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: 10336798
• 负责人: Jamie Lynn Maguire
• 金额: $ 52.51万
• 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/10336798
• 关键词: Affective; Allopregnanolone; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Behavioral; Brain; Chronic; Chronic stress; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; 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.

项目摘要 精神疾病的情节性质表明，大脑在病理和健康之间转移 大脑状态。恐惧和焦虑与媒体前额叶之间的振荡变化有关 这些网络中的皮质（MPFC）和基底外侧杏仁核（BLA）和异常 患有一系列精神疾病的患者，我们建议这些网络可能会影响情绪 处理更广泛。但是，我们对网络转移的机制知之甚少 在国家之间。已建议5α还原神经类固醇（包括异源性神经酮）在 情感切换，已被证明在临床前发挥了强大的抗焦虑和抗抑郁作用 模型和临床试验。实际上，最近的Allopregnanolone类似物最近获得了FDA的批准 产后抑郁症的治疗。当前的研究以这些发现为基础，以研究潜在的作用 内源性神经类固醇在健康和不健康网络与行为之间的介导过渡中 国家。鉴于多种精神疾病已经暗示了压力，我们建议利用慢性 不可预测的应力（CUS）模型，以评估对MPFC-BLA网络功能的影响。我们提出了这一点 压力通过损害BLA中的局部神经固醇信号来破坏网络功能（由初步支持 数据）以及增加内源性神经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Gabaarδ亚基的作用 接收器，以高密度表示白细胞蛋白（PV）阳性神经元，已知为 调节MPFC-BLA内和之间的振荡。这是该应用程序将检验的假设 内源性5α还原的神经类固醇信号的缺陷，通过PV上的GABAAR含有δ-亚基 中间神经元有助于网络和行为状态的压力引起的损害。