Cortical astrocytes regulate ethanol consumption and intoxication in mice

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Abstract

Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate behavior through multiple intracellular signaling pathways, including G-protein coupled-receptor (GPCR)-mediated calcium signals. To test the hypothesis that GPCR-induced calcium signaling is also involved in the behavioral effects of ethanol, we expressed astrocyte-specific excitatory DREADDs in the prefrontal cortex (PFC) of mice. Activating G _q-GPCR signaling in PFC astrocytes increased drinking in ethanol-naïve mice, but not in mice with a history of ethanol drinking. In contrast, reducing calcium signaling with an astrocyte-specific calcium extruder reduced ethanol intake. Cortical astrocyte calcium signaling also altered the acute stimulatory and sedative-hypnotic effects of ethanol. Astrocyte-specific G _q-DREADD activation increased both the locomotor-activating effects of low dose ethanol and the sedative-hypnotic effects of a high dose, while reduced astrocyte calcium signaling diminished sensitivity to the hypnotic effects. In addition, we found that adenosine A1 receptors were required for astrocyte calcium activation to increase ethanol sedation. These results support integral roles for PFC astrocytes in the behavioral actions of ethanol that are due, at least in part, to adenosine receptor activation.

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Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence

Hua Chai, Blanca Díaz-Castro, Eiji Shigetomi … (2017)

Astrocytes are ubiquitous in the brain and are widely held to be largely identical. However, this view has not been fully tested and the possibility that astrocytes are neural circuit-specialized remains largely unexplored. Here, we used multiple, integrated approaches including RNA-Seq, mass spectrometry, electrophysiology, immunohistochemistry, serial block-face scanning electron microscopy, morphological reconstructions, pharmacogenetics, as well as diffusible dye, calcium and glutamate imaging, to directly compare adult striatal and hippocampal astrocytes under identical conditions. We found significant differences between striatal and hippocampal astrocytes in electrophysiological properties, Ca 2+ signaling, morphology and astrocyte-synapse proximity. Unbiased evaluation of actively translated RNA and proteomic data confirmed significant astrocyte diversity between hippocampal and striatal circuits. We thus report core astrocyte properties, reveal evidence for specialized astrocytes within neural circuits and provide new, integrated database resources and approaches to explore astrocyte diversity and function throughout the adult brain. The Khakh lab used state-of-the-art optical, anatomical, electrophysiological, transcriptomic and proteomic approaches to explore astrocyte similarities and differences in two neural circuits. Candid evaluation of the data across ten approaches provided strong evidence for astrocyte diversity and provided an experimental workflow to explore astrocyte diversity across the brain.

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Astrocyte function from information processing to cognition and cognitive impairment

Mirko Santello, Nicolas Toni, Andrea Volterra (2019)

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.

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Norepinephrine controls astroglial responsiveness to local circuit activity.

Martin Paukert, Amit Agarwal, Jaepyeong Cha … (2014)

Astrocytes perform crucial supportive functions, including neurotransmitter clearance, ion buffering, and metabolite delivery. They can also influence blood flow and neuronal activity by releasing gliotransmitters in response to intracellular Ca(2+) transients. However, little is known about how astrocytes are engaged during different behaviors in vivo. Here we demonstrate that norepinephrine primes astrocytes to detect changes in cortical network activity. We show in mice that locomotion triggers simultaneous activation of astrocyte networks in multiple brain regions. This global stimulation of astrocytes was inhibited by alpha-adrenoceptor antagonists and abolished by depletion of norepinephrine from the brain. Although astrocytes in visual cortex of awake mice were rarely engaged when neurons were activated by light stimulation alone, pairing norepinephrine release with light stimulation markedly enhanced astrocyte Ca(2+) signaling. Our findings indicate that norepinephrine shifts the gain of astrocyte networks according to behavioral state, enabling astrocytes to respond to local changes in neuronal activity. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

E. K. Erickson:

ORCID: http://orcid.org/0000-0001-9327-346X

emmaerickson@utexas.edu

Journal

Journal ID (nlm-ta): Neuropsychopharmacology

Journal ID (iso-abbrev): Neuropsychopharmacology

Title: Neuropsychopharmacology

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0893-133X

ISSN (Electronic): 1740-634X

Publication date (Electronic): 28 May 2020

Publication date PMC-release: 28 May 2020

Publication date (Print): February 2021

Volume: 46

Issue: 3

Pages: 500-508

Affiliations

[1 ]GRID grid.89336.37, ISNI 0000 0004 1936 9924, Waggoner Center for Alcohol and Addiction Research, , The University of Texas at Austin, ; Austin, TX 78712-01095 USA

[2 ]GRID grid.89336.37, ISNI 0000 0004 1936 9924, Institute for Cell and Molecular Biology, , The University of Texas at Austin, ; Austin, TX 78712-0195 USA

[3 ]GRID grid.89336.37, ISNI 0000 0004 1936 9924, Department of Neuroscience, , The University of Texas at Austin, ; Austin, TX 78712-01095 USA

Author information

E. K. Erickson http://orcid.org/0000-0001-9327-346X

Article

Publisher ID: 721

DOI: 10.1038/s41386-020-0721-0

PMC ID: 8027025

PubMed ID: 32464636

SO-VID: b929562c-6a9f-47a6-885e-c6a07309d063

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.