Emergent Properties of in silico Synaptic Transmission in a Model of the Rat Neocortical Column

The cerebral cortex occupies nearly 80% of the entire volume of the mammalian brain and is thought to subserve higher cognitive functions like memory, attention and sensory perception. The neocortex is the newest part in the evolution of the cerebral cortex and is perhaps the most intricate brain region ever studied. The neocortical microcircuit is the smallest Œecosystem‚ of the neocortex that consists of a rich assortment of neurons, which are diverse in both their morphological and electrical properties. In the neocortical microcircuit, neurons are horizontally arranged in 6 distinct sheets called layers. The fundamental operating unit of the neocortical microcircuit is believed to be the Neocortical Column (NCC). Functionally, a single NCC is an arrangement of thousands of neurons in a vertical fashion spanning across all the 6 layers. The structure of the entire neocortex arises from a repeated and stereotypical arrangement of several thousands of such columns, where neurons transmit information to each other through specialized points of information transfer called synapses. The dynamics of synaptic transmission can be as diverse as the neurons defining a connection and are crucial to foster the functional properties of the neocortical microcircuit. The Blue Brain Project (BBP) is the first comprehensive endeavour to build a unifying model of the NCC by systematic data integration and biologically detailed simulations. Through the past 5 years, the BBP has built a facility for a data-constraint driven approach towards modelling and integrating biological information across multiple levels of complexity. Guided by fundamental principles derived from biological experiments, the BBP simulation toolchain has undergone a process of continuous refinement to facilitate the frequent construction of detailed in silico models of the NCC. The focus of this thesis lies in characterizing the functional properties of in silico synaptic transmission by incorporating principles of synaptic communication derived through biological experiments. In order to study in silico synaptic transmission it is crucial to gain an understanding of the key players influencing the manner in which synaptic signals are processed in the neocortical microcircuit - ion channel kinetics and distribution profiles, single neuron models and dynamics of synaptic pathways. First, by means of exhaustive literature survey, I identified ion channel kinetics and their distribution profiles on neocortical neurons to build in silico ion channel models. Thereafter, I developed a prototype framework to analyze the somatic and dendritic features of single neuron models constrained by ion channel kinetics. Finally, within a simulation framework integrating the ion channels, single neuron models and dynamics of synaptic transmission, I replicated in vitro experimental protocols in silico, to characterize the transmission properties of monosynaptic connections. These synaptic connections, arising from the axo-dendritric apposition of neuronal arbours were sampled across many instances of in silico NCC models constructed a priori through the BBP simulation toolchain. In this thesis, I show that when principles of synaptic transmission derived from in vitro experiments are incorporated to model in silico synaptic connections, the resulting anatomy and physiology of synaptic connections modelled from elementary biological rules closely match in vitro data. This thesis work demonstrates that the average synaptic response properties in silico are robust to perturbations in the anatomical and physiological properties of modelled connections in the local neocortical microcircuit. A fundamental discovery through this thesis is an insight into the function of the local neocortical microcircuit by examining the effect of morphological diversity on in silico synaptic transmission. I demonstrate here that intrinsic morphological diversity confers an invariance to the average synaptic response properties in silico in the local neocortical microcircuit, termed "microcircuit level robustness and invariance".

Predictive Engineering the Membrane Composition of Neocortical Neurons

Georges Khazen

The brain is the most mysterious and intricate biological structure known to man. It dominates the way we live, think, reason and behave. It is built of billions of neurons that communicate with each other through trillions of connections using electrical signals. The neocortex is undoubtedly the most complex brain region, hosting all higher brain functions such as sensory perception and cognitive behavior. Scientists have been struggling for more than a century to identify the anatomical blueprint of its cellular organization and to understand its dynamic behavior. The Blue Brain Project aims to develop the first simulation-based research environment for modeling and studying the basic building blocks of the neocortex, the neocortical column. The model column is based on data obtained from the juvenile rat somatosensory cortex. The best way to build such a large-scale model is by following a data-constraint driven approach and integrating biological information at different levels. In this thesis, I present novel informatics approaches to systematically constrain the membrane protein composition of different neocortical neuron types. In the first study, I investigate the single-cell gene expression patterns of ion channels in different neuron types and present a combinatorial rule extractor model that reverse engineers the observed expression rules in ten different neocortical neuron types. In the second study, I present a physical constrain checker that mines different publicly available data resources regarding all known membrane proteins such as channels and receptors, and extracts available information relating to their specific location on different parts of the neuronal morphologies, their 3D morphological structures as well as their genetic and proteomic annotations. Combining the results from both studies allows us to build neuronal models that better reflect the biological reality of neocortical neurons, ensuring the correct localization and distribution of membrane proteins across neuronal morphologies and computing their maximum count number based on their molecular surface areas and the available neuronal membrane surface area. This novel data-constraint driven approach is the first step towards integrating existing biological knowledge and constraints from various data sources into the process of building neuron models, in this way improving the neuron models as they come closer to the biological reality of real neurons.

EPFL2011

Emergent Connectivity Principles in the Neocortex

Imad Riachi

The neocortex makes up over 80% of the mammalian brain and is responsible for higher cognitive functions, processing of sensory inputs and orchestration of complex motor outputs. It is a 6-layered structure composed of billions of morphologically and electrically diverse neurons. Functionally, the basic unit is the neocortical column (NCC), a vertical structure of 0.5 mm wide, repeated millions of times across the neocortex and connected in an intricate but consistent way. In this thesis I investigated the role of morphologies (neurogeometry) in shaping the elaborate connectivity scheme within a column. First, I suggest a morphological basis for the higher than expected reciprocal connectivity reported experimentally between connected pairs, using a newly defined measure: the Reciprocity Index (RI), which arises from a purely mathematical concept and can be derived from the morphometric statistics of neurons. Second, I show that most experimentally reported synaptic patterns between different classes of neurons can be directly computed from the statistics of their morphologies, while some pathways would require additional functional mechanisms to refine an even more specific synaptic pattern. My thesis is done within the Blue Brain Project, the first comprehensive attempt to reverse-engineer the mammalian brain, starting with the somatosensory NCC of a P14 rat. I present in this thesis my contribution in constructing the framework for building biologically accurate circuitry. I explain how we start from 3D neuron morphologies obtained in vitro, repair them for slicing artefacts, build circuits and accurately detect potential synapses. I also explore how modelling of the experimental procedures can help us characterize biases and predict in vivo data from in vitro data. I finally present recent exploratory work on how to use the supercomputing power to design novel in silico protocols to investigate the emergent dynamics of the neocortical column.

EPFL2010

Predictive Engineering the Membrane Composition of Neocortical Neurons

Georges Khazen

EPFL2011

Emergent Connectivity Principles in the Neocortex

Imad Riachi

EPFL2010