Mammalian Brain As a Network of Networks

Acknowledgements AZ, SG and AL acknowledge support from the Russian Science Foundation (16-12-00077). Authors thank T. Kuznetsova for Fig. 6.Peer reviewedPublisher PD

Astrocytes: Orchestrating synaptic plasticity?

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes

Neuron-glial Interactions

Although lagging behind classical computational neuroscience, theoretical and computational approaches are beginning to emerge to characterize different aspects of neuron-glial interactions. This chapter aims to provide essential knowledge on neuron-glial interactions in the mammalian brain, leveraging on computational studies that focus on structure (anatomy) and function (physiology) of such interactions in the healthy brain. Although our understanding of the need of neuron-glial interactions in the brain is still at its infancy, being mostly based on predictions that await for experimental validation, simple general modeling arguments borrowed from control theory are introduced to support the importance of including such interactions in traditional neuron-based modeling paradigms.Junior Leader Fellowship Program by “la Caixa” Banking Foundation (LCF/BQ/LI18/11630006

A Neural-Astrocytic Network Architecture: Astrocytic calcium waves modulate synchronous neuronal activity

Understanding the role of astrocytes in brain computation is a nascent challenge, promising immense rewards, in terms of new neurobiological knowledge that can be translated into artificial intelligence. In our ongoing effort to identify principles endow-ing the astrocyte with unique functions in brain computation, and translate them into neural-astrocytic networks (NANs), we propose a biophysically realistic model of an astrocyte that preserves the experimentally observed spatial allocation of its distinct subcellular compartments. We show how our model may encode, and modu-late, the extent of synchronous neural activity via calcium waves that propagate intracellularly across the astrocytic compartments. This relationship between neural activity and astrocytic calcium waves has long been speculated but it is still lacking a mechanistic explanation. Our model suggests an astrocytic "calcium cascade" mechanism for neuronal synchronization, which may empower NANs by imposing periodic neural modulation known to reduce coding errors. By expanding our notions of information processing in astrocytes, our work aims to solidify a computational role for non-neuronal cells and incorporate them into artificial networks.Comment: International Conference on Neuromorphic Systems (ICONS) 201

Astrocytes: orchestrating synaptic plasticity?

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes.Comment: 63 pages, 4 figure

Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease

Because regional blood flow increases in association with the increased metabolic demand generated by localised increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer’s disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders

The spontaneous activity of organotypic and dissociated networks

In the absence of external stimuli, the nervous system exhibits a spontaneous electrical activity whose functions are not fully understood, and that represents the background noise of brain operations. In vitro models have long represented a simple and useful tool for studying the basic properties of neurons and networks. This study provides a detailed characterization of spontaneous activity of neuronal networks in different in vitro models. In particular, it clarifies the role of the extra-cellular environment and of the intrinsic architecture in shaping the spontaneous activity of networks by means of calcium imaging techniques. The results presented within this study come from three experimental works, each one addressing a particular feature of the network model: \u2022 Chemical composition of the extra-cellular environment: a comparison of dissociated hippocampal cultures grown in three different culturing media revealed that the use of an astrocyte-conditioned medium improves significantly the frequency and synchronization of neuronal signaling. \u2022 Mechanical and topographical properties of the extra-cellular environment: the design of a hybrid micro-nano substrate for dissociated hippocampal cultures revealed that nano-scaled patterns provide an improved artificial extra-cellular matrix for obtaining neuronal networks with a frequent spontaneous signaling. \u2022 Network architecture: synchronized events called Global Up states - involving the totality of neurons in the network - are observed in both organotypic and dissociated neurons; the duration of Global Up states increases by increasing the complexity of the network, while their frequency decreases. Simulations with simplified models of single- and multilayered networks confirm the experimental data. Taken together, these results show that the spontaneous synchronous activity of neurons is a result of their intrinsic biophysical properties, arising also after disruption of the original network architecture. However, dissociated neurons show different levels of synchrony depending on the chemical and topographical composition of the surrounding artificial extra-cellular matrix. Moreover, the specific architecture of the network and its single- or multilayered composition has an influence on the frequency and duration of spontaneous events, suggesting a potential explanation for the diversity of oscillatory rhythms observed in the brain

Human iPSC derived neural cells as models of brain development and as tools in pharmaceutical drug discovery

Human brain evolution has resulted in a cognitive superiority compared to all other animals. Unique cortical structures and expanding progenitor populations have been associated with the possibility for developing a highly folded neocortex and expanded surface area, which is linked to cognitive function. Alongside the development of the neuronal population there has been a remarkable evolution of a second population of brain cells called astrocytes. Astrocytes, which historically have been viewed as the glue of the brain, are now considered as a major regulator of brain homeostasis and neuron communication. Hypothesized to meet the increased complexity of neuronal sub-populations astrocytes have become highly diversified. Specific astrocytes can only be observed in higher primates and generally comprises a more advance form and structure enabling a single astrocyte to support a higher number of neurons. Additionally, it has been shown that human astrocytes can improve cognitive function in mice, an observation signifying the importance of astrocytes in human brain evolution. However, increased complexity is accompanied by biological errors resulting in human specific diseases. Disease mechanisms linked to human biological traits poses challenges when trying to uncover and develop treatments against its pathological conditions using animal models. With decreasing drug developmental programs in the pharmaceutical industry targeting neurological and psychiatric diseases there is a need to improve and accelerate drug discovery in this area. Studying cellular functions of the human brain is challenging partly due to limited accessibility of brain tissue. Historically, the main source of cells was derived from healthy tissue following surgical procedures as well as post-mortem and fetal tissue. However, since the discovery of induced pluripotent stem cells, having the potential to generate any cell type in the body, accessibility to neural like cells has changed dramatically. Common strategies for acquiring neurons and astrocytes from pluripotent stem cells are to try and mimic the naturally occurring embryonic development. However, this requires the establishment of defined and detailed protocols instructing the cells how to develop and becoming the cell type of interest. Neurons follow a step-wise development program which have been uncovered and in great parts mimicked in the lab. However, whether this step-wise developmental progression holds true for astrocytes is yet to be defined. The aim of this thesis was to develop a protocol to derive astrocytes from human induced pluripotent stem cells (hiPSC) and benchmark them against current models available for the pharmaceutical industry. Moreover, the project aimed to establish hiPSC derived neuronal and astrocyte models in a pharmaceutical setting to investigate their potential contribution in drug development. The characterization of four astrocytic models in comparison to a neural stem cell and nonneural model showed expected astrocyte specific characteristics. However, large differences in gene expression and astrocyte associated functions indicated a large heterogeneity among models which was also demonstrated in drug response stimulations. This clearly implies that discovery of new chemical compounds for further drug development will be context dependent, having identification bias towards the model of choice. Moreover, thorough characterization and diverse applications demonstrated a very robust and reproducible protocol for the generation of hiPSC derived astrocytes, a feature naturally critical if utilized in pharmaceutical assays. Finally, in addition to improved functionality compared to conventional models, hiPSC derived astrocytes show developmental traits linked to embryonic development increasing translability and model relevance. Furthermore, in a proof of principle study hiPSC derived neurons were shown to be able to predict unwanted side effect of a drug used to prevent excessive blood loss from major trauma or surgery. The drug is believed to affect specific neurons resulting in involuntary seizures. Besides demonstrating receptor activity of the drug, human iPSC derived neurons were shown to be applicable in the development of new drugs lacking this side effect. Finally, this was performed using a label-free and simple method which is highly applicable for drug screening. In conclusion this thesis presents a protocol for the derivation of an astrocytic model having translatability to the embryonic development and possesses several cellular functions observed by astrocytes in vivo. The application of hiPSC derived neurons and astrocytes in a pharmaceutical setting demonstrate that they can make a significant contribution in drug discovery

Emergence of Spatio-Temporal Pattern Formation and Information Processing in the Brain.

The spatio-temporal patterns of neuronal activity are thought to underlie cognitive functions, such as our thoughts, perceptions, and emotions. Neurons and glial cells, specifically astrocytes, are interconnected in complex networks, where large-scale dynamical patterns emerge from local chemical and electrical signaling between individual network components. How these emergent patterns form and encode for information is the focus of this dissertation. I investigate how various mechanisms that can coordinate collections of neurons in their patterns of activity can potentially cause the interactions across spatial and temporal scales, which are necessary for emergent macroscopic phenomena to arise. My work explores the coordination of network dynamics through pattern formation and synchrony in both experiments and simulations. I concentrate on two potential mechanisms: astrocyte signaling and neuronal resonance properties. Due to their ability to modulate neurons, we investigate the role of astrocytic networks as a potential source for coordinating neuronal assemblies. In cultured networks, I image patterns of calcium signaling between astrocytes, and reproduce observed properties of the network calcium patterning and perturbations with a simple model that incorporates the mechanisms of astrocyte communication. Understanding the modes of communication in astrocyte networks and how they form spatial temporal patterns of their calcium dynamics is important to understanding their interaction with neuronal networks. We investigate this interaction between networks and how glial cells modulate neuronal dynamics through microelectrode array measurements of neuronal network dynamics. We quantify the spontaneous electrical activity patterns of neurons and show the effect of glia on the neuronal dynamics and synchrony. Through a computational approach I investigate an entirely different theoretical mechanism for coordinating ensembles of neurons. I show in a computational model how biophysical resonance shifts in individual neurons can interact with the network topology to influence pattern formation and separation. I show that sub-threshold neuronal depolarization, potentially from astrocytic modulation among other sources, can shift neurons into and out of resonance with specific bands of existing extracellular oscillations. This can act as a dynamic readout mechanism during information storage and retrieval. Exploring these mechanisms that facilitate emergence are necessary for understanding information processing in the brain.PHDApplied PhysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111493/1/lshtrah_1.pd