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

压力引起的 BLA 内源性神经类固醇信号传导损伤会对网络和行为状态产生负面影响

• 批准号: 10491237
• 负责人: Jamie Lynn Maguire
• 金额: $ 49.89万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491237
• 关键词: Affective; Allopregnanolone; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Behavioral; Brain; CRISPR/Cas technology; Chronic; Chronic stress; Clinical Research; Clinical Trials; Communication; Data; Emotional; Enzymes; Fright; Impairment; Injections; Interneurons; Lentivirus; Link; Medial; Mediating; Mental disorders; Modeling; Mood Disorders; Moods; Mus; Nature; Neurons; Oxidoreductase; Parvalbumins; Pathologic; Patients; Play; Postpartum Depression; Pre-Clinical Model; Prefrontal Cortex; Process; Risk Factors; Role; Signal Transduction; Site; Stress; Testing; Time; analog; antidepressant effect; density; insight; knock-down; neurosteroids; novel; preclinical study; prevent; receptor; restoration

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.

项目概要 精神疾病的间歇性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相关 皮层（mPFC）和基底外侧杏仁核（BLA）以及这些网络中的异常已在 患有一系列精神疾病的患者，我们认为这些网络可能会影响情绪 处理更广泛。然而，我们对网络转变的机制知之甚少 状态之间。 5α-还原神经类固醇，包括四氢孕酮，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，四氢孕酮类似物最近获得 FDA 批准用于 治疗产后抑郁症。当前的研究以这些发现为基础来调查潜在的作用 内源性神经类固醇介导健康和不健康网络和行为之间的转变 州。鉴于压力与许多精神疾病有关，我们建议利用慢性压力 不可预测压力（CUS）模型来评估对 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来破坏网络功能（初步支持） 数据）并且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 GABAAR δ 亚基的作用 受体，在 BLA 的小白蛋白 (PV) 阳性神经元中高密度表达，已知这些神经元 调制 mPFC-BLA 内部和之间的振荡。因此，该应用程序将检验以下假设： BLA 中内源性 5α-减少的神经类固醇信号传导缺陷，通过 PV 上含有 GABAAR 的 δ 亚基 中间神经元会导致压力引起的网络和行为状态损伤。