Cited by 621Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorStress Responses and Cortisol

Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex

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Covington, Herbert E., Lobo, Mary Kay, Maze, Ian, Vialou, Vincent, Hyman, James M., Zaman, Samir, LaPlant, Quincey, Mouzon, Ezekiel +5 more·2010·The Journal of Neuroscience

Abstract

Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 ( egr1 ), c-fos , and arc , in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive “burst” patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.

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Crossref · 10.1523/jneurosci.1731-10.2010

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  • In mice subjected to social defeat stress, optogenetic stimulation of the ventral medial PFC increased social interaction and reduced anhedonia as measured via the sucrose preference test.

    “In mice subjected to social defeat stress, optogenetic stimulation of the ventral medial PFC increased social interaction and reduced anhedonia as measured via the sucrose preference test (174).”
  • Non-selective activation of the mPFC can reverse behavioral deficits in depression models.

    “Our findings build upon prior studies showing that non-selective activation of the mPFC can reverse behavioral deficits in depression models [36–39]”
  • After optogenetic stimulation of the medial prefrontal cortex in susceptible mice, susceptible mice show a reduction in social avoidance similar to what has been previously observed after antidepressant treatments.

    “After this manipulation in the medial prefrontal cortex, susceptible mice show a reduction in social avoidance similar to what has been previously observed after antidepressant treatments.”
  • Each glutamatergic projection to the NAcc from the PFC, thalamus, amygdala, and hippocampus has a distinct contribution to modulating social anhedonia following social stress.

    “each of these projections has been shown to have a distinct contribution to modulating social anhedonia following social stress”

    From Social functioning in major depressive disorder (2016) · cites this paper as Covington et al., 2010

  • Increased activity of thalamo-NAcc projections leads to increased social avoidance after social stress.

    “increased activity of thalamo-NAcc projections leads to increased social avoidance after social stress”

    From Social functioning in major depressive disorder (2016) · cites this paper as Covington et al., 2010

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Authors
Covington, H. E., Lobo, M. K., Maze, I., Vialou, V., Hyman, J. M., Zaman, S., LaPlant, Q., Mouzon, E., Ghose, S., Tamminga, C. A., Neve, R. L., Deisseroth, K., & Nestler, E. J.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • University of British Columbia (CA)
  • Duke University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Massachusetts Institute of Technology (US)
  • Stanford University (US)
Corresponding author
Nestler, Eric J.
Venue
The Journal of Neuroscience
Published
2010-12-01
Volume
30
Issue
48
Pages
16082-16090
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2025204726
Cited by
621
References
71
Citations by year
2026: 10 · 2025: 23 · 2024: 30 · 2023: 29 · 2022: 41 · 2021: 55 · 2020: 48 · 2019: 52 · 2018: 38 · 2017: 38 · 2016: 45 · 2015: 51 · 2014: 38 · 2013: 41 · 2012: 53
FWCI
28.78
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • National Institute of Mental Health (R01MH051399, P50MH066172)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
depression, medial prefrontal cortex, optogenetic stimulation, antidepressant effects, immediate early genes, Zif268, c-fos, Arc, chronic social defeat stress, channelrhodopsin-2, neuronal activity, postmortem brain, depression resilience, depression vulnerability, depression-like behavior
MeSH terms
Channelrhodopsins, Animals, Depressive Disorder, Gene Expression Regulation, Humans, Interpersonal Relations, Male, Mice, Inbred C57BL, Prefrontal Cortex, Genes, Immediate-Early, Mice, Early Growth Response Protein 1

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