Effective Stimuli for Constructing Reliable Neuron Models

The rich dynamical nature of neurons poses major conceptual and technical challenges for unraveling their nonlinear membrane properties. Traditionally, various current waveforms have been injected at the soma to probe neuron dynamics, but the rationale for selecting specific stimuli has never been rigorously justified. The present experimental and theoretical study proposes a novel framework, inspired by learning theory, for objectively selecting the stimuli that best unravel the neuron's dynamics. The efficacy of stimuli is assessed in terms of their ability to constrain the parameter space of biophysically detailed conductance-based models that faithfully replicate the neuron's dynamics as attested by their ability to generalize well to the neuron's response to novel experimental stimuli. We used this framework to evaluate a variety of stimuli in different types of cortical neurons, ages and animals. Despite their simplicity, a set of stimuli consisting of step and ramp current pulses outperforms synaptic-like noisy stimuli in revealing the dynamics of these neurons. The general framework that we propose paves a new way for defining, evaluating and standardizing effective electrical probing of neurons and will thus lay the foundation for a much deeper understanding of the electrical nature of these highly sophisticated and non-linear devices and of the neuronal networks that they compose

Automated optimization of a reduced layer 5 pyramidal cell model based on experimental data.

The construction of compartmental models of neurons involves tuning a set of parameters to make the model neuron behave as realistically as possible. While the parameter space of single-compartment models or other simple models can be exhaustively searched, the introduction of dendritic geometry causes the number of parameters to balloon. As parameter tuning is a daunting and time-consuming task when performed manually, reliable methods for automatically optimizing compartmental models are desperately needed, as only optimized models can capture the behavior of real neurons. Here we present a three-step strategy to automatically build reduced models of layer 5 pyramidal neurons that closely reproduce experimental data. First, we reduce the pattern of dendritic branches of a detailed model to a set of equivalent primary dendrites. Second, the ion channel densities are estimated using a multi-objective optimization strategy to fit the voltage trace recorded under two conditions - with and without the apical dendrite occluded by pinching. Finally, we tune dendritic calcium channel parameters to model the initiation of dendritic calcium spikes and the coupling between soma and dendrite. More generally, this new method can be applied to construct families of models of different neuron types, with applications ranging from the study of information processing in single neurons to realistic simulations of large-scale network dynamics

Global and Multiplexed Dendritic Computations under In Vivo-like Conditions.

Dendrites integrate inputs nonlinearly, but it is unclear how these nonlinearities contribute to the overall input-output transformation of single neurons. We developed statistically principled methods using a hierarchical cascade of linear-nonlinear subunits (hLN) to model the dynamically evolving somatic response of neurons receiving complex, in vivo-like spatiotemporal synaptic input patterns. We used the hLN to predict the somatic membrane potential of an in vivo-validated detailed biophysical model of a L2/3 pyramidal cell. Linear input integration with a single global dendritic nonlinearity achieved above 90% prediction accuracy. A novel hLN motif, input multiplexing into parallel processing channels, could improve predictions as much as conventionally used additional layers of local nonlinearities. We obtained similar results in two other cell types. This approach provides a data-driven characterization of a key component of cortical circuit computations: the input-output transformation of neurons during in vivo-like conditions

A stepwise neuron model fitting procedure designed for recordings with high spatial resolution : Application to layer 5 pyramidal cells

© 2017 The Author(s). Published by Elsevier B. V. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Background Recent progress in electrophysiological and optical methods for neuronal recordings provides vast amounts of high-resolution data. In parallel, the development of computer technology has allowed simulation of ever-larger neuronal circuits. A challenge in taking advantage of these developments is the construction of single-cell and network models in a way that faithfully reproduces neuronal biophysics with subcellular level of details while keeping the simulation costs at an acceptable level. New method In this work, we develop and apply an automated, stepwise method for fitting a neuron model to data with fine spatial resolution, such as that achievable with voltage sensitive dyes (VSDs) and Ca2+ imaging. Result We apply our method to simulated data from layer 5 pyramidal cells (L5PCs) and construct a model with reduced neuronal morphology. We connect the reduced-morphology neurons into a network and validate against simulated data from a high-resolution L5PC network model. Comparison with existing methods Our approach combines features from several previously applied model-fitting strategies. The reduced-morphology neuron model obtained using our approach reliably reproduces the membrane-potential dynamics across the dendrites as predicted by the full-morphology model. Conclusions The network models produced using our method are cost-efficient and predict that interconnected L5PCs are able to amplify delta-range oscillatory inputs across a large range of network sizes and topologies, largely due to the medium after hyperpolarization mediated by the Ca2+-activated SK current.Peer reviewedFinal Published versio

A Hierarchical Structure of Cortical Interneuron Electrical Diversity Revealed by Automated Statistical Analysis

Although the diversity of cortical interneuron electrical properties is well recognized, the number of distinct electrical types (e-types) is still a matter of debate. Recently, descriptions of interneuron variability were standardized by multiple laboratories on the basis of a subjective classification scheme as set out by the Petilla convention (Petilla Interneuron Nomenclature Group, PING). Here, we present a quantitative, statistical analysis of a database of nearly five hundred neurons manually annotated according to the PING nomenclature. For each cell, 38 features were extracted from responses to suprathreshold current stimuli and statistically analyzed to examine whether cortical interneurons subdivide into e-types. We showed that the partitioning into different e-types is indeed the major component of data variability. The analysis suggests refining the PING e-type classification to be hierarchical, whereby most variability is first captured within a coarse subpartition, and then subsequently divided into finer subpartitions. The coarse partition matches the well-known partitioning of interneurons into fast spiking and adapting cells. Finer subpartitions match the burst, continuous, and delayed subtypes. Additionally, our analysis enabled the ranking of features according to their ability to differentiate among e-types. We showed that our quantitative e-type assignment is more than 90 accurate and manages to catch several human errors

A novel method to rapidly fit conductance-based models to individual neurons

In this thesis, I present a new method of model optimisation that allows the calibration of conductance-based models of neuronal membrane potential to data from just a single neuron, and achieves good correspondence with the reference data in mere minutes. These properties are desirable because they allow investigations of individual variability among neurons of a given type, of homoeostatic processes and non-synaptic plasticity events, as well as of the contribution of particular neuronal properties to the dynamics of small circuits. In the first chapter, the thesis introduces in detail the working principle of the method, which can be summed up as model optimisation using stimuli to isolate parameter subsets (“MOSTIPS”), and represents a major part of the work and novelty of this project. The second chapter focusses on the construction of accurate models of two mammalian potassium channels which, being ectopically expressed in Xenopus laevis oocytes, served as a validation tool for the new method. In the third chapter, I evaluate the new method, presenting results from fitting models to data from synthetic sources as well as the above-mentioned oocytes. Finally, the fourth chapter contains a number of related results from closed-loop electrophysiology approaches, including extensions to the dynamic clamp protocol for both single neurons and hybrid circuits composed of live and simulated neurons, as well as preliminary results from a closed-loop model fitting approach closely related to the main work presented above. The thesis concludes that the newly developed approaches to model fitting constitute valuable additions to existing methods. The MOSTIPS method achieves tightly constrained parametrisations using both less data and less processing time than classical methods, while the related closed-loop fitting approach produces results that closely follow ongoing changes in evoked activity patterns in real time. Conversely, some issues have been left unanswered, including the contribution of the stimulus generation and selection algorithm, the success of which I have been unable to establish, as well as whether the methods developed herein can reliably identify relevant properties of individual cells. Nevertheless, both the particular methods and the general approach of using prior estimates of the model and its parameter values to propose stimulus patterns represent major advances in the field of neuron model optimisation

Feedback for neuronal system identification

In order to estimate reliable models from noisy input-output data, system identification techniques usually require that the data be generated by a process with a fading memory. Non-equilibrium systems such as neuronal and chaotic models lack a fading memory. Their identification is challenging, in particular in the presence of input noise. In this thesis, we propose a methodology based on the prediction-error method for the identification of neuronal systems subject to input-additive noise. We build on the fundamental observation that while a neuronal model does not have a fading memory, it can be transformed into a fading memory system by output feedback. Our ideas can be generalized to any non-equilibrium system sharing this property. At the core of the methodology is the use of output feedback in experiment design. We provide a theoretical justification for this design choice, which has been exploited in neurophysiology since the invention of the voltage-clamp experiment. To investigate the problem of feedback for identification, we first address the estimation of simple non-equilibrium systems in Lure form, and show that feedback allows estimating the nonlinearity in a static experiment. We then address the estimation of conductance-based models. Assuming that an informed choice can be made on the elements of the model structure, we show that consistent parameter estimates can be obtained when noise is only present at the system input. Finally, we approach the problem from a black-box perspective, and propose identifying the neuronal internal dynamics using a universal approximator with Generalized Orthogonal Basis Functions.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) – Brasil (Finance Code 001

A Brief History of Simulation Neuroscience

Our knowledge of the brain has evolved over millennia in philosophical, experimental and theoretical phases. We suggest that the next phase is simulation neuroscience. The main drivers of simulation neuroscience are big data generated at multiple levels of brain organization and the need to integrate these data to trace the causal chain of interactions within and across all these levels. Simulation neuroscience is currently the only methodology for systematically approaching the multiscale brain. In this review, we attempt to reconstruct the deep historical paths leading to simulation neuroscience, from the first observations of the nerve cell to modern efforts to digitally reconstruct and simulate the brain. Neuroscience began with the identification of the neuron as the fundamental unit of brain structure and function and has evolved towards understanding the role of each cell type in the brain, how brain cells are connected to each other, and how the seemingly infinite networks they form give rise to the vast diversity of brain functions. Neuronal mapping is evolving from subjective descriptions of cell types towards objective classes, subclasses and types. Connectivity mapping is evolving from loose topographic maps between brain regions towards dense anatomical and physiological maps of connections between individual genetically distinct neurons. Functional mapping is evolving from psychological and behavioral stereotypes towards a map of behaviors emerging from structural and functional connectomes. We show how industrialization of neuroscience and the resulting large disconnected datasets are generating demand for integrative neuroscience, how the scale of neuronal and connectivity maps is driving digital atlasing and digital reconstruction to piece together the multiple levels of brain organization, and how the complexity of the interactions between molecules, neurons, microcircuits and brain regions is driving brain simulation to understand the interactions in the multiscale brain