Activation of a neural stem cell transcriptional program in parenchymal astrocytes
- Stanford University, United States
- Karolinska Institutet, Sweden
- Francis Crick Institute, United Kingdom
- Karolinska Institute, Sweden
Abstract
Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells, progressing through a near-identical neurogenic program. Surprisingly, in the non-neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, these cortical astrocytes, and many striatal ones, stalled before entering transit-amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.
Data availability
The Cx30-CreER dataset (fastq files and processed expression matrix) has been deposited in ArrayExpress (accession E-MTAB-9268). The AAV-Cre dataset has been deposited in the Gene Expression Omnibus (GEO; accession GSE153916).SmartSeq2 dataset (ArrayExpress)http://www.ebi.ac.uk/arrayexpress/help/how_to_search_private_data.htmlUsername: Reviewer_E-MTAB-9268Password: hqhgiiqx10X dataset (GEO)To review GEO accession GSE153916:Go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153916Enter token mzoxeoigpranfub into the box
-
Transcriptomics analysis of neurogenesis by striatal astrocytes upon Rbpj-K deletionNCBI Gene Expression Omnibus, GSE153916.
Article and author information
Author details
Funding
Svenska Forskningsrådet Formas
- Jonas Frisén
Cancerfonden
- Jonas Frisén
Stiftelsen för Strategisk Forskning
- Jonas Frisén
H2020 European Research Council
- Jonas Frisén
Knut och Alice Wallenbergs Stiftelse
- Jonas Frisén
Torsten Söderbergs Stiftelse
- Jonas Frisén
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
Ethics
Animal experimentation: All animal experimental procedures were approved by the Stockholms Norra Djurförsöksetiska Nämnd (Permit reference numbers N571-11 and N155-16)
Version history
- Received: June 5, 2020
- Accepted: July 31, 2020
- Accepted Manuscript published: August 3, 2020 (version 1)
- Version of Record published: August 20, 2020 (version 2)
Copyright
© 2020, Magnusson 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
-
- 7,238
- views
-
- 829
- downloads
-
- 48
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Activation of a neural stem cell transcriptional program in parenchymal astrocytes
eLife 9:e59733.
https://doi.org/10.7554/eLife.59733
Further reading
-
- Neuroscience
Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6–11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain-machine interface that initiated task trials based on the magnitude of prefrontal-hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain-machine interfacing.
-
- Neuroscience
Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here, we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between ‘bimodal cells’ showing interleaved phase precession and procession, and ‘unimodal cells’ in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells’ firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.
