiling of ATR in BBMN68 suggested that, when the bacteria faced acid stress, the cells strengthened the integrity of cell wall and changed the permeability of membrane to keep the H⁺ from entering. Once the H⁺ entered the cytoplasm, the cells showed four main responses: First, the F₀F₁-ATPase system was initiated to discharge H⁺. Second, the ability to produce NH₃ by cysteine-cystathionine-cycle was strengthened to neutralize excess H⁺. Third, the cells started NER-UVR and NER-VSR systems to minimize the damage to DNA and upregulated HtpX, IbpA, and γ-glutamylcysteine production to protect proteins against damage. Fourth, the cells initiated global response signals ((p)ppGpp, polyP, and Sec-SRP) to bring the whole cell into a state of response to the stress. The cells also secreted the quorum sensing signal (AI-2) to communicate between intraspecies cells by the cellular signal system, such as two-component systems, to improve the overall survival rate. Besides, the cells varied the pathways of producing energy by shifting to BCAA metabolism and enhanced the ability to utilize sugar to supply sufficient energy for the operation of the mechanism mentioned above. Based on these reults, it was inferred that, during industrial applications, the acid resistance of bifidobacteria could be improved by adding BCAA, γ-glutamylcysteine, cysteine, and cystathionine into the acid-stress environment.     

Modeling Chemotaxis Reveals the Role of Reversed Phosphotransfer and a Bi-Functional Kinase-Phosphatase

Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases (HPKs) and response regulators (RRs). These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a HPK, CheA. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1) the main RR controlling flagellar rotation, CheY₆, aided by its specific phosphatase, the bifunctional kinase CheA₃, acts as a phosphate sink for the other RRs; and (2) a phosphorelay pathway involving CheB₂ connects the cytoplasmic cluster kinase CheA₃ with the polar localised kinase CheA₂, and allows CheA₃-P to phosphorylate non-cognate chemotaxis RRs. These two mechanisms enable the bifunctional kinase/phosphatase activity of CheA₃ to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50% of chemotactic bacteria have multiple cheA homologues and need to integrate signals from different sources.     

Transient Responses to Rapid Changes in Mean and Variance in Spiking Models

The mean input and variance of the total synaptic input to a neuron can vary independently, suggesting two distinct information channels. Here we examine the impact of rapidly varying signals, delivered via these two information conduits, on the temporal dynamics of neuronal firing rate responses. We examine the responses of model neurons to step functions in either the mean or the variance of the input current. Our results show that the temporal dynamics governing response onset depends on the choice of model. Specifically, the existence of a hard threshold introduces an instantaneous component into the response onset of a leaky-integrate-and-fire model that is not present in other models studied here. Other response features, for example a decaying oscillatory approach to a new steady-state firing rate, appear to be more universal among neuronal models. The decay time constant of this approach is a power-law function of noise magnitude over a wide range of input parameters. Understanding how specific model properties underlie these response features is important for understanding how neurons will respond to rapidly varying signals, as the temporal dynamics of the response onset and response decay to new steady-state determine what range of signal frequencies a population of neurons can respond to and faithfully encode.     

Ocellar interneurons in the honeybee

Summary Morphologically identified spiking ocellar interneurons (L_B and L_D-neurons) of the honeybee (Apis melliferd) were investigated by combined intracellular recording and staining techniques using multimodal stimulus programs.Response patterns containing both graded and action potentials (mixed response), and pure spiking responses were analysed. Mixed responses allow a comparison of information coded simultaneously by graded and action potentials in one neuron. In most cases the intensity dependence coded by spikes was found to be similar to the intensity dependence coded by one of two different parameters evaluated from the graded signal. Lneurons with mixed responses were unimodal, i.e. they reacted exclusively to stationary illumination of the ocelli, as do nonspiking L-neurons.In contrast, spiking L-neurons that lacked a graded response component could also respond to stimuli of other sensory modalities: moving patterns, compound eye illumination, airstreams, mechanical and gustatory stimulation. One L_D-neuron was also excited by the wing beat.Recordings from the same type of neuron in different individuals demonstrate that the input modalities and response patterns of L-neurons vary remarkably. Consequently many recordings are required to properly characterise the physiological properties of these neurons even though anatomically they are identified.The existence of graded and action potentials in the same cell and the fact that these two signals carry different information is discussed in the context of a possible role for information transmission from L-neurons to postsynaptic cells.Abbreviation R/I response/intensity     

Antennal morphology as a physical filter of olfaction: temporal tuning of the antennae of the honeybee,Apis mellifera

There are many different antennal morphologies for insects, yet they all have the same functional role in olfaction. Chemical signals are dispersed through two physical forces; diffusion and fluid flow. The interaction between antennal morphology and fluid flow generates a region of changing flow velocity called the boundary layer. The boundary layer determines signal dispersion dynamics and therefore influences the signal structure and information that arrives at the receptor cells. To investigate how the boundary layer changes the information in the signals arriving at receptor cells, we measured chemical dynamics within the boundary layer around the bee antennae using microelectrodes. We used two types of chemical signals: pulsed and continuous. The results showed that the boundary layer increased the decay time of the chemical signal for the pulsatile stimuli and increased the peak height for the continuous data. Spectral analysis of continuous signals showed that the temporal aspects of the chemical signal are changed by the boundary layer. Particularly the temporal dynamics of the signal are dampened at the slowest flow speed and amplified at the intermediate and fast flow speeds. By altering the structure of the chemical signal, the morphology will function as a sensory filter.     

Presynaptic Gαo (GOA-1) signals to depress command neuron excitability and allow stretch-dependent modulation of egg laying in Caenorhabditis elegans

Egg laying in the nematode worm Caenorhabditis elegans is a two-state behavior modulated by internal and external sensory input. We have previously shown that homeostatic feedback of embryo accumulation in the uterus regulates bursting activity of the serotonergic HSN command neurons that sustains the egg-laying active state. How sensory feedback of egg release signals to terminate the egg-laying active state is less understood. We find that Gα_o, a conserved Pertussis Toxin-sensitive G protein, signals within HSN to inhibit egg-laying circuit activity and prevent entry into the active state. Gα_o signaling hyperpolarizes HSN, reducing HSN Ca²⁺ activity and input onto the postsynaptic vulval muscles. Loss of inhibitory Gα_o signaling uncouples presynaptic HSN activity from a postsynaptic, stretch-dependent homeostat, causing precocious entry into the egg-laying active state when only a few eggs are present in the uterus. Feedback of vulval opening and egg release activates the uv1 neuroendocrine cells which release NLP-7 neuropeptides which signal to inhibit egg laying through Gα_o-independent mechanisms in the HSNs and Gα_o-dependent mechanisms in cells other than the HSNs. Thus, neuropeptide and inhibitory Gα_o signaling maintain a bi-stable state of electrical excitability that dynamically controls circuit activity in response to both external and internal sensory input to drive a two-state behavior output.     

Predicting Chemical Environments of Bacteria from Receptor Signaling

Sensory systems have evolved to respond to input stimuli of certain statistical properties, and to reliably transmit this information through biochemical pathways. Hence, for an experimentally well-characterized sensory system, one ought to be able to extract valuable information about the statistics of the stimuli. Based on dose-response curves from in vivo fluorescence resonance energy transfer (FRET) experiments of the bacterial chemotaxis sensory system, we predict the chemical gradients chemotactic Escherichia coli cells typically encounter in their natural environment. To predict average gradients cells experience, we revaluate the phenomenological Weber''s law and its generalizations to the Weber-Fechner law and fold-change detection. To obtain full distributions of gradients we use information theory and simulations, considering limitations of information transmission from both cell-external and internal noise. We identify broad distributions of exponential gradients, which lead to log-normal stimuli and maximal drift velocity. Our results thus provide a first step towards deciphering the chemical nature of complex, experimentally inaccessible cellular microenvironments, such as the human intestine.     

The potential for signal integration and processing in interacting MAP kinase cascades

The cellular response to environmental stimuli requires biochemical information processing through which sensory inputs and cellular status are integrated and translated into appropriate responses by way of interacting networks of enzymes. One such network, the mitogen-activated protein (MAP) kinase cascade is a highly conserved signal transduction module that propagates signals from cell surface receptors to various cytosolic and nuclear targets by way of a phosphorylation cascade. We have investigated the potential for signal processing within a network of interacting feed-forward kinase cascades typified by the MAP kinase cascade. A genetic algorithm was used to search for sets of kinetic parameters demonstrating representative key input-output patterns of interest. We discuss two of the networks identified in our study, one implementing the exclusive-or function (XOR) and another implementing what we refer to as an in-band detector (IBD) or two-sided threshold. These examples confirm the potential for logic and amplitude-dependent signal processing in interacting MAP kinase cascades demonstrating limited cross-talk. Specifically, the XOR function allows the network to respond to either one, but not both signals simultaneously, while the IBD permits the network to respond exclusively to signals within a given range of strength, and to suppress signals below as well as above this range. The solution to the XOR problem is interesting in that it requires only two interacting pathways, crosstalk at only one layer, and no feedback or explicit inhibition. These types of responses are not only biologically relevant but constitute signal processing modules that can be combined to create other logical functions and that, in contrast to amplification, cannot be achieved with a single cascade or with two non-interacting cascades. Our computational results revealed surprising similarities between experimental data describing the JNK/MKK4/MKK7 pathway and the solution for the IBD that evolved from the genetic algorithm. The evolved IBD not only exhibited the required non-monotonic signal strength-response, but also demonstrated transient and sustained responses that properly reflected the input signal strength, dependence on both of the MAPKKs for signaling, phosphorylation site preferences by each of the MAPKKs, and both activation and inhibition resulting from the overexpression of one of the MAPKKs.     

Signal processing through a generalized module of adaptation and spatial sensing

Signal transduction in many cellular processes is accompanied by the feature of adaptation, which allows certain key signalling components to respond to temporal and/or spatial variation of external signals, independent of the absolute value of the signal. We extend and formulate a more general module which accounts for robust temporal adaptation and spatial response. In this setting, we examine various aspects of spatial and temporal signalling, as well as the signalling consequences and restrictions imposed by virtue of adaptation. This module is able to exhibit a variety of behaviour in response to temporal, spatial and spatio-temporal inputs. We carefully examine the roles of various parameters in this module and how they affect signal processing and propagation. Overall, we demonstrate how a simple module can account for a range downstream responses to a variety of input signals, and how elucidating the downstream response of many cellular components in systems with such adaptive signalling can be consequently very non-trivial.     

Coevolution of visual signals and eye morphology in Polistes paper wasps

To be effective, signals must propagate through the environment and be detected by receivers. As a result, signal form evolves in response to both the constraints imposed by the transmission environment and receiver perceptual abilities. Little work has examined the extent to which signals may act as selective forces on receiver sensory systems to improve the efficacy of communication. If receivers benefit from accurate signal assessment, selection could favour sensory organs that improve discrimination of established signals. Here, we provide evidence that visual resolution coevolves with visual signals in Polistes wasps. Multiple Polistes species have variable facial patterns that function as social signals, whereas other species lack visual signals. Analysis of 19 Polistes species shows that maximum eye facet size is positively associated with both eye size and presence of visual signals. Relatively larger facets within the eye''s acute zone improve resolution of small images, such as wasp facial signals. Therefore, sensory systems may evolve to optimize signal assessment. Sensory adaptations to facilitate signal detection may represent an overlooked area of the evolution of animal communication.     

Contributions of electric fish to the understanding of sensory processing by reafferent systems.

Sensory systems must solve the inverse problem of determining environmental events based on patterns of neural activity in the central nervous system that are affected by those environmental events. Different environmental events can give rise to indistinguishable patterns of neural activity, so that there will often, perhaps even always, be multiple solutions to a sensory inverse problem. Imaging strategies and brain organization confine these multiple solutions within a bounded set. Three different active strategies may be employed by animals to constrain the number of solutions to the sensory inverse problem: active generation of the energy (carrier) that stimulates receptors; reorientation of the point of view; and control of signal conditioning before transduction (pre-receptor mechanisms). This paper describes how these strategies are used in sensory-motor systems, using electric fish as a paradigmatic example. Carrier generation and receptor tuning to the carrier improve signal to noise ratio. Receptor tuning to different frequency bands of the carrier spectrum allows a sensory system to evaluate different kinds of carrier modulations and to extract the different features of objects in the environment. Pre-receptor mechanisms condition the signals, optimizing their detection at a foveal region where the sensory resolution is maximum. Active orientation of the sensory surface redirects the fovea to explore in detail the source of interesting signals. Sensory input generated by these active exploration mechanisms ('reafference') has two components: one, necessary, derived from the self-generated actions and another, contingent, consisting of the information obtained from the external world. Extracting environmental information ('exafference') requires that the self generated afference be subtracted from the sensory inflow. Such subtraction is often associated with the generation and storage of expectations about sensory inputs. It can be concluded that an animal's perceptual world and its ability to transform the world are inextricably linked. Understanding sensory systems must, therefore, always require understanding the organization of motor behavior.