A Bayesian approach for inferring neuronal connectivity from calcium fluorescent imaging data

Deducing the structure of neural circuits is one of the central problems of modern neuroscience. Recently-introduced calcium fluorescent imaging methods permit experimentalists to observe network activity in large populations of neurons, but these techniques provide only indirect observations of neural spike trains, with limited time resolution and signal quality. In this work we present a Bayesian approach for inferring neural circuitry given this type of imaging data. We model the network activity in terms of a collection of coupled hidden Markov chains, with each chain corresponding to a single neuron in the network and the coupling between the chains reflecting the network's connectivity matrix. We derive a Monte Carlo Expectation--Maximization algorithm for fitting the model parameters; to obtain the sufficient statistics in a computationally-efficient manner, we introduce a specialized blockwise-Gibbs algorithm for sampling from the joint activity of all observed neurons given the observed fluorescence data. We perform large-scale simulations of randomly connected neuronal networks with biophysically realistic parameters and find that the proposed methods can accurately infer the connectivity in these networks given reasonable experimental and computational constraints. In addition, the estimation accuracy may be improved significantly by incorporating prior knowledge about the sparseness of connectivity in the network, via standard L$_1$ penalization methods.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS303 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

State-Space Models and Latent Processes in the Statistical Analysis of Neural Data

This thesis develops and applies statistical methods for the analysis of neural data. In the second chapter we incorporate a latent process to the Generalized Linear Model framework. We develop and apply our framework to estimate the linear filters of an entire population of retinal ganglion cells while taking into account the effects of common-noise the cells might share. We are able to capture the encoding and decoding of visual stimulus to neural code. Our formalism gives us insight into the underlying architecture of the neural system. And we are able to estimate the common-noise that the cells receive. In the third chapter we discuss methods for optimally inferring the synaptic inputs to an electrotonically compact neuron, given intracellular voltage-clamp or current-clamp recordings from the postsynaptic cell. These methods are based on sequential Monte Carlo techniques ("particle filtering"). We demonstrate, on model data, that these methods can recover the time course of excitatory and inhibitory synaptic inputs accurately on a single trial. In the fourth chapter we develop a more general approach to the state-space filtering problem. Our method solves the same recursive set of Markovian filter equations as the particle filter, but we replace all importance sampling steps with a more general Markov chain Monte Carlo (MCMC) step. Our algorithm is especially well suited for problems where the model parameters might be misspecified

Training deep neural density estimators to identify mechanistic models of neural dynamics

Mechanistic modeling in neuroscience aims to explain observed phenomena in terms of underlying causes. However, determining which model parameters agree with complex and stochastic neural data presents a significant challenge. We address this challenge with a machine learning tool which uses deep neural density estimators-- trained using model simulations-- to carry out Bayesian inference and retrieve the full space of parameters compatible with raw data or selected data features. Our method is scalable in parameters and data features, and can rapidly analyze new data after initial training. We demonstrate the power and flexibility of our approach on receptive fields, ion channels, and Hodgkin-Huxley models. We also characterize the space of circuit configurations giving rise to rhythmic activity in the crustacean stomatogastric ganglion, and use these results to derive hypotheses for underlying compensation mechanisms. Our approach will help close the gap between data-driven and theory-driven models of neural dynamics

Sequential estimation of neural models by Bayesian filtering

Un dels reptes més difícils de la neurociència és el d'entendre la connectivitat del cervell. Aquest problema es pot tractar des de diverses perspectives, aquí ens centrem en els fenòmens locals que ocorren en una sola neurona. L'objectiu final és, doncs, entendre la dinàmica de les neurones i com la interconnexió amb altres neurones afecta al seu estat. Les observacions de traces del potencial de membrana constitueixen la principal font d'informació per a derivar models matemàtics d'una neurona, amb cert sentit biofísic. En particular, la dinàmica de les variables auxiliars i els paràmetres del model són estimats a partir d'aquestes traces de voltatge. El procés és en general costós i típicament implica una gran varietat de blocatges químics de canals iònics, així com una certa incertesa en els valors dels paràmetres a causa del soroll de mesura. D'altra banda, les traces de potencial de membrana també són útils per obtenir informació valuosa sobre l'entrada sinàptica, un problema invers sense solució satisfactòria a hores d'ara. En aquesta Tesi, estem interessats en mètodes d'estimació seqüencial, que permetin evitar la necessitat de repeticions que podrien ser contaminades per la variabilitat neuronal. En particular, ens concentrem en mètodes per extreure l'activitat intrínseca dels canals iònics, és a dir, les probabilitats d'obertura i tancament de canals iònics, i la contribució de les conductàncies sinàptiques. Hem dissenyat un mètode basat en la teoria Bayesiana de filtrat per inferir seqüencialment aquestes quantitats a partir d'una única traça de voltatge, potencialment sorollosa. El mètode d'estimació proposat està basat en la suposició d'un model de neurona conegut. Això és cert fins a cert punt, però la majoria dels paràmetres en el model han de ser estimats per endavant (això és valid per a qualsevol model). Per tant, el mètode s'ha millorat pel cas de models amb paràmetres desconeguts, incloent-hi un procediment per estimar conjuntament els paràmetres i les variables dinàmiques. Hem validat els mètodes d'inferència proposats mitjançant simulacions realistes. Les prestacions en termes d'error d'estimació s'han comparat amb el límit teòric, que s'ha derivat també en el marc d'aquesta Tesi

Estimation of synaptic conductances in presence of nonlinear effects caused by subthreshold ionic currents

Subthreshold fluctuations in neuronal membrane potential traces contain nonlinear components, and employing nonlinear models might improve the statistical inference. We propose a new strategy to estimate synaptic conductances, which has been tested using in silico data and applied to in vivo recordings. The model is constructed to capture the nonlinearities caused by subthreshold activated currents, and the estimation procedure can discern between excitatory and inhibitory conductances using only one membrane potential trace. More precisely, we perform second order approximations of biophysical models to capture the subthreshold nonlinearities, resulting in quadratic integrate-and-fire models, and apply approximate maximum likelihood estimation where we only suppose that conductances are stationary in a 50–100 ms time window. The results show an improvement compared to existent procedures for the models tested here.Peer ReviewedPostprint (published version