Imbalanced glucocorticoid and mineralocorticoid stress hormone receptor function has sex-dependent and independent regulatory effects in the mouse hippocampus

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2023-11-17 DOI:10.1016/j.ynstr.2023.100589
Robert H. Oakley , Natallia V. Riddick , Sheryl S. Moy , John A. Cidlowski
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Abstract

Many stress-related neuropsychiatric disorders display pronounced sex differences in their frequency and clinical symptoms. Glucocorticoids are primary stress hormones that have been implicated in the development of these disorders but whether they contribute to the observed sex bias is poorly understood. Glucocorticoids signal through two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR). To elucidate the sex-specific and independent actions of glucocorticoids in the hippocampus, we developed knockout mice lacking hippocampal GR, MR, or both GR and MR. Mice deficient in hippocampal MR or both GR and MR showed an altered molecular phenotype of CA2 neurons and reduced anxiety-like behavior in both sexes, but altered stress adaptation behavior only in females and enhanced fear-motivated cue learning only in males. All three knockout mouse models displayed reduced sociability but only in male mice. Male and female mice deficient in both hippocampal GR and MR exhibited extensive neurodegeneration in the dentate gyrus. Global transcriptomic analysis revealed a marked expansion in the number of dysregulated genes in the hippocampus of female knockout mice compared to their male counterparts; however, the overall patterns of gene dysregulation were remarkably similar in both sexes. Within and across sex comparisons identified key GR and MR target genes and associated signaling pathways underlying the knockout phenotypes. These findings define major sex-dependent and independent effects of GR/MR imbalances on gene expression and functional profiles in the hippocampus and inform new strategies for treating men and women with stress-related neuropsychiatric disorders.

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糖皮质激素和矿皮质激素应激激素受体功能失衡在小鼠海马中具有性别依赖和独立的调节作用
许多与压力相关的神经精神疾病在发病频率和临床症状上表现出明显的性别差异。糖皮质激素是主要的应激激素,与这些疾病的发展有关,但它们是否有助于观察到的性别偏见尚不清楚。糖皮质激素通过两个密切相关的核受体糖皮质激素(GR)和矿皮质激素受体(MR)发出信号。为了阐明糖皮质激素在海马体中的性别特异性和独立作用,我们开发了缺乏海马GR、MR或同时缺乏GR和MR的敲除小鼠,海马MR或同时缺乏GR和MR的小鼠在两性中都表现出CA2神经元分子表型的改变和焦虑样行为的减少,但仅在雌性中改变了应激适应行为,仅在雄性中增强了恐惧动机线索学习。所有三种基因敲除小鼠模型都表现出社交能力下降,但仅在雄性小鼠中。海马GR和MR均缺乏的雄性和雌性小鼠在齿状回表现出广泛的神经变性。全球转录组学分析显示,与雄性敲除小鼠相比,雌性敲除小鼠海马中失调基因的数量显着增加;然而,基因失调的总体模式在两性中是非常相似的。性别内部和跨性别比较确定了关键的GR和MR靶基因以及敲除表型的相关信号通路。这些发现确定了GR/MR失衡对海马体基因表达和功能谱的主要性别依赖和独立影响,并为治疗男性和女性压力相关神经精神疾病提供了新的策略。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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