Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor

Georgiou, Polymnia; Zanos, Panos; Mou, Ta-Chung M.; An, Xiaoxian; Gerhard, Danielle M.; Dryanovski, Dilyan I.; Potter, Liam E.; Highland, Jaclyn N.; Jenne, Carleigh; Stewart, Brent W.; Pultorak, Katherine; Yuan, Peixiong; Powels, Chris F; Lovett, Jacqueline; Pereira, Edna F. R.; Clark, Sarah M.; Tonelli, Leonardo H.; Moaddel, Ruin; Zarate, Carlos A.; Duman, Ronald S.; Thompson, Scott M.; Gould, Todd D.

doi:10.1038/s41593-022-01146-x

Cited by 81 publications

(48 citation statements)

References 42 publications

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“…Although we and others show that GluA1 levels are selectively increased in the hippocampus within one hour after ketamine treatment in mice (23, 27–31), other groups have also demonstrated an increase in both GluA1 and GluA2 levels following ketamine treatment (27, 28). Interestingly, GluA1 and GluA2 levels were measured more than one hour after ketamine treatment in these studies.…”

Section: Discussioncontrasting

confidence: 68%

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Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Zaytseva

Bouckova

Wiles

et al. 2022

Preprint

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Ketamine is shown to enhance excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamines therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that inhibits excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+ - permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. When a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamines effects on animals behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.

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Section: Discussioncontrasting

confidence: 68%

“…Interestingly, following ketamine treatment in animals, many studies find elevated levels of GluA1, particularly in the hippocampus, whereas the results of other subunits' expression are less consistent (23,(27)(28)(29)(30)(31). This suggests that subtype specific activation of AMPARs is crucial for ketamine's antidepressant actions.…”

Section: Figures 1 Tomentioning

confidence: 99%

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Zaytseva

Bouckova

Wiles

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…[42]. For example, a recent study found that the antidepressant effects of ketamine in mice was only apparent when administered by male experimenters, and established that this was mediated by CRF activation by male experimenter scent [43]. Moreover, from an ethological perspective, focusing on specific readouts in short paradigms might leave relevant behavioral phenomena affected by temporal dynamics in a group context and the underlying neurobiological processes indiscernible [44].…”

Section: Acknowledging the Limitations Of Short Reductive Behavioral ...mentioning

confidence: 99%

A paradigm shift in translational psychiatry through rodent neuroethology

Shemesh

Chen

2023

Mol Psychiatry

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Mental disorders are a significant cause of disability worldwide. They profoundly affect individuals’ well-being and impose a substantial financial burden on societies and governments. However, despite decades of extensive research, the effectiveness of current therapeutics for mental disorders is often not satisfactory or well tolerated by the patient. Moreover, most novel therapeutic candidates fail in clinical testing during the most expensive phases (II and III), which results in the withdrawal of pharma companies from investing in the field. It also brings into question the effectiveness of using animal models in preclinical studies to discover new therapeutic agents and predict their potential for treating mental illnesses in humans. Here, we focus on rodents as animal models and propose that they are essential for preclinical investigations of candidate therapeutic agents’ mechanisms of action and for testing their safety and efficiency. Nevertheless, we argue that there is a need for a paradigm shift in the methodologies used to measure animal behavior in laboratory settings. Specifically, behavioral readouts obtained from short, highly controlled tests in impoverished environments and social contexts as proxies for complex human behavioral disorders might be of limited face validity. Conversely, animal models that are monitored in more naturalistic environments over long periods display complex and ethologically relevant behaviors that reflect evolutionarily conserved endophenotypes of translational value. We present how semi-natural setups in which groups of mice are individually tagged, and video recorded continuously can be attainable and affordable. Moreover, novel open-source machine-learning techniques for pose estimation enable continuous and automatic tracking of individual body parts in groups of rodents over long periods. The trajectories of each individual animal can further be subjected to supervised machine learning algorithms for automatic detection of specific behaviors (e.g., chasing, biting, or fleeing) or unsupervised automatic detection of behavioral motifs (e.g., stereotypical movements that might be harder to name or label manually). Compared to studies of animals in the wild, semi-natural environments are more compatible with neural and genetic manipulation techniques. As such, they can be used to study the neurobiological mechanisms underlying naturalistic behavior. Hence, we suggest that such a paradigm possesses the best out of classical ethology and the reductive behaviorist approach and may provide a breakthrough in discovering new efficient therapies for mental illnesses.

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“…It may even be that the sex of the experimenter can affect outcomes. Whilst this has not been systematically investigated in EAE, as far as we are aware, there are several reports that rodents of both sexes are more stressed when the person doing the experiments on them is male, and that this can lead to differences in behavioral assays of pain and stress ( 142 , 143 ). This could potentially add another layer of complexity to investigation of the effects of biological sex on the pathophysiology of EAE.…”

Section: Effects Of Biological Sex On Various Parameters Relevant To ...mentioning

confidence: 99%

Effects of biological sex and pregnancy in experimental autoimmune encephalomyelitis: It’s complicated

McCombe

Greer

2022

Front. Immunol.

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Experimental autoimmune encephalomyelitis (EAE) can be induced in many animal strains by inoculation with central nervous system antigens and adjuvant or by the passive transfer of lymphocytes reactive with these antigens and is widely used as an animal model for multiple sclerosis (MS). There are reports that female sex and pregnancy affect EAE. Here we review the effects of biological sex and the effects of pregnancy on the clinical features (including disease susceptibility) and pathophysiology of EAE. We also review reports of the possible mechanisms underlying these differences. These include sex-related differences in the immune system and in the central nervous system, the effects of hormones and the sex chromosomes and molecules unique to pregnancy. We also review sex differences in the response to factors that can modify the course of EAE. Our conclusion is that the effects of biological sex in EAE vary amongst animal models and should not be widely extrapolated. In EAE, it is therefore essential that studies looking at the effects of biological sex or pregnancy give full information about the model that is used (i.e. animal strain, sex, the inducing antigen, timing of EAE induction in relation to pregnancy, etc.). In addition, it would be preferable if more than one EAE model were used, to show if any observed effects are generalizable. This is clearly a field that requires further work. However, understanding of the mechanisms of sex differences could lead to greater understanding of EAE, and suggest possible therapies for MS.

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Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor

Cited by 81 publications

References 42 publications

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

A paradigm shift in translational psychiatry through rodent neuroethology

Effects of biological sex and pregnancy in experimental autoimmune encephalomyelitis: It’s complicated

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Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor

Cited by 81 publications

References 42 publications

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

A paradigm shift in translational psychiatry through rodent neuroethology

Effects of biological sex and pregnancy in experimental autoimmune encephalomyelitis: It’s complicated

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Product

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Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus