Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
J Neuroendocrinol. 2023 Feb;35(2):e13195. doi: 10.1111/jne.13195. Epub 2022 Sep 7.
Sex differences in emotional behaviors and affective disorders have been widely noted, of which sexually dimorphic secretion of gonadal steroid hormones such as estrogen is suspected to play a role. However, the underlying neural mechanisms remain poorly understood. We noted that the expression of estrogen receptor 2 (Esr2, or ERβ), a key mediator of estrogen signaling in the brain, was enriched in the dorsal raphe nucleus (DRN), a region involved in emotion regulation. To investigate whether DRN Esr2 expression confers sex-specific susceptibility or vulnerability in emotional behaviors, we generated a conditional allele of Esr2 that allowed for site-specific deletion of Esr2 in the DRN via local injection of Cre-expressing viruses. DRN-specific Esr2 deletion mildly increased anxiety behaviors in females, as shown by decreased time spent in the center zone of an open field in knockout females. By contrast, DRN Esr2 deletion had no effects on anxiety levels in males, as demonstrated by knockout males spending comparable time in the center zone of an open field and open arms of an elevated-plus maze. Furthermore, in the tail suspension test, DRN Esr2 deletion reduced immobility, a depression-like behavior, in a male-biased manner. Together, these results reveal sex-specific functions of DRN Esr2 in regulating emotional behaviors and suggest targeted manipulation of DRN Esr2 signaling as a potential therapeutic strategy to treat sex-biased affective disorders.
性别的情感行为和情感障碍存在广泛差异，其中，性腺类固醇激素（如雌激素）的性别二态分泌被怀疑起到一定作用。然而，其潜在的神经机制仍不清楚。我们注意到，雌激素信号转导的关键介质——雌激素受体 2（Esr2，即 ERβ）在中缝背核（DRN）中的表达丰富，而 DRN 参与了情绪调节。为了研究 DRN 中的 Esr2 表达是否赋予了情感行为中特有的易感性或易损性，我们生成了 Esr2 的条件性等位基因，通过向 DRN 中注射表达 Cre 的病毒，可以实现 Esr2 的特异性缺失。DRN 特异性 Esr2 缺失轻度增加了雌性动物的焦虑行为，表现在敲除雌性动物在开阔场的中央区域花费的时间减少。相比之下，DRN Esr2 缺失对雄性动物的焦虑水平没有影响，这表明敲除雄性动物在开阔场的中央区域和高架十字迷宫的开放臂中花费的时间相当。此外，在悬尾试验中，DRN Esr2 缺失以雄性偏倚的方式减少了不动行为，即一种类似抑郁的行为。总的来说，这些结果揭示了 DRN Esr2 在调节情感行为方面的性别特异性功能，并提示靶向调控 DRN Esr2 信号可能是治疗性别偏倚情感障碍的一种潜在治疗策略。
