Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions
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Significance: Clinical studies report that a single, low dose of ketamine produces a rapid antidepressant response in treatment-resistant depressed patients. Although rodent studies have begun to elucidate the molecular mechanisms underlying the behavioral actions of ketamine, the brain regions and cellular mechanisms have not been defined. Using a combination of pharmacological silencing and optogenetic stimulation approaches, the results of the current study demonstrate that ketamine infusion or optogenetic stimulation of the infalimbic prefrontal cortex produces antidepressant behavioral and synaptic responses similar to the actions of systemic ketamine. These findings further elucidate the mechanisms underlying the therapeutic actions of ketamine and will enhance the development of safer rapid-acting and efficacious agents.
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Prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference.
“In contrast, prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference, while neuronal silencing of ILc (and not PLc), using the GABA-A agonist, muscimol, blocked the actions of ketamine, 24 h later [63].”
From Prefrontal cortex and depression (2022) · cites this paper as [63]
Methods and Materials specify 60 minutes of optical stimulation, and the Fig. 4 caption reports a significant sucrose-preference effect. The Optogenetic Stimulation results qualify that finding: the increase was small and occurred with bilateral IL-PFC stimulation, not unilateral stimulation. The Neuronal Inactivation results also support the citing sentence’s separate point that IL, but not PrL, muscimol infusion blocked ketamine’s behavioral effects assessed 24 hours later. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNon-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]”
From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [37]
The section “Optogenetic Stimulation of IL-PFC Produces Antidepressant Behavioral” reports antidepressant-like effects after activating the infralimbic PFC, but not after activating the prelimbic PFC; it does not establish the effect for non-selective activation of the mPFC as a whole. The Discussion states that the animals were unstressed and that chronic-stress or social-defeat models remain to be tested, so reversal of deficits in depression models was not demonstrated. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOptogenetic stimulation of the infralimbic cortex produces rapid and sustained antidepressant-like effects comparable to ketamine in the forced swim, novelty-suppressed feeding, and sucrose preference tests.
“Duman et al. found that optogenetic stimulation of the infralimbic cortex produces rapid and sustained antidepressant-like effects comparable to ketamine in the forced swim, novelty-suppressed feeding, and sucrose preference tests (181).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [181]
Microinfusion of ketamine into the infralimbic cortex produces comparable antidepressant effects as systemic administration of ketamine, and inactivation of the infralimbic cortex with muscimol is sufficient to block the antidepressant-like effects of systemic ketamine.
“microinfusion of ketamine into the infralimbic cortex produces comparable antidepressant-effects as systemic administration of ketamine and inactivation of the infralimbic cortex with muscimol was sufficient to block the antidepressant-like effects of systemic ketamine (181).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [181]
Neuronal silencing of ILc (and not PLc) using muscimol blocked the actions of ketamine 24 h later.
“In contrast, prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference, while neuronal silencing of ILc (and not PLc), using the GABA-A agonist, muscimol, blocked the actions of ketamine, 24 h later [63].”
From Prefrontal cortex and depression (2022) · cites this paper as [63]
Neuronal silencing of IL (and not PL) blocks the actions of ketamine 24 h later.
“neuronal silencing of IL (and not PL) blocks the actions of ketamine, 24 h later [63]”
From Prefrontal cortex and depression (2022) · cites this paper as [63]
Prolonged ILc pyramidal stimulation for 60 min promotes active coping on FST, mirroring ketamine.
“prolonged ILc pyramidal stimulation for 60 min, mirroring the actions of ketamine to promote active coping on FST [63].”
From Prefrontal cortex and depression (2022) · cites this paper as [63]
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- Authors
- Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., & Duman, R. S.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-08
- Volume
- 112
- Issue
- 26
- Pages
- 8106-8111
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4491758
- OpenAlex
- W1812482953
- Cited by
- 265
- References
- 44
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 27 · 2023: 22 · 2022: 25 · 2021: 35 · 2020: 31 · 2019: 35 · 2018: 24 · 2017: 22 · 2016: 13 · 2015: 7
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R37MH45481, R01MH93897)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- ketamine, antidepressant effects, optogenetic stimulation, infralimbic cortex, anxiolytic effects, neural inactivation, layer 5 pyramidal neurons, synaptic plasticity, depression
- MeSH terms
- Animals, Antidepressive Agents, Behavior, Animal, Ketamine, Limbic System, Male, Rats, Sprague-Dawley, Prefrontal Cortex, Rats, Optogenetics
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