Stress-induced impairments in endogenous neurosteroid signaling in the BLA negatively impacts network and behavioral states

项目摘要 精神疾病的间歇性特征表明大脑在病理性和健康性之间转换。 大脑状态。恐惧和焦虑与内侧前额叶之间的振荡变化有关 大脑皮质(MPFC)和基底外侧杏仁核(BLA)以及这些网络中的异常已经在 患有一系列精神障碍的患者，我们认为这些网络可能会影响情绪 处理范围更广。然而，我们对网络转移的机制(S)知之甚少 州与州之间。5α减少的神经类固醇，包括别孕酮，已被认为在 情感转换，并已被证明在临床前发挥强大的抗焦虑和抗抑郁作用 模型和临床试验中。事实上，一种别孕酮类似物最近获得了FDA的批准 产后抑郁症的治疗。目前的研究建立在这些发现的基础上，以调查潜在的作用 内源性神经类固醇在调节健康与不健康网络和行为之间转换中的作用 各州。鉴于压力与许多精神疾病有关，我们建议使用一种慢性 采用不可预测应激(CUS)模型评估对mPFC-BLA网络功能的影响。我们建议 应激通过损害BLA中的局部神经类固醇信号来扰乱网络功能(由初步支持 数据)，增加内源性神经类固醇生成的能力可以恢复健康的网络 功能。我们提出的机制涉及神经类固醇对含有GABA的δ亚单位的作用 受体，在BLA中的小白蛋白(PV)阳性神经元中高密度表达，已知 调节mPFC-BLA内部和之间的振荡。因此，此应用程序将测试以下假设 白血球中内源性5α减少的神经类固醇信号的缺陷，通过PV上含有GABA受体的δ亚单位 中间神经元参与了应激引起的网络和行为状态的损伤。

Project Summary The episodic nature of psychiatric disorders suggests that the brain shifts between pathological and healthy brain states. Fear and anxiety have been correlated with changes in oscillations between the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) and abnormalities in these networks have been identified in patients with a range of psychiatric disorders and we propose that these networks may impact emotional processing more broadly. However, we understand very little about the mechanism(s) whereby networks shift between states. 5α-reduced neurosteroids, including allopregnanolone, have been suggested to play a role in affective switching and have been shown to exert robust anxiolytic and antidepressant effects in preclinical models and in clinical trials. In fact, an allopregnanolone analog recently received FDA approval for the treatment of postpartum depression. The current study builds on these findings to investigate the potential role of endogenous neurosteroids in mediating transitions between healthy and unhealthy network and behavioral states. Given that stress has been implicated in numerous psychiatric disorders, we propose to utilize a chronic unpredictable stress (CUS) model to evaluate the impact on mPFC-BLA network function. We propose that stress disrupts network function by impairing local neurosteroid signaling in the BLA (supported by preliminary data) and that increasing the capacity for endogenous neurosteroidogenesis can restore healthy network function. Our proposed mechanism involves the action of neurosteroids on GABAAR δ subunit-containing receptors, expressed at a high density in parvalbumin (PV)-positive neurons in the BLA, which are known to modulate oscillations within and between the mPFC-BLA. Thus, this application will test the hypothesis that deficits in endogenous 5α-reduced neurosteroid signaling in the BLA, via δ-subunit containing GABAARs on PV interneurons, contribute to the stress-induced impairments in network and behavioral states.