Water Hydrogen-Bond Mediated Layer by Layer Alignment of Lipid Rafts as a Precursor of Intermembrane Processes.

Lipid rafts, which are dynamic nanodomains in the plasma membrane, play a crucial role in intermembrane processes by clustering together and growing in size within the plane of the membrane while also aligning with each other across different membranes. However, the physical origin of layer by layer alignment of lipid rafts remains to be elucidated. Here, by using fluorescence imaging and synchrotron X-ray reflectivity in a phase-separated multilayer system, we find that the alignment of raft-mimicking Lo domains is regulated by the distance between bilayers. Molecular dynamics simulations reveal that the aligned state is energetically preferred when the intermembrane distance is small due to its ability to minimize the volume of surface water, which has fewer water hydrogen bonds (HBs) compared to bulk water. Our results suggest that water HB-driven alignment of lipid rafts plays a role as a precursor of intermembrane processes such as cell-cell fusion, virus entry, and signaling.

A unified framework for inferring the multi-scale organization of chromatin domains from Hi-C.

Chromosomes are giant chain molecules organized into an ensemble of three-dimensional structures characterized with its genomic state and the corresponding biological functions. Despite the strong cell-to-cell heterogeneity, the cell-type specific pattern demonstrated in high-throughput chromosome conformation capture (Hi-C) data hints at a valuable link between structure and function, which makes inference of chromatin domains (CDs) from the pattern of Hi-C a central problem in genome research. Here we present a unified method for analyzing Hi-C data to determine spatial organization of CDs over multiple genomic scales. By applying statistical physics-based clustering analysis to a polymer physics model of the chromosome, our method identifies the CDs that best represent the global pattern of correlation manifested in Hi-C. The multi-scale intra-chromosomal structures compared across different cell types uncover the principles underlying the multi-scale organization of chromatin chain: (i) Sub-TADs, TADs, and meta-TADs constitute a robust hierarchical structure. (ii) The assemblies of compartments and TAD-based domains are governed by different organizational principles. (iii) Sub-TADs are the common building blocks of chromosome architecture. Our physically principled interpretation and analysis of Hi-C not only offer an accurate and quantitative view of multi-scale chromatin organization but also help decipher its connections with genome function.

Implications for human odor sensing revealed from the statistics of odorant-receptor interactions.

Binding of odorants to olfactory receptors (ORs) elicits downstream chemical and neural signals, which are further processed to odor perception in the brain. Recently, Mainland and colleagues have measured more than 500 pairs of odorant-OR interaction by a high-throughput screening assay method, opening a new avenue to understanding the principles of human odor coding. Here, using a recently developed minimal model for OR activation kinetics, we characterize the statistics of OR activation by odorants in terms of three empirical parameters: the half-maximum effective concentration EC50, the efficacy, and the basal activity. While the data size of odorants is still limited, the statistics offer meaningful information on the breadth and optimality of the tuning of human ORs to odorants, and allow us to relate the three parameters with the microscopic rate constants and binding affinities that define the OR activation kinetics. Despite the stochastic nature of the response expected at individual OR-odorant level, we assess that the confluence of signals in a neuron released from the multitude of ORs is effectively free of noise and deterministic with respect to changes in odorant concentration. Thus, setting a threshold to the fraction of activated OR copy number for neural spiking binarizes the electrophysiological signal of olfactory sensory neuron, thereby making an information theoretic approach a viable tool in studying the principles of odor perception.

Adaptive stimulus selection for multi-alternative psychometric functions with lapses.

Psychometric functions (PFs) quantify how external stimuli affect behavior, and they play an important role in building models of sensory and cognitive processes. Adaptive stimulus-selection methods seek to select stimuli that are maximally informative about the PF given data observed so far in an experiment and thereby reduce the number of trials required to estimate the PF. Here we develop new adaptive stimulus-selection methods for flexible PF models in tasks with two or more alternatives. We model the PF with a multinomial logistic regression mixture model that incorporates realistic aspects of psychophysical behavior, including lapses and multiple alternatives for the response. We propose an information-theoretic criterion for stimulus selection and develop computationally efficient methods for inference and stimulus selection based on adaptive Markov-chain Monte Carlo sampling. We apply these methods to data from macaque monkeys performing a multi-alternative motion-discrimination task and show in simulated experiments that our method can achieve a substantial speed-up over random designs. These advances will reduce the amount of data needed to build accurate models of multi-alternative PFs and can be extended to high-dimensional PFs that would be infeasible to characterize with standard methods.

Spyglass: a framework for reproducible and shareable neuroscience research.

Scientific progress depends on reliable and reproducible results. Progress can also be accelerated when data are shared and re-analyzed to address new questions. Current approaches to storing and analyzing neural data typically involve bespoke formats and software that make replication, as well as the subsequent reuse of data, difficult if not impossible. To address these challenges, we created Spyglass, an open-source software framework that enables reproducible analyses and sharing of data and both intermediate and final results within and across labs. Spyglass uses the Neurodata Without Borders (NWB) standard and includes pipelines for several core analyses in neuroscience, including spectral filtering, spike sorting, pose tracking, and neural decoding. It can be easily extended to apply both existing and newly developed pipelines to datasets from multiple sources. We demonstrate these features in the context of a cross-laboratory replication by applying advanced state space decoding algorithms to publicly available data. New users can try out Spyglass on a Jupyter Hub hosted by HHMI and 2i2c: https://spyglass.hhmi.2i2c.cloud/.

Resolving Non-identifiability Mitigates Bias in Models of Neural Tuning and Functional Coupling.

In the brain, all neurons are driven by the activity of other neurons, some of which maybe simultaneously recorded, but most are not. As such, models of neuronal activity need to account for simultaneously recorded neurons and the influences of unmeasured neurons. This can be done through inclusion of model terms for observed external variables (e.g., tuning to stimuli) as well as terms for latent sources of variability. Determining the influence of groups of neurons on each other relative to other influences is important to understand brain functioning. The parameters of statistical models fit to data are commonly used to gain insight into the relative importance of those influences. Scientific interpretation of models hinge upon unbiased parameter estimates. However, evaluation of biased inference is rarely performed and sources of bias are poorly understood. Through extensive numerical study and analytic calculation, we show that common inference procedures and models are typically biased. We demonstrate that accurate parameter selection before estimation resolves model non-identifiability and mitigates bias. In diverse neurophysiology data sets, we found that contributions of coupling to other neurons are often overestimated while tuning to exogenous variables are underestimated in common methods. We explain heterogeneity in observed biases across data sets in terms of data statistics. Finally, counter to common intuition, we found that model non-identifiability contributes to bias, not variance, making it a particularly insidious form of statistical error. Together, our results identify the causes of statistical biases in common models of neural data, provide inference procedures to mitigate that bias, and reveal and explain the impact of those biases in diverse neural data sets.

Extracting the dynamics of behavior in sensory decision-making experiments.

Decision-making strategies evolve during training and can continue to vary even in well-trained animals. However, studies of sensory decision-making tend to characterize behavior in terms of a fixed psychometric function that is fit only after training is complete. Here, we present PsyTrack, a flexible method for inferring the trajectory of sensory decision-making strategies from choice data. We apply PsyTrack to training data from mice, rats, and human subjects learning to perform auditory and visual decision-making tasks. We show that it successfully captures trial-to-trial fluctuations in the weighting of sensory stimuli, bias, and task-irrelevant covariates such as choice and stimulus history. This analysis reveals dramatic differences in learning across mice and rapid adaptation to changes in task statistics. PsyTrack scales easily to large datasets and offers a powerful tool for quantifying time-varying behavior in a wide variety of animals and tasks.

Inferring learning rules from animal decision-making.

How do animals learn? This remains an elusive question in neuroscience. Whereas reinforcement learning often focuses on the design of algorithms that enable artificial agents to efficiently learn new tasks, here we develop a modeling framework to directly infer the empirical learning rules that animals use to acquire new behaviors. Our method efficiently infers the trial-to-trial changes in an animal's policy, and decomposes those changes into a learning component and a noise component. Specifically, this allows us to: (i) compare different learning rules and objective functions that an animal may be using to update its policy; (ii) estimate distinct learning rates for different parameters of an animal's policy; (iii) identify variations in learning across cohorts of animals; and (iv) uncover trial-to-trial changes that are not captured by normative learning rules. After validating our framework on simulated choice data, we applied our model to data from rats and mice learning perceptual decision-making tasks. We found that certain learning rules were far more capable of explaining trial-to-trial changes in an animal's policy. Whereas the average contribution of the conventional REINFORCE learning rule to the policy update for mice learning the International Brain Laboratory's task was just 30%, we found that adding baseline parameters allowed the learning rule to explain 92% of the animals' policy updates under our model. Intriguingly, the best-fitting learning rates and baseline values indicate that an animal's policy update, at each trial, does not occur in the direction that maximizes expected reward. Understanding how an animal transitions from chance-level to high-accuracy performance when learning a new task not only provides neuroscientists with insight into their animals, but also provides concrete examples of biological learning algorithms to the machine learning community.

Efficient inference for time-varying behavior during learning.

The process of learning new behaviors over time is a problem of great interest in both neuroscience and artificial intelligence. However, most standard analyses of animal training data either treat behavior as fixed or track only coarse performance statistics (e.g., accuracy, bias), providing limited insight into the evolution of the policies governing behavior. To overcome these limitations, we propose a dynamic psychophysical model that efficiently tracks trial-to-trial changes in behavior over the course of training. Our model consists of a dynamic logistic regression model, parametrized by a set of time-varying weights that express dependence on sensory stimuli as well as task-irrelevant covariates, such as stimulus, choice, and answer history. Our implementation scales to large behavioral datasets, allowing us to infer 500K parameters (e.g., 10 weights over 50K trials) in minutes on a desktop computer. We optimize hyperparameters governing how rapidly each weight evolves over time using the decoupled Laplace approximation, an efficient method for maximizing marginal likelihood in non-conjugate models. To illustrate performance, we apply our method to psychophysical data from both rats and human subjects learning a delayed sensory discrimination task. The model successfully tracks the psychophysical weights of rats over the course of training, capturing day-to-day and trial-to-trial fluctuations that underlie changes in performance, choice bias, and dependencies on task history. Finally, we investigate why rats frequently make mistakes on easy trials, and suggest that apparent lapses can be explained by sub-optimal weighting of known task covariates.