Biology subjects

Cali, C.

Publications and source records attributed to Cali, C..

4 recordsLinked to original sources

bioRxiv2022

Ultraliser: a framework for creating multiscale, high-fidelity and geometrically realistic 3D models for in silico neuroscience

UO_SCPLOWLTRALISERC_SCPLOW is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. UO_SCPLOWLTRALISERC_SCPLOW implements a high performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of UO_SCPLOWLTRALISERC_SCPLOW is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. UO_SCPLOWLTRALISERC_SCPLOW is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser). SignificanceThere is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present UO_SCPLOWLTRALISERC_SCPLOW, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations. Key pointsO_LIUltraliser creates spatial models of neuro-glia-vascular (NGV) structures with realistic geometries. C_LIO_LIUltraliser creates high fidelity watertight manifolds and large scale volumes from centerline descriptions, non-watertight surfaces, and binary masks. C_LIO_LIResulting models enable scalable in silico experiments that can probe intricate structure-function relationships. C_LIO_LIThe framework is unrivalled both in ease-of-use and in the accuracy of resulting geometry representing a major leap forward in simulation-based neuroscience. C_LI

bioinformatics↗

bioRxiv2022

The endoplasmic reticulum in perisynaptic astrocytic processes: shape, distribution and effect on calcium activity

Astrocytes are now widely accepted as key regulators of brain function and behavior. Calcium (Ca2+) signals in perisynaptic astrocytic processes (PAPs) enable astrocytes to fine-tune neurotransmission at tripartite synapses. As most PAPs are below the diffraction limit, their content in Ca2+ stores and the contribution of the latter to astrocytic Ca2+ activity is unclear. Here, we reconstruct hippocampal tripartite synapses in 3D from a high resolution electron microscopy (EM) dataset and find that 75% of PAPs contain some endoplasmic reticulum (ER), a major calcium store in astrocytes. The ER in PAPs displays strikingly diverse shapes and intracellular spatial distributions. To investigate the causal relationship between each of these geometrical properties and the spatio-temporal characteristics of Ca2+ signals, we implemented an algorithm that generates 3D PAP meshes by altering the distribution of the ER independently from ER and cell shape. Reaction-diffusion simulations in these meshes reveal that astrocyte activity is governed by a complex interplay between the location of Ca2+ channels, ER surface-volume ratio and spatial distribution. In particular, our results suggest that ER-PM contact sites can act as local signal amplifiers if equipped with IP3R clusters but attenuate PAP Ca2+ activity in the absence of clustering. This study sheds new light on the ultrastructural basis of the diverse astrocytic Ca2+ microdomain signals and on the mechanisms that regulate neuron-astrocyte signal transmission at tripartite synapses. Main pointsO_LI6 nm isotropic volume EM reveals that 75% of perisynaptic astrocytic processes (PAPs) contain some ER C_LIO_LIPAPs & ER of the same cell display diverse geometric properties C_LIO_LISimulations in EM-derived meshes hint that ER geometry governs Ca2+ signals in PAPs C_LI TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/482292v4_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@e2387aorg.highwire.dtl.DTLVardef@1e9db45org.highwire.dtl.DTLVardef@3ab0d1org.highwire.dtl.DTLVardef@12e9ab2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Astrocytic VMAT2 in the developing prefrontal cortex is required for normal grooming behavior in mice

Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD).

neuroscience↗

bioRxiv2021

Architecture of the Neuro-Glia-Vascular System

Astrocytes connect the vasculature to neurons and mediate the supply of nutrients and biochemicals. They also remove metabolites from the neurons and extracellular environment. They are involved in a growing number of physiological and pathophysiological processes. Understanding the biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV) and how they support brain function is severely restricted by the lack of detailed cytoarchitecture. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of rat somatosensory cortical tissue with approximately 16000 morphologically detailed neurons, its microvasculature, and approximately 2500 morphologically detailed protoplasmic astrocytes. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the numbers and locations of astrocytes and astrocytic processes that support different types of neurons. This allows anatomical reconstruction of the spatial microdomains of astrocytes and their overlapping regions. The number and locations of end-feet connecting each astrocyte to the vasculature can be determined as well as the extent to which they cover the microvasculature. The structural analysis of the NGV circuit showed that astrocytic shape and numbers are constrained by vasculatures spatial occupancy and their functional role to form NGV connections. The digital reconstruction of the NGV is a resource that will enable a better understanding of the anatomical principles and geometric constraints which govern how astrocytes support brain function. Table of contentsO_ST_ABSMain pointsC_ST_ABSO_LIThe Blue Brain Project digitally reconstructs a part of neocortical Neuro-Glia-Vascular organization C_LIO_LIInterdependencies and topological methods allow dense in silico reconstruction from sparse experimental data C_LIO_LIThe polarized role of protoplasmic astrocytes constrains their shapes and numbers C_LI Table of contents image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/427241v3_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1260843org.highwire.dtl.DTLVardef@1e88718org.highwire.dtl.DTLVardef@fd66c5org.highwire.dtl.DTLVardef@6628a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗