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Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

Shannon Cole, Ramesh Chandra, Maya Harris, Ishan Patel, Torrance Wang, Hyunjae Kim, Leah Jensen, Scott J Russo, Gustavo Turecki, Amy M Gancarz-Kausch, David M Dietz, Mary Kay Lobo
doi: https://doi.org/10.1101/2020.06.27.175349
Shannon Cole
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Ramesh Chandra
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Maya Harris
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Ishan Patel
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Torrance Wang
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Hyunjae Kim
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Leah Jensen
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Scott J Russo
2Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Gustavo Turecki
3McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada
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Amy M Gancarz-Kausch
4Department of Pharmacology and Toxicology, The Research Institution on Addictions, State University of New York at Buffalo, Buffalo, NY, USA
5Department of Psychology, California State University Bakersfield, Bakersfield, CA, USA
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David M Dietz
4Department of Pharmacology and Toxicology, The Research Institution on Addictions, State University of New York at Buffalo, Buffalo, NY, USA
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Mary Kay Lobo
1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
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  • For correspondence: mklobo@som.umaryland.edu
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Abstract

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. We further show that blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Additional File 3 Corrected

  • List of abbreviations

    AAV
    adeno-associated viruses
    ChIP
    chromatin immunoprecipitation
    CPP
    conditioned place preference
    D1-MSN
    dopamine receptor-1 containing medium spiny neurons
    D2-MSN
    dopamine receptor-2 containing medium spiny neurons
    DSM-IV
    Diagnostic and Statistical Manual of Mental Disorders-IV
    DIO
    double inverted open
    Drp1
    dynamin related protein 1
    Egr3
    early growth response factor 3
    Egr3-miR
    Egr3 microRNA
    IACUC
    Institutional Animal Care and Use Committee
    Mfn1
    Mitofusin 1
    Mfn2
    Mitofusin 2
    MSNs
    medium spiny neurons
    NAc
    Nucleus accumbens
    Opa1
    Optic atrophy 1 (alternative: OPA1 mitochondrial dynamin like GTPase)
    PBS
    phosphate buffered saline
    PGC1α
    peroxisome proliferator-activated receptor gamma coactivator
    Polγ
    mitochondrial DNA polymerase subunit gamma
    Nrf1
    transcription factors nuclear respiratory factor 1
    Nrf2
    transcription factors nuclear respiratory factor 2
    qRT-PCR
    quantitative real time polymerase chain reaction
    RT
    RiboTag
    SS-miR
    scramble sequence microRNA
    Tfam
    mitochondria-specific transcription factor a
    Tfb1
    mitochondria-specific transcription factor b
    Tomm20
    translocase of the outer mitochondrial membrane 20
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    Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation
    Shannon Cole, Ramesh Chandra, Maya Harris, Ishan Patel, Torrance Wang, Hyunjae Kim, Leah Jensen, Scott J Russo, Gustavo Turecki, Amy M Gancarz-Kausch, David M Dietz, Mary Kay Lobo
    bioRxiv 2020.06.27.175349; doi: https://doi.org/10.1101/2020.06.27.175349
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    Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation
    Shannon Cole, Ramesh Chandra, Maya Harris, Ishan Patel, Torrance Wang, Hyunjae Kim, Leah Jensen, Scott J Russo, Gustavo Turecki, Amy M Gancarz-Kausch, David M Dietz, Mary Kay Lobo
    bioRxiv 2020.06.27.175349; doi: https://doi.org/10.1101/2020.06.27.175349

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