DEVELOPMENT OF A CEREBELLAR MEAN FIELD MODEL: THE THEORETICAL FRAMEWORK, THE IMPLEMENTATION AND THE FIRST APPLICATION

Brain modeling constantly evolves to improve the accuracy of the simulated brain dynamics with the ambitious aim to build a digital twin of the brain. Specific models tuned on brain regions specific features empower the brain simulations introducing bottom-up physiology properties into data-driven simulators. Despite the cerebellum contains 80 % of the neurons and is deeply involved in a wide range of functions, from sensorimotor to cognitive ones, a specific cerebellar model is still missing. Furthermore, its quasi-crystalline multi-layer circuitry deeply differs from the cerebral cortical one, therefore is hard to imagine a unique general model suitable for the realistic simulation of both cerebellar and cerebral cortex. The present thesis tackles the challenge of developing a specific model for the cerebellum. Specifically, multi-neuron multi-layer mean field (MF) model of the cerebellar network, including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells, was implemented, and validated against experimental data and the corresponding spiking neural network microcircuit model. The cerebellar MF model was built using a system of interdependent equations, where the single neuronal populations and topological parameters were captured by neuron-specific inter- dependent Transfer Functions. The model time resolution was optimized using Local Field Potentials recorded experimentally with high-density multielectrode array from acute mouse cerebellar slices. The present MF model satisfactorily captured the average discharge of different microcircuit neuronal populations in response to various input patterns and was able to predict the changes in Purkinje Cells firing patterns occurring in specific behavioral conditions: cortical plasticity mapping, which drives learning in associative tasks, and Molecular Layer Interneurons feed-forward inhibition, which controls Purkinje Cells activity patterns. The cerebellar multi-layer MF model thus provides a computationally efficient tool that will allow to investigate the causal relationship between microscopic neuronal properties and ensemble brain activity in health and pathological conditions. Furthermore, preliminary attempts to simulate a pathological cerebellum were done in the perspective of introducing our multi-layer cerebellar MF model in whole-brain simulators to realize patient-specific treatments, moving ahead towards personalized medicine. Two preliminary works assessed the relevant impact of the cerebellum on whole-brain dynamics and its role in modulating complex responses in causal connected cerebral regions, confirming that a specific model is required to further investigate the cerebellum-on- cerebrum influence. The framework presented in this thesis allows to develop a multi-layer MF model depicting the features of a specific brain region (e.g., cerebellum, basal ganglia), in order to define a general strategy to build up a pool of biology grounded MF models for computationally feasible simulations. Interconnected bottom-up MF models integrated in large-scale simulators would capture specific features of different brain regions, while the applications of a virtual brain would have a substantial impact on the reality ranging from the characterization of neurobiological processes, subject-specific preoperative plans, and development of neuro-prosthetic devices

A new Mathematical Framework to Understand Single Neuron Computations

An important feature of the nervous system is its ability to adapt to new stimuli. This adaptation allows for optimal encoding of the incoming information by dynamically changing the coding strategy based upon the incoming inputs to the neuron. At the level of single cells, this widespread phenomena is often referred to as spike-frequency adaptation, since it manifests as a history-dependent modulation of the neurons firing frequency. In this thesis I focus on how a neuron is able to adapt its activity to a specific input as well as on the function of such adaptive mechanisms. To study these adaptive processes different approaches have been used, from empirical observations of neural activities to detailed modeling of single cells. Here, I approach these problems by using simplified threshold models. In particular, I introduced a new generalization of the integrate-and-fire model (GIF) along with a convex fitting method allowing for efficient estimation of model parameters. Despite its relative simplicity I show that this neuron model is able to reproduce neuron behaviors with a high degree of accuracy. Moreover, using this method I was able to show that cortical neurons are equipped with two distinct adaptation mechanisms. First, a spike-triggered current that captures the complex influx of ions generated after the emission of a spike. While the second is a movement of the firing threshold, which possibly reflects the slow inactivation of sodium channels induced by the spiking activity. The precise dynamics of these adaptation processes is cell-type specific, explaining the difference of firing activity reported in different neuron types. Consequently, neuronal types can be classified based on model parameters. In Pyramidal neurons spike-dependent adaptation lasts for seconds and follows a scale-free dynamics, which is optimally tuned to encodes the natural inputs that pyramidal neurons receive in vivo. Finally using an extended version of the GIF model, I show that adaptation is not only a spike-dependent phenomenon, but also acts at the subthreshold level. In Pyramidal neurons the dynamics of the firing threshold is influenced by the subthreshold membrane potential. Spike-dependent and voltage-dependent adaptation interact in an activity-dependent way to ultimately shape the filtering properties of the membrane on the input statistics. Equipped with such a mechanism, Pyramidal neurons behave as integrators at low inputs and as a coincidence detectors at high inputs, maintaining sensitivity to input fluctuations across all regimes

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

A multi-layer mean-field model of the cerebellum embedding microstructure and population-specific dynamics

Mean-field (MF) models are computational formalism used to summarize in a few statistical parameters the salient biophysical properties of an inter-wired neuronal network. Their formalism normally incorporates different types of neurons and synapses along with their topological organization. MFs are crucial to efficiently implement the computational modules of large-scale models of brain function, maintaining the specificity of local cortical microcircuits. While MFs have been generated for the isocortex, they are still missing for other parts of the brain. Here we have designed and simulated a multi-layer MF of the cerebellar microcircuit (including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells) and validated it against experimental data and the corresponding spiking neural network (SNN) microcircuit model. The cerebellar MF was built using a system of equations, where properties of neuronal populations and topological parameters are embedded in inter-dependent transfer functions. The model time constant was optimised using local field potentials recorded experimentally from acute mouse cerebellar slices as a template. The MF reproduced the average dynamics of different neuronal populations in response to various input patterns and predicted the modulation of the Purkinje Cells firing depending on cortical plasticity, which drives learning in associative tasks, and the level of feedforward inhibition. The cerebellar MF provides a computationally efficient tool for future investigations of the causal relationship between microscopic neuronal properties and ensemble brain activity in virtual brain models addressing both physiological and pathological conditions

The Dynamics of Adapting Neurons

How do neurons dynamically encode and treat information? Each neuron communicates with its distinctive language made of long silences intermitted by occasional spikes. The spikes are prompted by the pooled effect of a population of pre-synaptic neurons. To understand the operation made by single neurons is to create a quantitative description of their dynamics. The results presented in this thesis describe the necessary elements for a quantitative description of single neurons. Almost all chapters can be unified under the theme of adaptation. Neuronal adaptation plays an important role in the transduction of a given stimulation into a spike train. The work described here shows how adaptation is brought by every spike in a stereotypical fashion. The spike-triggered adaptation is then measured in three main types of cortical neurons. I analyze in detail how the different adaptation profiles can reproduce the diversity of firing patterns observed in real neurons. I also summarize the most recent results concerning the spike-time prediction in real neurons, resulting in a well-founded single-neuron model. This model is then analyzed to understand how populations can encode time-dependent signals and how time-dependent signals can be decoded from the activity of populations. Finally, two lines of investigation in progress are described, the first expands the study of spike-triggered adaptation on longer time scales and the second extends the quantitative neuron models to models with active dendrites

Complex dynamics in simplified neuronal models: reproducing Golgi cell electroresponsiveness

Brain neurons exhibit complex electroresponsive properties – including intrinsic subthreshold oscillations and pacemaking, resonance and phase-reset – which are thought to play a critical role in controlling neural network dynamics. Although these properties emerge from detailed representations of molecular-level mechanisms in “realistic” models, they cannot usually be generated by simplified neuronal models (although these may show spike-frequency adaptation and bursting). We report here that this whole set of properties can be generated by the extended generalized leaky integrate-and-fire (E-GLIF) neuron model. E-GLIF derives from the GLIF model family and is therefore mono-compartmental, keeps the limited computational load typical of a linear low-dimensional system, admits analytical solutions and can be tuned through gradient-descent algorithms. Importantly, E-GLIF is designed to maintain a correspondence between model parameters and neuronal membrane mechanisms through a minimum set of equations. In order to test its potential, E-GLIF was used to model a specific neuron showing rich and complex electroresponsiveness, the cerebellar Golgi cell, and was validated against experimental electrophysiological data recorded from Golgi cells in acute cerebellar slices. During simulations, E-GLIF was activated by stimulus patterns, including current steps and synaptic inputs, identical to those used for the experiments. The results demonstrate that E-GLIF can reproduce the whole set of complex neuronal dynamics typical of these neurons – including intensity-frequency curves, spike-frequency adaptation, post-inhibitory rebound bursting, spontaneous subthreshold oscillations, resonance, and phase-reset – providing a new effective tool to investigate brain dynamics in large-scale simulations