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Biology subjects

Nemenman, I.

Publications and source records attributed to Nemenman, I..

At least 19 recordsLinked to original sources

Hormones: what are they good for?

Animals use long-range signals, such as hormones and neural signals, to coordinate the actions of distant organs. There is no precise, quantitative framework that explains the problems these control systems must solve and thus predicts their behavior under varied conditions. We consider this problem in the context of blood glucose regulation by the hormone insulin, the failure of which produces diabetes. We show that existing mathematical models of glucose regulation admit equivalent control strategies with no hormones at all, and thus cannot explain the need for hormonal regulation. We therefore introduce a minimal model of inter-organ variations in local glucose, and show that control strategies based on local glucose measurements face severe trade-offs between different control objectives. In contrast, we show that hormonal control signals from the pancreas can overcome these limitations. By exposing the benefits of hormonal control, our work paves the way to a detailed understanding of physiological design principles, with possible implications for the engineering of an artificial pancreas.

physiology↗

Variance in C. elegans gut bacterial load suggests complex host-microbe dynamics

Variation in bacterial composition inside a host is a result of complex dynamics of microbial community assembly, but little is known about these dynamics. To deconstruct the factors that contribute to this variation, we used a combination of experimental and modeling approaches. We found that demographic stochasticity and stationary heterogeneity in the host carrying capacity or bacterial growth rate are insufficient to explain quantitatively the variation observed in our empirical data. Instead, we found that the data can be understood if the host-bacteria system can be viewed as stochastically switching between high and low growth rates phenotypes. This suggests the dynamics significantly more complex than logistic growth used in canonical models of microbiome assembly. We develop mathematical models of this process that can explain various aspects of our data. We highlight the limitations of snapshot data in describing variation in host-associated communities and the importance of using time-series data along with mathematical models to understand microbial dynamics within a host.

biophysics↗

Millisecond-scale motor control precedes sensorimotor learning in Bengalese finches

The changes in neural activity that underlie motor skill acquisition during development are unknown. Juvenile songbirds learn their songs by an imitative process, and after learning adults use a millisecond-precise spike timing code to control vocal acoustics. Current theories suggest that developmental changes in neural firing rates, rather than precisely timed spike patterns, underlie the emergence of learning. Here we tested the hypothesis that songbirds transition from a rate-based to a spike-timing-based motor code during the process of vocal development. To do so, we recorded vocal motor neurons across development as individual Bengalese finches learned their songs. Contrary to our hypothesis, we found that despite dramatic changes in firing statistics during development, millisecond-scale spike pattern codes for vocal acoustics are present throughout all stages of vocal development. Furthermore, firing rate fluctuations are no more predictive of song output in young learners than in expert adults. The dramatic changes in spiking statistics observed during song learning therefore do not reflect a developmental change in the timescale of motor coding, but instead signals the selection of a particular subset of precisely timed spike patterns. We speculate that such patterns are favored because they most reliably modulate behavior.

neuroscience↗

Correlations in microbial abundance data reveal host-bacteria and bacteria-bacteria interactions jointly shaping the C. elegans microbiome

Compositional structure of host-associated microbiomes is potentially affected by interactions among the microbes and between the microbes and the host. To quantify the relative importance of these contributions to the microbiome composition and variation, here we analyze absolute abundance (count) data for a minimal eight-species native microbiome in the Caenorhabditis elegans intestine. We find that a simple neutral model only considering migration, birth, death, and competition for space among the bacteria can capture the means and variances of bacterial abundance, but not the experimental bacteria-bacteria covariances. We find that either bacteria-bacteria interactions or correlations among bacterial population dynamics parameters induced by the host can qualitatively recapitulate the observed correlations among bacterial taxa. However, neither model is uniquely or completely sufficient to explain the data. Further, we observe that different interactions are required to explain (co)variance data in microbiota associated with different host genotypes, suggesting different community dynamics associated with these host types. Finally, we find that many of these signals are obscured when data are converted to proportions from counts, consistent with a growing literature on the limitations of compositional data for inference of population dynamics. We end with discussing the limitations of Lotka-Volterra type assumptions for microbial community data analysis revealed by our results.

biophysics↗

A mathematical model for ketosis-prone diabetes suggests the existence of multiple pancreatic β-cell inactivation mechanisms

Ketosis-prone diabetes mellitus (KPD) is a subtype of type 2 diabetes, which presents much like type 1 diabetes, with dramatic hyperglycemia and ketoacidosis. Although KPD patients are initially insulin-dependent, after a few months of insulin treatment, roughly 70% undergo near-normoglycemia remission and can maintain blood glucose without insulin, as in early type 2 diabetes or prediabetes. Here, we propose that these phenomena can be explained by the existence of a fast, reversible glucotoxicity process, which may exist in all people but be more pronounced in those susceptible to KPD. We develop a simple mathematical model of the pathogenesis of KPD, which incorporates this assumption, and show that it reproduces the phenomenology of KPD, including variations in the ability for patients to achieve and sustain remission. These results suggest that a variation of our model may be able to quantitatively describe variations in the course of remission among individuals with KPD.

systems biology↗

Maximum Likelihood Estimators For Colony Forming Units

There is a recognized need to measure the abundance of microbes in hospital environments, in the sanitation industry, and in food preparation. Doctors, microbiologists, and food safety experts have been addressing this need by using serial dilution methods to grow bacterial colonies in small enough numbers to count and, from these counts, to infer bacterial concentrations measured in Colony Forming Units (CFUs). There are two primary types of such methods: plating bacteria on a growth medium and counting their resulting colonies or counting the number of tubes at a given dilution that have growth. Traditionally, these types of data have been analyzed separately using different analytic methods. Here we build a direct correspondence between these approaches, which allows one to extend the use of the Most Probable Number (MPN) method from the liquid tubes experiments, for which it was developed, to the growth plates. We also discuss how to combine measurements taken at different dilutions, and we review several ways of analyzing colony counts, including the Poison and truncated Poison methods. For all methods, we discuss their relevant error bounds, assumptions, strengths, and weaknesses. We provide an online calculator for these estimators.

biophysics↗

Multi-dimensional structure of C. elegans thermal learning

Quantitative models of associative learning that explain behavior of real animals with high precision have turned out very difficult to construct. We do this in the context of the dynamics of the thermal preference of C. elegans. For this, we quantify C. elegans thermotaxis in response to various conditioning parameters, genetic perturbations, and operant behavior using a fast, high-throughput microfluidic droplet assay. We then model this data comprehensively, within a new, biologically interpretable, multi-modal framework. We discover that the dynamics of thermal preference are described by two independent contributions and require a model with at least four dynamical variables. One pathway positively associates the experienced temperature independently of food and the other negatively associates to the temperature when food is absent.

biophysics↗

Constrained brain volume in an efficient coding model explains the fraction of excitatory and inhibitory neurons in sensory cortices

The number of neurons in mammalian cortex varies by multiple orders of magnitude across different species. In contrast, the ratio of excitatory to inhibitory neurons (E:I ratio) varies in a much smaller range, from 3:1 to 9:1 and remains roughly constant for different sensory areas within a species. Despite this structure being important for understanding the function of neural circuits, the reason for this consistency is not yet understood. While recent models of vision based on the efficient coding hypothesis show that increasing the number of both excitatory and inhibitory cells improves stimulus representation, the two cannot increase simultaneously due to constraints on brain volume. In this work, we implement an efficient coding model of vision under a volume (i.e., total number of neurons) constraint while varying the E:I ratio. We show that the performance of the model is optimal at biologically observed E:I ratios under several metrics. We argue that this happens due to trade-offs between the computational accuracy and the representation capacity for natural stimuli. Further, we make experimentally testable predictions that 1) the optimal E:I ratio should be higher for species with a higher sparsity in the neural activity and 2) the character of inhibitory synaptic distributions and firing rates should change depending on E:I ratio. Our findings, which are supported by our new preliminary analyses of publicly available data, provide the first quantitative and testable hypothesis based on optimal coding models for the distribution of neural types in the mammalian sensory cortices.

neuroscience↗

Latent dynamical variables produce signatures of spatiotemporal criticality in large biological systems

Understanding the activity of large populations of neurons is difficult due to the combinatorial complexity of possible cell-cell interactions. To reduce the complexity, coarse-graining had been previously applied to experimental neural recordings, which showed over two decades of scaling in free energy, activity variance, eigenvalue spectra, and correlation time, hinting that the mouse hippocampus operates in a critical regime. We model the experiment by simulating conditionally independent binary neurons coupled to a small number of long-timescale stochastic fields and then replicating the coarse-graining procedure and analysis. This reproduces the experimentally-observed scalings, suggesting that they may arise from coupling the neural population activity to latent dynamic stimuli. Further, parameter sweeps for our model suggest that emergence of scaling requires most of the cells in a population to couple to the latent stimuli, predicting that even the celebrated place cells must also respond to non-place stimuli.

biophysics↗

Unsupervised Bayesian Ising Approximation for revealing the neural dictionary in songbirds

The problem of deciphering how low-level patterns (action potentials in the brain, amino acids in a protein, etc.) drive high-level biological features (sensorimotor behavior, enzymatic function) represents the central challenge of quantitative biology. The lack of general methods for doing so from the size of datasets that can be collected experimentally severely limits our understanding of the biological world. For example, in neuroscience, some sensory and motor codes have been shown to consist of precisely timed multi-spike patterns. However, the combinatorial complexity of such pattern codes have precluded development of methods for their comprehensive analysis. Thus, just as it is hard to predict a proteins function based on its sequence, we still do not understand how to accurately predict an organisms behavior based on neural activity. Here we derive a method for solving this class of problems. We demonstrate its utility in an application to neural data, detecting precisely timed spike patterns that code for specific motor behaviors in a songbird vocal system. Our method detects such codewords with an arbitrary number of spikes, does so from small data sets, and accounts for dependencies in occurrences of codewords. Detecting such dictionaries of important spike patterns - rather than merely identifying the timescale on which such patterns exist, as in some prior approaches - opens the door for understanding fine motor control and the neural bases of sensorimotor learning in animals. For example, for the first time, we identify differences in encoding motor exploration versus typical behavior. Crucially, our method can be used not only for analysis of neural systems, but also for understanding the structure of correlations in other biological and nonbiological datasets.

biophysics↗

Precise Spatial Memory in Local Random Networks

Self-sustained, elevated neuronal activity persisting on time scales of ten seconds or longer is thought to be vital for aspects of working memory, including brain representations of real space. Continuous-attractor neural networks, one of the most well-known modeling frameworks for persistent activity, have been able to model crucial aspects of such spatial memory. These models tend to require highly structured or regular synaptic architectures. In contrast, we elaborate a geometrically-embedded model with a local but otherwise random connectivity profile which, combined with a global regulation of the mean firing rate, produces localized, finely spaced discrete attractors that effectively span a 2D manifold. We demonstrate how the set of attracting states can reliably encode a representation of the spatial locations at which the system receives external input, thereby accomplishing spatial memory via attractor dynamics without synaptic fine-tuning or regular structure. We measure the networks storage capacity and find that the statistics of retrievable positions are also equivalent to a full tiling of the plane, something hitherto achievable only with (approximately) translationally invariant synapses, and which may be of interest in modeling such biological phenomena as visuospatial working memory in two dimensions.

neuroscience↗

Randomly connected networks generate emergent selectivity and predict decoding properties of large populations of neurons

Advances in neural recording methods enable sampling from populations of thousands of neurons during the performance of behavioral tasks, raising the question of how recorded activity relates to the theoretical models of computations underlying performance. In the context of decision making in rodents, patterns of functional connectivity between choice-selective cortical neurons, as well as broadly distributed choice information in both excitatory and inhibitory populations, were recently reported [1]. The straightforward interpretation of these data suggests a mechanism relying on specific patterns of anatomical connectivity to achieve selective pools of inhibitory as well as excitatory neurons. We investigate an alternative mechanism for the emergence of these experimental observations using a computational approach. We find that a randomly connected network of excitatory and inhibitory neurons generates single-cell selectivity, patterns of pairwise correlations, and indistinguishable excitatory and inhibitory readout weight distributions, as observed in recorded neural populations. Further, we make the readily verifiable experimental predictions that, for this type of evidence accumulation task, there are no anatomically defined sub-populations of neurons representing choice, and that choice preference of a particular neuron changes with the details of the task. This work suggests that distributed stimulus selectivity and patterns of functional organization in population codes could be emergent properties of randomly connected networks.\n\nAuthor summaryWhat can we learn about neural circuit organization and function from recordings of large populations of neurons? For example, in population recordings in the posterior parietal cortex of mice performing an evidence integration task, particular patterns of selectivity and correlations between cells were observed. One hypothesis for an underlying mechanism generating these patterns is that they follow from intricate rules of connectivity between specific neurons, but this raises the question of how such intricate patterns arise during learning or development. An alternative hypothesis, which we explore here, is that such patterns emerge from networks with broad spectra of eigenvalues, which is a generic property of certain random networks. We find that a random network model matches many features of experimental recordings, from single cells to populations. We suggest that such emergent selectivity could be an important principle in brain areas, in which a broad distribution of selectivity is observed.

neuroscience↗

Physical limit to concentration sensing in a changing environment

Cells adapt to changing environments by sensing ligand concentrations using specific receptors. The accuracy of sensing is ultimately limited by the finite number of ligand molecules bound by receptors. Previously derived physical limits to sensing accuracy have assumed that the concentration was constant and ignored its temporal fluctuations. We formulate the problem of concentration sensing in a strongly fluctuating environment as a non-linear field-theoretic problem, for which we find an excellent approximate Gaussian solution. We derive a new physical bound on the relative error in concentration c which scales as{delta} c/c ~ (Dac{tau})-1/4 with ligand diffusivity D, receptor cross-section a, and characteristic fluctuation time scale{tau} , in stark contrast with the usual Berg and Purcell bound{delta} c/c ~ (DacT)-1/2 for a perfect receptor sensing concentration during time T. We show how the bound can be achieved by a simple biochemical network downstream the receptor that adapts the kinetics of signaling as a function of the square root of the sensed concentration.

biophysics↗

Estimation of mutual information for real-valued data with error bars and controlled bias

Estimation of mutual information between (multidimensional) real-valued variables is used in analysis of complex systems, biological systems, and recently also quantum systems. This estimation is a hard problem, and universally good estimators provably do not exist. Kraskov et al. (PRE, 2004) introduced a successful mutual information estimation approach based on the statistics of distances between neighboring data points, which empirically works for a wide class of underlying probability distributions. Here we improve this estimator by (i) expanding its range of applicability, and by providing (ii) a self-consistent way of verifying the absence of bias, (iii) a method for estimation of its variance, and (iv) a criterion for choosing the values of the free parameter of the estimator. We demonstrate the performance of our estimator on synthetic data sets, as well as on neurophysiological and systems biology data sets.

bioinformatics↗

Receptor crosstalk improves concentration sensing of multiple ligands

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptors cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.

cell biology↗

Automated, predictive, and interpretable inference of C. elegans escape dynamics

The roundworm C. elegans exhibits robust escape behavior in response to rapidly rising temperature. The behavior lasts for a few seconds, shows history dependence, involves both sensory and motor systems, and is too complicated to model mechanistically using currently available knowledge. Instead we model the process phenomenologically, and we use the Sir Isaac dynamical inference platform to infer the model in a fully automated fashion directly from experimental data. The inferred model requires incorporation of an unobserved dynamical variable, and is biologically interpretable. The model makes accurate predictions about the dynamics of the worm behavior, and it can be used to characterize the functional logic of the dynamical system underlying the escape response. This work illustrates the power of modern artificial intelligence to aid in discovery of accurate and interpretable models of complex natural systems.

systems biology↗

Increased adaptability to rapid environmental change can more than make up for the two-fold cost of males

The famous \"two-fold cost of sex\" is really the cost of anisogamy - why should females mate with males who do not contribute resources to offspring, rather than isogamous partners who contribute equally? In typical anisogamous populations, a single very fit male can have an enormous number of offspring, far larger than is possible for any female or isogamous individual. If the sexual selection on males aligns with the natural selection on females, anisogamy thus allows much more rapid adaptation via super-successful males. We show via simulations that this effect can be sufficient to overcome the two-fold cost and maintain anisogamy against isogamy in populations adapting to environmental change. The key quantity is the variance in male fitness - if this exceeds what is possible in an isogamous population, anisogamous populations can win out in direct competition by adapting faster.

evolutionary biology↗

Chance, long tails, and inference: a non-Gaussian, Bayesian theory of vocal learning in songbirds

Traditional theories of sensorimotor learning posit that animals use sensory error signals to find the optimal motor command in the face of Gaussian sensory and motor noise. However, most such theories cannot explain common behavioral observations, for example that smaller sensory errors are more readily corrected than larger errors and that large abrupt (but not gradually introduced) errors lead to weak learning. Here we propose a new theory of sensorimotor learning that explains these observations. The theory posits that the animal learns an entire probability distribution of motor commands rather than trying to arrive at a single optimal command, and that learning arises via Bayesian inference when new sensory information becomes available. We test this theory using data from a songbird, the Bengalese finch, that is adapting the pitch (fundamental frequency) of its song following perturbations of auditory feedback using miniature headphones. We observe the distribution of the sung pitches to have long, non-Gaussian tails, which, within our theory, explains the observed dynamics of learning. Further, the theory makes surprising predictions about the dynamics of the shape of the pitch distribution, which we confirm experimentally.

animal behavior and cognition↗