Yawata Yosuke, Tashima Ryoichi, Aritomi Hiroyuki, Shimada Shinji, Onodera Tsukasa, Taishi Teruhiko, Takasu Keiko, Ogawa Koichi
Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Osaka, Japan.
Shionogi TechnoAdvance Research, Osaka, Japan.
Front Cell Neurosci. 2024 Jun 5;18:1404603. doi: 10.3389/fncel.2024.1404603. eCollection 2024.
Effective treatments for major depressive disorder (MDD) have long been needed. One hypothesis for the mechanism of depression involves a decrease in neuroactive steroids such as allopregnanolone, an endogenous positive allosteric modulator of the γ-aminobutyric acid-gated chloride channel (GABA) receptor. In our previous study, we discovered that allopregnanolone, not diazepam, exhibited antidepressant-like effects in the social interaction test (SIT) of social defeat stress (SDS) model mice. However, the dynamics of neuronal activity underlying the antidepressant-like effect remain unknown. In the current study, we conducted local field potentials (LFPs) recordings from the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) during the SIT to elucidate the relationship between the antidepressant-like effect and neuronal oscillation. We discovered that allopregnanolone has antidepressant-like effects in the SIT of SDS model mice by decreasing intervals of repetitive social interaction (inter-event intervals), resulting in increase of total social interaction time. We also found that theta and beta oscillation increased in BLA at the onset of social interaction following administration of allopregnanolone, which differed from the effects of diazepam. Theta and beta power in BLA within the social interaction zone exhibited a positive correlation with interaction time. This increase of theta and beta power was negatively correlated with inter-event intervals. Regarding theta-band coordinated activity between the BLA and mPFC, theta power correlation decreased at the onset of social interaction with the administration of allopregnanolone. These findings suggest that theta activity in BLA following social interaction and the reduced theta-band coordinated activity between the BLA and mPFC are implicated in social interaction, which is one of the antidepressant behaviors. These differences in neural activity could elucidate the distinctive mechanism underlying antidepressant-like effects of neuroactive steroids, as opposed to benzodiazepines.
长期以来，人们一直需要针对重度抑郁症（MDD）的有效治疗方法。关于抑郁症机制的一种假说是，神经活性类固醇（如别孕烯醇酮，一种γ-氨基丁酸门控氯离子通道（GABA）受体的内源性正变构调节剂）减少。在我们之前的研究中，我们发现别孕烯醇酮而非地西泮在社会挫败应激（SDS）模型小鼠的社会互动测试（SIT）中表现出抗抑郁样作用。然而，抗抑郁样作用背后的神经元活动动态仍不清楚。在当前研究中，我们在SIT期间从基底外侧杏仁核（BLA）和内侧前额叶皮质（mPFC）进行了局部场电位（LFP）记录，以阐明抗抑郁样作用与神经元振荡之间的关系。我们发现，别孕烯醇酮通过缩短重复性社会互动的间隔时间（事件间隔），在SDS模型小鼠的SIT中具有抗抑郁样作用，从而导致总社会互动时间增加。我们还发现，给予别孕烯醇酮后，在社会互动开始时BLA中的θ和β振荡增加，这与地西泮的作用不同。社会互动区域内BLA中的θ和β功率与互动时间呈正相关。这种θ和β功率的增加与事件间隔呈负相关。关于BLA和mPFC之间的θ频段协同活动，给予别孕烯醇酮后，在社会互动开始时θ功率相关性降低。这些发现表明，社会互动后BLA中的θ活动以及BLA和mPFC之间θ频段协同活动的减少与社会互动有关，而社会互动是一种抗抑郁行为。这些神经活动的差异可以阐明神经活性类固醇与苯二氮䓬类药物相比，其抗抑郁样作用背后的独特机制。
