Veterans Affairs Maryland Health Care System, Baltimore, MD, USA.
Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA.
Nat Neurosci. 2022 Sep;25(9):1191-1200. doi: 10.1038/s41593-022-01146-x. Epub 2022 Aug 30.
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.
我们表明，人类实验者的性别会影响给予快速抗抑郁药氯胺酮及其生物活性代谢物（2R,6R）-羟基去甲氯胺酮后小鼠的行为和反应。与女性实验者相比，雄性实验者的气味会使老鼠产生厌恶感，而雄性实验者的气味则会使老鼠产生偏好，并且在雄性实验者处理时，老鼠的压力易感性会增加。这种由雄性实验者气味引起的厌恶感和压力易感性是通过激活投射到海马 CA1 区的内嗅皮层中的促肾上腺皮质释放因子 (CRF) 神经元来介导的。在给予氯胺酮之前，暴露于雄性实验者的气味会激活 CA1 投射内嗅皮层 CRF 神经元，并且该 CRF 途径的激活会调节氯胺酮的体内和体外抗抑郁样作用。更好地了解人类实验者的性别对啮齿动物研究结果的具体和定量贡献，可能会提高研究之间的可重复性，并且正如我们所表明的那样，揭示生物学和药理学机制。
