New tools and specification languages for biophysically detailed neuronal network modelling

Increasingly detailed data are being gathered on the molecular, electrical and anatomical properties of neuronal systems both in vitro and in vivo. These range from the kinetic properties and distribution of ion channels, synaptic plasticity mechanisms, electrical activity in neurons, and detailed anatomical connectivity within neuronal microcircuits from connectomics data. Publications describing these experimental results often set them in the context of higher level network behaviour. Biophysically detailed computational modelling provides a framework for consolidating these data, for quantifying the assumptions about underlying biological mechanisms, and for ensuring consistency in the explanation of the phenomena across scales. Such multiscale biophysically detailed models are not currently in wide- spread use by the experimental neuroscience community however. Reasons for this include the relative inaccessibility of software for creating these models, the range of specialised scripting languages used by the available simulators, and the difficulty in creating and managing large scale network simulations. This thesis describes new solutions to facilitate the creation, simulation, analysis and reuse of biophysically detailed neuronal models. The graphical application neuroConstruct allows detailed cell and network models to be built in 3D, and run on multiple simulation platforms without detailed programming knowledge. NeuroML is a simulator independent language for describing models containing detailed neuronal morphologies, ion channels, synapses, and 3D network connectivity. New solutions have also been developed for creating and analysing network models at much closer to biological scale on high performance computing platforms. A number of detailed neocortical, cerebellar and hippocampal models have been converted for use with these tools. The tools and models I have developed have already started to be used for original scientific research. It is hoped that this work will lead to a more solid foundation for creating, validating, simulating and sharing ever more realistic models of neurons and networks

Computational principles of single neuron adaptation

Cortical neurons continuously transform sets of incoming spike trains into output spike trains. This input-output transformation is referred to as single-neuron computation and constitutes one of the most fundamental process in the brain. A deep understanding of single-neuron dynamics is therefore required to study how neural circuits support complex behaviors such as sensory perception, learning and memory. The results presented in this thesis focus on single-neuron computation. In particular, I address the question of how and why cortical neurons adapt their coding strategies to the statistical properties of their inputs. A new spiking model and a new fitting procedure are introduced that enable reliable nonparametric feature extraction from in vitro intracellular recordings. By applying this method to a new set of data from L5 pyramidal neurons, I found that cortical neurons adapt their firing rate over multiple timescales, ranging from tens of milliseconds to tens of second. This behavior results from two cellular processes, which are triggered by the emission of individual action potentials and decay according to a power-law. An analysis performed on in vivo intracellular recordings further indicates that power-law adaptation is near-optimally tuned to efficiently encode natural inputs received by single neurons in biologically relevant situations. These results shade light on the functional role of spike-frequency adaptation in the cortex. The second part of this thesis focuses on the long-standing question of whether cortical neurons act as temporal integrators or coincidence detectors. According to standard theories relying on simplified spiking models, cortical neurons are expected to feature both coding strategies, depending on the statistical properties of their inputs. A model-based analysis performed on a second set of in vitro recordings demonstrates that the spike initiation dynamics implements a complex form of adaptation to make cortical neurons act as coincidence detectors, regardless of the input statistics. This result indicates that cortical neurons are well-suited to support a temporal code in which the relevant information is carried by the precise timing of spikes. The spiking model introduced in this thesis was not designed to study a particular aspect of single-neuron computation and achieves good performances in predicting the spiking activity of different neuronal types. The proposed method for parameter estimation is efficient and only requires a limited amount of data. If applied on large datasets, the mathematical framework presented in this thesis could therefore lead to automated high-throughput single-neuron characterization