Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Molecular Brain |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13041-021-00800-y |
| _version_ | 1818655247634006016 |
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| author | Shannon L. 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 |
| author_facet | Shannon L. 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 |
| author_sort | Shannon L. Cole |
| collection | DOAJ |
| description | 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. Further, 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. |
| first_indexed | 2024-12-17T03:06:40Z |
| format | Article |
| id | doaj.art-9d6dd2987a8d4db7bdc5e26bc0388cab |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-17T03:06:40Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-9d6dd2987a8d4db7bdc5e26bc0388cab2022-12-21T22:05:55ZengBMCMolecular Brain1756-66062021-06-0114111410.1186/s13041-021-00800-yCocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulationShannon L. Cole0Ramesh Chandra1Maya Harris2Ishan Patel3Torrance Wang4Hyunjae Kim5Leah Jensen6Scott J. Russo7Gustavo Turecki8Amy M. Gancarz-Kausch9David M. Dietz10Mary Kay Lobo11Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences At the Icahn School of Medicine At Mount SinaiMcGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill UniversityDepartment of Pharmacology and Toxicology, The Research Institution On Addictions, State University of New York At BuffaloDepartment of Pharmacology and Toxicology, The Research Institution On Addictions, State University of New York At BuffaloDepartment of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265Abstract 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. Further, 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.https://doi.org/10.1186/s13041-021-00800-yCocaineD1-MSNsD2-MSNsMitochondriaNucleus accumbens |
| spellingShingle | Shannon L. 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 Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation Molecular Brain Cocaine D1-MSNs D2-MSNs Mitochondria Nucleus accumbens |
| title | Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation |
| title_full | Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation |
| title_fullStr | Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation |
| title_full_unstemmed | Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation |
| title_short | Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation |
| title_sort | cocaine induced neuron subtype mitochondrial dynamics through egr3 transcriptional regulation |
| topic | Cocaine D1-MSNs D2-MSNs Mitochondria Nucleus accumbens |
| url | https://doi.org/10.1186/s13041-021-00800-y |
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