Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor
Polymnia Georgiou, Panos Zanos, Ta-Chung M. Mou, Xiao-jing An, Danielle M. Gerhard, Dilyan I. Dryanovski, L. E. Potter, Jaclyn N. Highland, Carleigh E. Jenne, Brent W. Stewart, Katherine J. Pultorak, P. Yuan, Chris F. Powels, Jacqueline Lovett, E. Pereira, Sarah M. Clark, L. Tonelli, Ruin Moaddel, Carlos A. Zarate, Ronald S. Duman, S. Thompson, T. Gould
Nature Neuroscience August 30, 2022 DOI: 10.1038/s41593-022-01146-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine (2R 6R)-hydroxynorketamine |
| Topics | Esketamine Ketamine |
| Key findings | Mice avoided the scent of male experimenters, preferred the scent of female experimenters, and showed increased stress susceptibility when handled by male experimenters. This aversion and stress susceptibility was mediated by activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to male experimenter scent before ketamine administration activated these CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. |
Abstract
We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms. Georgiou et al. found that the sex of the person performing experiments affects mouse behavior, including responses to stress and ketamine. This effect was mediated by corticotropin-releasing factor neurons in the entorhinal cortex that project to CA1.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 24
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice ACS Pharmacology & Translational Science August 2, 2023
- Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine. Journal of Affective Disorders March 15, 2025
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity. Neuropsychopharmacology May 1, 2025
and 19 more in the library
Cites 11
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine Proceedings of the National Academy of Sciences December 17, 2018
- Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function Proceedings of the National Academy of Sciences February 22, 2019
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