Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors
Abstract
Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generated GFAP-ChR2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics. We found that after memory acquisition within a temporal window, astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavior. In vivo microdialysis experiments showed astrocyte photoactivation increased extracellular ATP and adenosine concentrations. Intracerebral blockade of adenosine A1 receptors (A1Rs) reversed the attenuation of fear memory. Furthermore, intracerebral or intraperitoneal injection of A1R agonist mimicked the effects of astrocyte activation. Therefore, our findings provide a deeper understanding of the astrocyte-mediated regulation of fear memory, and suggest a new and important therapeutic strategy against pathological fear-related disorders.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all manuscript figures.Source data has been provided online at datadryad.org https://doi.org/10.5061/dryad.p8cz8w9mc
-
Activation of Astrocytes in Hippocampus Decreases Fear Memory through Adenosine A1 ReceptorsDryad Digital Repository, 10.5061/dryad.p8cz8w9mc.
Article and author information
Author details
Funding
The National Key Research and Development Program (2016YFC1306700)
- Yan-Qin Yu
The National Key Research and Development Program (2016YFA0501000)
- Shumin Duan
The National Natural Science Fundation of China (31970939,31771167,31571090)
- Yan-Qin Yu
The National Natural Science Fundation of China (81527901,81821091,31490592)
- Shumin Duan
The Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2018PT31041)
- Shumin Duan
Science and technology Planning Project of Guangdong Province (2018B030331001)
- Shumin Duan
Science and technology Planning Project of Guangdong Province (2018B030331001)
- Yan-Qin Yu
Fundamental Research Funds for the Central Universitues (2019FZA7009)
- Shumin Duan
- Yan-Qin Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental procedures were approved by the Animal Advisory Committee at Zhejiang University (2019-2#) and were performed in strict accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (2006-398#). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Reviewing Editor
- Margaret M McCarthy, University of Maryland School of Medicine, United States
Publication history
- Received: March 23, 2020
- Accepted: August 31, 2020
- Accepted Manuscript published: September 1, 2020 (version 1)
- Version of Record published: September 21, 2020 (version 2)
Copyright
© 2020, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,606
- Page views
-
- 855
- Downloads
-
- 38
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas – together with patient age – were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.
-
- Chromosomes and Gene Expression
- Neuroscience
Sensory feedback is required for the stable execution of learned motor skills, and its loss can severely disrupt motor performance. The neural mechanisms that mediate sensorimotor stability have been extensively studied at systems and physiological levels, yet relatively little is known about how disruptions to sensory input alter the molecular properties of associated motor systems. Songbird courtship song, a model for skilled behavior, is a learned and highly structured vocalization that is destabilized following deafening. Here, we sought to determine how the loss of auditory feedback modifies gene expression and its coordination across the birdsong sensorimotor circuit. To facilitate this system-wide analysis of transcriptional responses, we developed a gene expression profiling approach that enables the construction of hundreds of spatially-defined RNA-sequencing libraries. Using this method, we found that deafening preferentially alters gene expression across birdsong neural circuitry relative to surrounding areas, particularly in premotor and striatal regions. Genes with altered expression are associated with synaptic transmission, neuronal spines, and neuromodulation and show a bias toward expression in glutamatergic neurons and Pvalb/Sst-class GABAergic interneurons. We also found that connected song regions exhibit correlations in gene expression that were reduced in deafened birds relative to hearing birds, suggesting that song destabilization alters the inter-region coordination of transcriptional states. Finally, lesioning LMAN, a forebrain afferent of RA required for deafening-induced song plasticity, had the largest effect on groups of genes that were also most affected by deafening. Combined, this integrated transcriptomics analysis demonstrates that the loss of peripheral sensory input drives a distributed gene expression response throughout associated sensorimotor neural circuitry and identifies specific candidate molecular and cellular mechanisms that support the stability and plasticity of learned motor skills.