An essential role for MEF2C in the cortical response to loss of sleep in mice
- The University of Texas Southwestern Medical Center, United States
- University of Texas Southwestern Medical Center, United States
- Medical University of South Carolina, United States
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
Abstract
Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss in C57BL/6J mice. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function.
Data availability
The NCBI Gene Expression Omnibus (GEO) accession number for the RNA-seq data reported in this paper is GSE 144957
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An essential role for MEF2C in the cortical response to loss of sleepNCBI Gene Expression Omnibus, GSE144957.
Article and author information
Author details
Ashwinikumar Kulkarni
Christopher W Cowan
Joseph S Takahashi
Funding
National Institute of Neurological Disorders and Stroke (NS103422)
- Robert W Greene
International Institute for Integrative Sleep Medicine
- Robert W Greene
National Institute of Mental Health (MH102603)
- Robert W Greene
National Institute on Deafness and Other Communication Disorders (DC014702)
- Genevieve Konopka
James S. McDonnell Foundation (220020467)
- Genevieve Konopka
National Institute on Aging (AG045795)
- Joseph S Takahashi
National Institute of Neurological Disorders and Stroke (NS106657)
- Joseph S Takahashi
Howard Hughes Medical Institute
- Joseph S Takahashi
National Institute of Mental Health (MH111464)
- Christopher W Cowan
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD098893)
- Catherine Bridges
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#102096) of the UT Southwestern Medical Center. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Reviewing Editor
- Anne E West, Duke University School of Medicine, United States
Publication history
- Received: April 27, 2020
- Accepted: August 26, 2020
- Accepted Manuscript published: August 27, 2020 (version 1)
- Version of Record published: September 14, 2020 (version 2)
Copyright
© 2020, Bjorness 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.
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An essential role for MEF2C in the cortical response to loss of sleep in mice
eLife 9:e58331.
https://doi.org/10.7554/eLife.58331
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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.
