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Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice
Open accessAbstract
UNLABELLED: Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress. SIGNIFICANCE STATEMENT: Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.
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In the citing paper
“Drugs that inhibit HDAC4/5 and GSK3 have antidepressant-like effects on behavior.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
In the citing paper
“We also recently reported that administration of an HDAC4/5 inhibitor into the hippocampus prevents chronic stress-induced depression-related behaviors”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
In the citing paper
“We recently demonstrated that miRNA mediate behavioral responses to chronic stress in rodents by regulating gene expression and synapse number”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
In the citing paper
“In contrast, reduced miR-124 expression enhances behavioral susceptibility to a subthreshold stress episode.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
In the citing paper
“miR-124 targets Hdac4, Hdac5, and Gsk3b.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
In the citing paper
“given that HDAC inhibitors and DNMT inhibitors exert antidepressant-like actions in several rodent models, [15][16][17]66,69,[71][72][73][74][75][76][77][78][79][80]164”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [17]
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Citations
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“The hippocampal formation is vulnerable to damage from a variety of psychological stressors (McEwen, 2001; Schoenfeld and Gould, 2012) and aberrant structural and functional changes in this brain structure have been implicated in the pathophysiology of depression (Nestler et al., 2002; McEwen, 2007; Schmidt and Duman,…”
BackgroundCombinatorial microRNA target predictions
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Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
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The recent progress in animal models of depression
Wang, Q., Timberlake, M. A., Prall, K., & Dwivedi, Y. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.04.008 · Cited by 370
Neurobiology of Resilience: Interface Between Mind and Body
Cathomas, F., Murrough, J. W., Nestler, E. J., Han, M.-H., & Russo, S. J. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.011 · Cited by 296
Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders
Sanacora, G., Yan, Z., & Popoli, M. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00540-x · Cited by 197
Epigenetic mechanisms of major depression: Targeting neuronal plasticity
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Self-citation
Metadata
- Authors
- Higuchi, F., Uchida, S., Yamagata, H., Abe-Higuchi, N., Hobara, T., Hara, K., Kobayashi, A., Shintaku, T., Itoh, Y., Suzuki, T., & Watanabe, Y.
- Affiliations
- Yamaguchi University (JP)
- Kyoto Prefectural University of Medicine (JP)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-07-06
- Volume
- 36
- Issue
- 27
- Pages
- 7253-7267
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6705534
- OpenAlex
- W2474895768
- Cited by
- 158
- References
- 81
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 11 · 2023: 17 · 2022: 16 · 2021: 23 · 2020: 14 · 2019: 21 · 2018: 17 · 2017: 17 · 2016: 2
- FWCI
- 15.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 日本生物学的精神医学会(Web)
- Funders
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- chronic stress, depression-like behavior, stress resilience, hippocampus, glycogen synthase kinase-3β, post-transcriptional regulation, neuroplasticity, antidepressant-like effects, viral overexpression, mood disorders, histone deacetylase inhibition, GSK-3β inhibition, chronic unpredictable mild stress, miRNA target genes, depression pathophysiology
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Antidepressive Agents, Depression, Disease Models, Animal, Food Preferences, Gene Expression Regulation, Hippocampus, Histone Deacetylases, Imipramine, Male, Mice, Inbred BALB C, Neurons, Stress, Psychological, Oligodeoxyribonucleotides, Antisense, Fluoroquinolones, MicroRNAs, Mice, Topoisomerase II Inhibitors
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