The Strategic Location of Glycogen and Lactate: From Body Energy Reserve to Brain Plasticity

Brain energy metabolism has been the object of intense research in recent years. Pioneering work has identified the different cell types involved in energy production and use. Recent evidence has demonstrated a key role of L-Lactate in brain energy metabolism, producing a paradigm-shift in our understanding of the neuronal energy metabolism. At the center of this shift, is the identification of a central role of astrocytes in neuroenergetics. Thanks to their morphological characteristics, they are poised to take up glucose from the circulation and deliver energy substrates to neurons. Astrocyte neuron lactate shuttle (ANLS) model, has shown that the main energy substrate that astrocytes deliver to neurons is L-Lactate, to sustain neuronal oxidative metabolism. L-Lactate can also be produced from glycogen, the storage form of glucose, which is exclusively localized in astrocytes. Inhibition of glycogen metabolism and the ensuing inhibition of L-Lactate production leads to cognitive dysfunction. Experimental evidence indicates that the role of lactate in cognitive function relates not only to its role as a metabolic substrate for neurons but also as a signaling molecule for synaptic plasticity. Interestingly, a similar metabolic uncoupling appears to exist in peripheral tissues plasma, whereby glucose provides L-Lactate as the substrate for cellular oxidative metabolism. In this perspective article, we review the known information on the distribution of glycogen and lactate within brain cells, and how this distribution relates to the energy regime of glial vs. neuronal cells

Inferring connection proximity in networks of electrically coupled cells by subthreshold frequency response analysis

Electrical synapses continuously transfer signals bi-directionally from one cell to another, directly or indirectly via intermediate cells. Electrical synapses are common in many brain structures such as the inferior olive, the subcoeruleus nucleus and the neocortex, between neurons and between glial cells. In the cortex, interneurons have been shown to be electrically coupled and proposed to participate in large, continuous cortical syncytia, as opposed to smaller spatial domains of electrically coupled cells. However, to explore the significance of these findings it is imperative to map the electrical synaptic microcircuits, in analogy with in vitro studies on monosynaptic and disynaptic chemical coupling. Since "walking” from cell to cell over large distances with a glass pipette is challenging, microinjection of (fluorescent) dyes diffusing through gap-junctions remains so far the only method available to decipher such microcircuits even though technical limitations exist. Based on circuit theory, we derive analytical descriptions of the AC electrical coupling in networks of isopotential cells. We then suggest an operative electrophysiological protocol to distinguish between direct electrical connections and connections involving one or more intermediate cells. This method allows inferring the number of intermediate cells, generalizing the conventional coupling coefficient, which provides limited information. We validate our method through computer simulations, theoretical and numerical methods and electrophysiological paired recording

Stochastic Spatially-Extended Simulations Predict the Effect of ER Distribution on Astrocytic Microdomain Ca²⁺ Activity

Astrocytes are cells of the central nervous system that can regulate neuronal activity. Most astrocyte-neuron communication occurs at so-called tripartite synapses, where calcium signals are triggered in astrocytes by neuronal activity, resulting in the release of neuroactive molecules by the astrocyte. Most astrocytic Ca²⁺ signals occur in very thin astrocytic branchlets, containing low copy number of molecules, so that reactions are highly stochastic. As those sub-cellular compartments cannot be resolved by diffraction-limited microscopy techniques, stochastic reaction-diffusion computational approaches can give crucial insights on astrocyte activity. Here, we use our stochastic voxel-based model of IP3R-mediated Ca²⁺ signals to investigate the effect of the distance between the synapse and the closest astrocytic endoplasmic reticulum (ER) on neuronal activity-induced Ca²⁺ signals. Simulations are performed in three dimensional meshes characterized by various ER-synapse distances. Our results suggest that Ca2+ peak amplitude, duration and frequency decrease rapidly as ER-synapse distance increases. We propose that this effect mostly results from the increased cytosolic volume of branchlets that are characterized by larger ER-synapse distances. In particular, varying ER-synapse distance with constant cytosolic volume does not affect local Ca²⁺ activity. This study illustrates the insights that can be provided by three-dimensional stochastic reaction-diffusion simulations on the biophysical constraints that shape the spatio-temporal characteristics of astrocyte activity at the nanoscale

A Process for Digitizing and Simulating Biologically Realistic Oligocellular Networks Demonstrated for the Neuro-Glio-Vascular Ensemble

One will not understand the brain without an integrated exploration of structure and function, these attributes being two sides of the same coin: together they form the currency of biological computation. Accordingly, biologically realistic models require the re-creation of the architecture of the cellular components in which biochemical reactions are contained. We describe here a process of reconstructing a functional oligocellular assembly that is responsible for energy supply management in the brain and creating a computational model of the associated biochemical and biophysical processes. The reactions that underwrite thought are both constrained by and take advantage of brain morphologies pertaining to neurons, astrocytes and the blood vessels that deliver oxygen, glucose and other nutrients. Each component of this neuro-glio-vasculature ensemble (NGV) carries-out delegated tasks, as the dynamics of this system provide for each cell-type its own energy requirements while including mechanisms that allow cooperative energy transfers. Our process for recreating the ultrastructure of cellular components and modeling the reactions that describe energy flow uses an amalgam of state-of the-art techniques, including digital reconstructions of electron micrographs, advanced data analysis tools, computational simulations and in silico visualization software. While we demonstrate this process with the NGV, it is equally well adapted to any cellular system for integrating multimodal cellular data in a coherent framework

Emerging evidence for astrocyte dysfunction in schizophrenia

Schizophrenia is a complex, chronic mental health disorder whose heterogeneous genetic and neurobiological background influences early brain development, and whose precise etiology is still poorly understood. Schizophrenia is not characterized by gross brain pathology, but involves subtle pathological changes in neuronal populations and glial cells. Among the latter, astrocytes critically contribute to the regulation of early neurodevelopmental processes, and any dysfunctions in their morphological and functional maturation may lead to aberrant neurodevelopmental processes involved in the pathogenesis of schizophrenia, such as mitochondrial biogenesis, synaptogenesis, and glutamatergic and dopaminergic transmission. Studies of the mechanisms regulating astrocyte maturation may therefore improve our understanding of the cellular and molecular mechanisms underlying the pathogenesis of schizophrenia