Background

Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABA_A (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects.

Methods

We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states.

Results

We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABA_A receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6–12 Hz) through δ-containing GABA_A receptors, a mechanism distinct from other GABA_A positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress–induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress.

Conclusions

Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

中文翻译：

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Allopregnanolone 通过调节基底外侧杏仁核的振荡状态介导情感转换

背景

Brexanolone（allopregnanolone）最近被美国食品和药物管理局批准用于治疗产后抑郁症，显示出持久的抗抑郁作用。尽管我们了解神经类固醇作为 GABA _A（γ-氨基丁酸 A）受体的正变构调节剂的作用机制，但我们仍然不完全了解 allopregnanolone 如何发挥持久的抗抑郁作用。

方法

我们使用大鼠和人类的脑电图记录以及局部场电位、功能磁共振成像和小鼠行为测试来评估神经类固醇对与情绪有关的大脑区域网络状态的影响，并使用光遗传学操作直接检查它们与行为的关系状态。

结果

我们证明了别孕醇酮和合成的神经活性类固醇类似物，其分子药理学类似于别孕醇酮（SGE-516 [工具化合物] 和 zuranolone [SAGE-217，研究化合物]）调节物种间的振荡。我们进一步证明了中间神经元在基底外侧杏仁核 (BLA) 中产生振荡中的关键作用以及含 δ 的 GABA _A受体在介导神经类固醇调节网络和行为状态的能力中的作用。_{BLA 中的 Allopregnanolone 通过含 δ 的 GABA A}受体增强 BLA 高θ振荡（6-12 Hz），这是一种不同于其他 GABA _A的机制正变构调节剂，如苯二氮卓类药物，并改变行为状态。用别孕烯醇酮类似物 SGE-516 治疗可保护小鼠免受慢性压力诱导的网络和行为状态破坏，这与 BLA 中θ振荡的调节有关。网络状态的光遗传学操作会影响慢性不可预测压力后的行为状态。

结论

我们的研究结果表明，一种新的分子和细胞机制介导了神经活性类固醇的公认抗焦虑和抗抑郁作用。