skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Astrocyte development—More questions than answers
The past 15–20 years has seen a remarkable shift in our understanding of astrocyte contributions to central nervous system (CNS) function. Astrocytes have emerged from the shadows of neuroscience and are now recognized as key elements in a broad array of CNS functions. Astrocytes comprise a substantial fraction of cells in the human CNS. Nevertheless, fundamental questions surrounding their basic biology remain poorly understood. While recent studies have revealed a diversity of essential roles in CNS function, from synapse formation and function to blood brain barrier maintenance, fundamental mechanisms of astrocyte development, including their expansion, migration, and maturation, remain to be elucidated. The coincident development of astrocytes and synapses highlights the need to better understand astrocyte development and will facilitate novel strategies for addressing neurodevelopmental and neurological dysfunction. In this review, we provide an overview of the current understanding of astrocyte development, focusing primarily on mammalian astrocytes and highlight outstanding questions that remain to be addressed. We also include an overview of Drosophila glial development, emphasizing astrocyte-like glia given their close anatomical and functional association with synapses. Drosophila offer an array of sophisticated molecular genetic tools and they remain a powerful model for elucidating fundamental cellular and molecular mechanisms governing astrocyte development. Understanding the parallels and distinctions between astrocyte development in Drosophila and vertebrates will enable investigators to leverage the strengths of each model system to gain new insights into astrocyte function.  more » « less
Award ID(s):
1921065
PAR ID:
10447606
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Frontiers in Cell and Developmental Biology
Volume:
11
ISSN:
2296-634X
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract Astrocytes, a subtype of glial cells with a complex morphological structure, are active players in many aspects of the physiology of the central nervous system (CNS). However, due to their highly involved interaction with other cells in the CNS, made possible by their morphological complexity, the precise mechanisms regulating astrocyte function within the CNS are still poorly understood. This knowledge gap is also due to the current limitations of existing quantitative image analysis tools that are unable to detect and analyze images of astrocyte with sufficient accuracy and efficiency. To address this need, we introduce a new deep learning framework for the automated detection of GFAP-immunolabeled astrocytes in brightfield or fluorescent micrographs. A major novelty of our approach is the applications of YOLOv5, a sophisticated deep learning platform designed for object detection, that we customized to derive optimized classification models for the task of astrocyte detection. Extensive numerical experiments using multiple image datasets show that our method performs very competitively against both conventional and state-of-the-art methods, including the case of images where astrocytes are very dense. In the spirit of reproducible research, our numerical code and annotated data are released open source and freely available to the scientific community. 
    more » « less
  2. For decades, theDrosophilalarval neuromuscular junction (NMJ) has been a go-to model for synaptic development. This simple, accessible system is composed of a repeating pattern of 33 distinct neurons that stereotypically innervate 30 muscles. Fundamental mechanisms that underlie diverse aspects of axon pathfinding, synaptic form, and function have been uncovered at the NMJ, and new pathways continue to be uncovered. These discoveries are fueled by the ease of dissections and an extensive array of techniques. Chief among these techniques are various microscopy approaches, including super-resolution and electron microscopy. Functionally, theDrosophilaNMJ is glutamatergic, similar to the vertebrate central synapses, making it a great model to study normal development and neurological diseases. Here we provide a brief overview of the larval neuromuscular system, highlighting the connectivity patterns, development, and some of the mechanisms underlying these processes. 
    more » « less
  3. Astrocytes are a ubiquitous and enigmatic type of non-neuronal cell and are found in the brain of all vertebrates. While traditionally viewed as being supportive of neurons, it is increasingly recognized that astrocytes play a more direct and active role in brain function and neural computation. On account of their sensitivity to a host of physiological covariates and ability to modulate neuronal activity and connectivity on slower time scales, astrocytes may be particularly well poised to modulate the dynamics of neural circuits in functionally salient ways. In the current paper, we seek to capture these features via actionable abstractions within computational models of neuron-astrocyte interaction. Specifically, we engage how nested feedback loops of neuron-astrocyte interaction, acting over separated time-scales, may endow astrocytes with the capability to enable learning in context-dependent settings, where fluctuations in task parameters may occur much more slowly than within-task requirements. We pose a general model of neuron-synapse-astrocyte interaction and use formal analysis to characterize how astrocytic modulation may constitute a form of meta-plasticity, altering the ways in which synapses and neurons adapt as a function of time. We then embed this model in a bandit-based reinforcement learning task environment, and show how the presence of time-scale separated astrocytic modulation enables learning over multiple fluctuating contexts. Indeed, these networks learn far more reliably compared to dynamically homogeneous networks and conventional non-network-based bandit algorithms. Our results fuel the notion that neuron-astrocyte interactions in the brain benefit learning over different time-scales and the conveyance of task-relevant contextual information onto circuit dynamics. 
    more » « less
  4. This study investigates the therapeutic effect of astrocyte-derived extracellular vesicles (EVs) in mitigating neurotoxicity-induced transcriptome changes, mitochondrial function, and base excision repair mechanisms in human brain endothelial cells (HBECs). Neurodegenerative disorders are marked by inflammatory processes impacting the blood–brain barrier (BBB) that involve its main components- HBECs and astrocytes. Astrocytes maintain homeostasis through various mechanisms, including EV release. The effect of these EVs on mitigating neurotoxicity in HBECs has not been investigated. This study assesses the impact of astrocyte-derived EVs on global transcriptome changes, cell proliferation, cytotoxicity, oxidative DNA damage, and mitochondrial morphology in HBECs exposed to the neurotoxic reagent Na2Cr2O7. Exposure to Na2Cr2O7 for 5 and 16 h induced oxidative DNA damage, measured by an increase in genomic 8OHdG, while the EVs reduced the accumulation of the adduct. A neurotoxic environment caused a non-statistically significant upregulation of the DNA repair enzyme OGG1 while the addition of astrocyte-derived EVs was associated with the same level of expression. EVs caused increased cell proliferation and reduced cytotoxicity in Na2Cr2O7-treated cells. Mitochondrial dysfunction associated with a reduced copy number and circular morphology induced by neurotoxic exposure was not reversed by astrocyte-derived EVs. High-throughput RNA sequencing revealed that exposure to Na2Cr2O7 suppressed immune response genes. The addition of astrocyte-derived EVs resulted in the dysregulation of long noncoding RNAs impacting genes associated with brain development and angiogenesis. These findings reveal the positive impact of astrocytes-derived EVs in mitigating neurotoxicity and as potential therapeutic avenues for neurodegenerative diseases. 
    more » « less
  5. The blood–brain barrier (BBB) is a multicellular construct that regulates the diffusion and transport of metabolites, ions, toxins, and inflammatory mediators into and out of the central nervous system (CNS). Its integrity is essential for proper brain physiology, and its breakdown has been shown to contribute to neurological dysfunction. The BBB in vertebrates exists primarily through the coordination between endothelial cells, pericytes, and astrocytes, while invertebrates, which lack a vascularized circulatory system, typically have a barrier composed of glial cells that separate the CNS from humoral fluids. Notably, the invertebrate barrier is molecularly and functionally analogous to the vertebrate BBB, and the fruit fly, Drosophila melanogaster, is increasingly recognized as a useful model system in which to investigate barrier function. The most widely used technique to assess barrier function in the fly is the dye-exclusion assay, which involves monitoring the infiltration of a fluorescent-coupled dextran into the brain. In this study, we explore analytical and technical considerations of this procedure that yield a more reliable assessment of barrier function, and we validate our findings using a traumatic injury model. Together, we have identified parameters that optimize the dye-exclusion assay and provide an alternative framework for future studies examining barrier function in Drosophila. 
    more » « less