Background

Major depressive disorder is one of the most commonly diagnosed mental illnesses worldwide, with a higher prevalence in women than in men. Although currently available pharmacological therapeutics help many individuals, they are not effective for most. Animal models have been important for the discovery of molecular alterations in stress and depression, but difficulties in adapting animal models of depression for females has impeded progress in developing novel therapeutic treatments that may be more efficacious for women.

Methods

Using the California mouse social defeat model, we took a multidisciplinary approach to identify stress-sensitive molecular targets that have translational relevance for women. We determined the impact of stress on transcriptional profiles in male and female California mouse nucleus accumbens (NAc) and compared these results with data from postmortem samples of the NAc from men and women diagnosed with major depressive disorder.

Results

Our cross-species computational analyses identified Rgs2 (regulator of G protein signaling 2) as a transcript downregulated by social defeat stress in female California mice and in women with major depressive disorder. RGS2 plays a key role in signal regulation of neuropeptide and neurotransmitter receptors. Viral vector–mediated overexpression of Rgs2 in the NAc restored social approach and sucrose preference in stressed female California mice.

Conclusions

These studies show that Rgs2 acting in the NAc has functional properties that translate to changes in anxiety- and depression-related behavior. Future studies should investigate whether targeting Rgs2 represents a novel target for treatment-resistant depression in women.

中文翻译：

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伏核中的比较转录分析将 RGS2 鉴定为抑郁相关行为的关键介体

背景

重度抑郁症是世界上最常见的精神疾病之一，女性患病率高于男性。尽管目前可用的药理学治疗对许多人有帮助，但它们对大多数人无效。动物模型对于发现压力和抑郁症的分子变化很重要，但将抑郁症动物模型应用于女性的困难阻碍了开发可能对女性更有效的新型治疗方法的进展。

方法

使用加利福尼亚小鼠社交失败模型，我们采用多学科方法来识别对女性具有转化相关性的压力敏感分子靶标。我们确定了压力对雄性和雌性加利福尼亚小鼠伏隔核 (NAc) 转录谱的影响，并将这些结果与来自被诊断患有重度抑郁症的男性和女性的 NAc 尸检样本的数据进行了比较。

结果

我们的跨物种计算分析将Rgs2（G 蛋白信号转导 2 的调节因子）鉴定为在雌性加利福尼亚小鼠和患有重度抑郁症的女性中被社交失败压力下调的转录物。RGS2 在神经肽和神经递质受体的信号调节中起关键作用。病毒载体介导的Rgs2在 NAc 中的过表达恢复了应激的雌性加利福尼亚小鼠的社交方式和蔗糖偏好。

结论

这些研究表明，在 NAc 中起作用的Rgs2具有可转化为焦虑和抑郁相关行为变化的功能特性。未来的研究应该调查靶向Rgs2是否代表了女性难治性抑郁症的新靶点。