Dissecting locus coeruleus contributions to stress-induced antinociception

项目摘要/摘要 慢性疼痛是导致长期残疾的最常见原因，据估计，20.4%的美国成年人患有 2016年的慢性疼痛，估计每年直接医疗成本为5600亿美元，工作效率下降，以及 残障项目。尽管有这种巨大的影响，但对于疼痛和那些 随着时间的推移，这些措施确实会改善患者的病情，影响会变得越来越小。此外，压力诱导的心理 焦虑、抑郁和疼痛灾变等疾病与糖尿病预后不良有关。 有疼痛症状的人。有必要开发疼痛研究的替代方法来解决这一问题 系统性问题。集中精力研究影响机械过程的更广泛的神经系统 与疼痛相关的可能是一种可行的新方法。更具体地说，调查机制 应激改变动态平衡的疼痛处理将有助于分离慢性 疼痛。在这里，我们关注蓝斑去甲肾上腺素系统作为压力和疼痛处理的纽带。 在这项建议中，我们将表征LC-NE系统在调节应激诱导的变化中的作用 蜂窝、电路和网络层面的伤害性感受。我们假设LC-NE系统是 压力影响伤害性输出的过程。我们将在一系列实验中检验这一假设 目标。目标1将检验假设，即LC-NE活动仅在处理外部 应激源最终会产生抗伤害效应。目标2将调查LC-NE末端的假设 在更广泛的应激诱导机制中，中缝背核(DRN)的活动是必需的步骤 抗伤害感受器。具体地说，我们已经提出了实验来确定LC-DRN电路的激活是否 应激后对伤害性刺激的反应增强，以及1肾上腺素能受体是否在 DRN是应激诱导的抗伤害感受所必需的。这一结果将使我们更好地理解LC是如何 在应激和疼痛期间，NE系统的活动都被利用来诱导应激诱导的抗伤害感觉。这 奖学金将为我提供关于体内细胞类型选择性光遗传学、体内纤维的强化科学培训 光度学、行为药理学和免疫组织化学。多种实验的结合 方法提供了极好的培训潜力，并与出色的指导承诺相结合 来自华盛顿大学的教职员工和外部合作者将帮助我实现成为 一位独立的学术和企业家科学家。

Project Summary/Abstract Chronic pain is the most common cause of long-term disability with an estimated 20.4% of U.S. adults had chronic pain in 2016 and an estimated $560 billion each year in direct medical costs, lost productivity, and disability programs. Despite this immense impact, there are insufficient therapeutic options for pain and those that do improve patient conditions become less impactful over time. In addition, stress-induced psychological disorders such as anxiety, depression, and pain catastrophizing have been associated with poor prognosis in people with pain conditions. There is a need to develop alternative approaches to pain research to tackle this systemic problem. Focusing efforts on broader neuronal systems that influence the mechanistic processes associated with pain may be a viable novel approach. More specifically, investigating mechanisms by which homeostatic pain processing is altered by stress will aid in isolating neurobiological underpinnings of chronic pain. Here, we focus on the locus coeruleus norepinephrine system as a nexus of stress and pain processing. In this proposal we will characterize the role of the LC-NE system in modulating stress-induced changes to nociception at cellular, circuit, and network levels. We hypothesize the LC-NE system is a critical component to the process by which stress influences nociceptive output. We will test this hypothesis in a series of experimental aims. Aim 1 will test the hypothesis that LC-NE activity is required exclusively during the processing of an external stressor to ultimately result in an antinociceptive effect. Aim 2 will investigate the hypothesis that LC-NE terminal activity in the dorsal raphe nucleus (DRN) is a required step within the broader mechanism of stress-induced antinociception. Specifically, we have proposed experiments to determine whether LC-DRN circuit activation is potentiated in response to noxious stimuli after stress exposure and whether 1-adrenergic receptors within the DRN are required for stress-induced antinociception. The results will provide a better understanding of how LC- NE system activity is leveraged during both stress and pain to elicit stress-induced antinociception. This fellowship will provide me with intensive scientific training in cell-type selective in vivo optogenetics, in vivo fiber photometry, behavioral pharmacology, and immunohistochemistry. The combination of diverse experimental approaches provides excellent training potential and compounded with outstanding mentorship commitment from faculty at Washington University and external collaborators will help me achieve my career goal of becoming an independent academic and entrepreneurial scientist.