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

项目摘要 精神疾病的发作性本质表明大脑在病理和健康之间转换 大脑状态恐惧和焦虑与内侧前额叶皮层之间的振荡变化有关 大脑皮层（mPFC）和基底外侧杏仁核（BLA）以及这些网络的异常已经在 我们认为，这些网络可能会影响患者的情绪， 处理更广泛。然而，我们对网络转移的机制知之甚少 国家之间。5α-还原型神经类固醇，包括别孕烯醇酮，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。事实上，一种别孕烯醇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， 内源性神经类固醇在介导健康和不健康的网络和行为之间的过渡 states.鉴于压力与许多精神疾病有关，我们建议利用慢性 不可预测的压力（CUS）模型，以评估对mPFC-BLA网络功能的影响。我们建议 压力通过损害BLA中的局部神经类固醇信号传导来破坏网络功能（由初步的 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甾体对GABAAR δ亚基的作用。 受体，在BLA的小清蛋白（PV）阳性神经元中以高密度表达，已知其 调制mPFC-BLA内和之间的振荡。因此，本申请将检验以下假设： BLA中内源性5α-还原性神经类固醇信号传导缺陷，通过PV上含GABAAR的δ-亚基 中间神经元，有助于网络和行为状态中的应激诱导的损伤。

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.