Experimenters' Sex Modulates Mouse Behaviors and Neural Responses to Ketamine Via Corticotropin Releasing Factor

Overview

Journal Nat Neurosci

Date 2022 Aug 30

PMID 36042309

Authors

Polymnia Georgiou

Panos Zanos

Ta-Chung M Mou

Xiaoxian An

Danielle M Gerhard

Dilyan I Dryanovski

Liam E Potter

Jaclyn N Highland

Carleigh E Jenne

Brent W Stewart

Katherine J Pultorak

Peixiong Yuan

Chris F Powels

Jacqueline Lovett

Edna F R Pereira

Sarah M Clark

Leonardo H Tonelli

Ruin Moaddel

Carlos A Zarate Jr

Ronald S Duman

Scott M Thompson

Todd D Gould

Affiliations

Soon will be listed here.

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.

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