Model-based Bayesian inference of neural activity and connectivity from all-optical interrogation of a neural circuit

Neural information processing systems foundation. All rights reserved. Population activity measurement by calcium imaging can be combined with cellular resolution optogenetic activity perturbations to enable the mapping of neural connectivity in vivo. This requires accurate inference of perturbed and unperturbed neural activity from calcium imaging measurements, which are noisy and indirect, and can also be contaminated by photostimulation artifacts. We have developed a new fully Bayesian approach to jointly inferring spiking activity and neural connectivity from in vivo all-optical perturbation experiments. In contrast to standard approaches that perform spike inference and analysis in two separate maximum-likelihood phases, our joint model is able to propagate uncertainty in spike inference to the inference of connectivity and vice versa. We use the framework of variational autoencoders to model spiking activity using discrete latent variables, low-dimensional latent common input, and sparse spike-and-slab generalized linear coupling between neurons. Additionally, we model two properties of the optogenetic perturbation: off-target photostimulation and photostimulation transients. Using this model, we were able to fit models on 30 minutes of data in just 10 minutes. We performed an all-optical circuit mapping experiment in primary visual cortex of the awake mouse, and use our approach to predict neural connectivity between excitatory neurons in layer 2/3. Predicted connectivity is sparse and consistent with known correlations with stimulus tuning, spontaneous correlation and distance

A roadmap to integrate astrocytes into Systems Neuroscience

Systems Neuroscience is still mainly a neuronal field, despite the plethora of evidence supporting the fact that astrocytes modulate local neural circuits, networks, and complex behaviors. In this article, we sought to identify which types of studies are necessary to establish whether astrocytes, beyond their well-documented homeostatic and metabolic functions, perform computations implementing mathematical algorithms that sub-serve coding and higher-brain functions. First, we reviewed Systems-like studies that include astrocytes in order to identify computational operations that these cells may perform, using Ca$^{2+}$ transients as their encoding language. The analysis suggests that astrocytes may carry out canonical computations in time scales of sub-seconds to seconds in sensory processing, neuromodulation, brain state, memory formation, fear, and complex homeostatic reflexes. Next, we propose a list of actions to gain insight into the outstanding question of which variables are encoded by such computations. The application of statistical analyses based on machine learning, such as dimensionality reduction and decoding in the context of complex behaviors, combined with connectomics of astrocyte-neuronal circuits, are, in our view, fundamental undertakings. We also discuss technical and analytical approaches to study neuronal and astrocytic populations simultaneously, and the inclusion of astrocytes in advanced modeling of neural circuits, as well as in theories currently under exploration, such as predictive coding and energy-efficient coding. Clarifying the relationship between astrocytic Ca$^{2+}$ and brain coding may represent a leap forward towards novel approaches in the study of astrocytes in health and disease.Junior Leader Fellowhip Program by 'la Caixa' Banking Foundation, LCF/BQ/LI18/11630006 BFU2017-85936-P BFU2016-75107-P BFU2016-79735-P FLAGERA-PCIN-2015-162-C02-02 HHMI 55008742 FPU13/05377 NIH R01NS099254 NSF 1604544 Agència de Gestio d’Ajuts Universitaris i de Recerca, 2017 SGR54

Efficient "Shotgun" Inference of Neural Connectivity from Highly Sub-sampled Activity Data

<div><p>Inferring connectivity in neuronal networks remains a key challenge in statistical neuroscience. The “common input” problem presents a major roadblock: it is difficult to reliably distinguish causal connections between pairs of observed neurons versus correlations induced by common input from unobserved neurons. Available techniques allow us to simultaneously record, with sufficient temporal resolution, only a small fraction of the network. Consequently, naive connectivity estimators that neglect these common input effects are highly biased. This work proposes a “shotgun” experimental design, in which we observe multiple sub-networks briefly, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe much larger subsets of the network over the course of the entire experiment, thus ameliorating the common input problem. Using a generalized linear model for a spiking recurrent neural network, we develop a scalable approximate expected loglikelihood-based Bayesian method to perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin. We demonstrate in simulation that the shotgun experimental design can eliminate the biases induced by common input effects. Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, can be quickly and accurately estimated, achieving orders of magnitude speed up over previous approaches.</p></div

Graph quilting: graphical model selection from partially observed covariances

We investigate the problem of conditional dependence graph estimation when several pairs of nodes have no joint observation. For these pairs even the simplest metric of covariability, the sample covariance, is unavailable. This problem arises, for instance, in calcium imaging recordings where the activities of a large population of neurons are typically observed by recording from smaller subsets of cells at once, and several pairs of cells are never recorded simultaneously. With no additional assumption, the unavailability of parts of the covariance matrix translates into the unidentifiability of the precision matrix that, in the Gaussian graphical model setting, specifies the graph. Recovering a conditional dependence graph in such settings is fundamentally an extremely hard challenge, because it requires to infer conditional dependences between network nodes with no empirical evidence of their covariability. We call this challenge the "graph quilting problem". We demonstrate that, under mild conditions, it is possible to correctly identify not only the edges connecting the observed pairs of nodes, but also a superset of those connecting the variables that are never observed jointly. We propose an $\ell_1$ regularized graph estimator based on a partially observed sample covariance matrix and establish its rates of convergence in high-dimensions. We finally present a simulation study and the analysis of calcium imaging data of ten thousand neurons in mouse visual cortex.Comment: 6 figure