LOCUS COERULEUS NEURAL CIRCUITS AND SIGNALING IN NOCICEPTION AND STRESS

描述（由申请人提供）：由慢性无法控制的疼痛引起的压力与许多心理健康疾病直接相关。在表现出慢性疼痛的患者中，抑郁、焦虑和成瘾的发生率是一个主要问题，也是一个日益严重的健康问题。蓝斑（LC）去肾上腺素能（NE）系统与许多情感障碍有关，包括应激性焦虑和抑郁样行为状态。此外，有报道称LC-NE系统也是疼痛神经轴上行传递和下行调制整合的关键组成部分。在本R21提案中，我们通过使用药理学和光遗传学方法检查涉及厌恶、焦虑和疼痛行为的回路和受体介导的信号通路，重点进一步解剖这种假定的去甲肾上腺素能神经回路的聚合作用。本研究建议的中心假设是，脑皮层-杏仁核回路是协调对疼痛的负面影响的关键聚合位点。为了更好地理解这个系统在行为中的作用，我们提出了两个目标。1)探讨蓝斑-杏仁核神经回路在控制厌恶和疼痛样行为反应中的作用。利用光遗传学、药理学和行为学方法，我们将选择性表达ChR2/NpH3.0并刺激和/或抑制lc -去甲肾上腺素能和CeA-CRF神经元，确定这些神经元的细胞类型特异性激活或抑制如何介导小鼠的厌恶、焦虑和慢性疼痛样状态。2)通过使用和设计一种新型的光敏感偏置G蛋白偶联受体，确定杏仁核中G蛋白和/或抑制素介导的信号转导的去甲肾上腺素能激活是否足以导致厌恶和焦虑样行为。总之，这个项目和所描述的实验可以为去甲肾上腺素能功能和负面影响与疼痛的交叉提供新的和重要的信息。

DESCRIPTION (provided by applicant): Stress resulting from chronic uncontrollable pain has been directly linked to numerous mental health diseases. In patients exhibiting chronic pain the incidence of depression, anxiety, and addiction are a major concern and a growing health problem. The locus coeruleus (LC) noradrenergic (NE) system has been implicated in numerous affective disorders including stress-induced anxiety and depression-like behavioral states. Additionally, some have reported that the LC-NE system is also a critical component for integration of the pain neuraxis of ascending transmission and descending modulation. In this R21 proposal we focus on further dissection of this putative convergent role of noradrenergic neural circuits by examining the circuits and receptor-mediated signaling pathways involved in aversion, anxiety, and pain behavior using pharmacological and optogenetic approaches. The central hypothesis of this research proposal is that the LC-amygdala circuit is a key site of convergence for the coordination of the negative affect in response to pain. In order to better understand the role of this system in behavior we propose 2 aims. 1) To dissect the function of the locus coeruleus (LC) - Amygdala neural circuits in the control of aversive and pain-like behavioral responses. Using optogenetic, pharmacological, and behavioral approaches we will selectively express ChR2/NpH3.0 and stimulate and/or inhibit LC-noradrenergic and CeA-CRF neurons determine how cell-type specific activation or inhibition of these neurons are mediate aversion, anxiety, and chronic pain-like states in mice. 2) To determine whether noradrenergic activation of G-protein and/or arrestin-mediated signal transduction in the amygdala is sufficient for aversive and anxiety-like behaviors by using and engineering a novel optically sensitive biased G- protein coupled receptors. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and pain.