Data-driven whole mouse brain modeling for multi-scale simulations

In this thesis, we present a data-driven iterative pipeline to generate, simulate and validate point-neuron models of the whole mouse brain. The ultimate goal is to replicate close loop experiments with a virtual body in a virtual world. This pipeline was origi-nally created by a PhD student of the Blue Brain Project and this pioneer work has yielded the first versions of the model and their simulations. My objective is to refine, extend and consolidate the previous version of the workflow and in particular to extend the repertoire of neuron types by integrating and consolidating available literature data.The pipeline has four main parts. First, we define a pair of reference atlases to create a spatial reference for every dataset that we want to integrate. Second, we create a cell atlas with estimates of the number and density of the major cell types in each brain region. Then, we build a connectivity atlas that describes the connections of each neuron of the mouse brain and their properties. Finally, we assign point-neuron parameters to each of the neuron types, and synaptic parameters to each of the connection types of our model to obtain a point-neuron network of the mouse brain. This network can be simulated to perform mouse brain experi-ments in-silico.In this thesis, we evaluate the quality of the different reference atlases, released by the Allen Institute for Brain Science and pro-vide methods to mitigate the impact of artifacts in the original images. We further extend the cell atlas with density estimates of more inhibitory neuron types. To do so, we introduce a new method to combine estimates of inhibitory neuron counts from the literature into a consistent framework. We also estimate inhibitory neuron density in regions where no literature data are avai-lable, using collected literature estimates and gene expression data from in situ hybridization image stacks. Our approach can be further extended to other cell types and provides a resource to build more detailed circuits of the mouse brain. Next, we refine the connectivity atlas, including literature findings on short-range connectivity. Additionally, we construct a database to store data collected on neuron types point-neuron parameters and synaptic parameters. With the results of the previous steps, we generate a new version of the whole mouse brain point-neuron network. We tested this new model against its previous version using three benchmark experiments. We explore the possibility to embed and connect detailed circuit reconstructions of the mouse brain to our point neuron model and co-simulate them. Finally, we constrain a 3D skeleton model of the mouse with joint constraints from the literature and attach muscle to its bones to create a musculoskeletal model of the mouse body that can be simulated in close-loop with our model to reproduce motor control experiments.