Decoding Locus Coeruleus Neural Circuits and Signaling in Negative Affect

摘要：压力与许多心理健康疾病直接相关。患者的压力增加 疼痛、抑郁和焦虑的发生率，也是一个主要关注和日益严重的健康问题。焦虑感 目前，疾病影响了18%的美国人口。蓝斑(LC)去甲肾上腺素能系统 与许多情感障碍有牵连，包括应激引起的焦虑。此外，一些人还拥有 报道称，LC-NE系统也是整合应激样焦虑症的关键组成部分 通过其升高的活性和输出到下游电路来响应。此外，最近有证据表明， 提示中央杏仁核促肾上腺皮质激素释放因子阳性细胞可能提供离散的输入和 应激过程中LC的调节。在本提案中，我们将重点放在对这一假定收敛的进一步剖析上 促肾上腺皮质激素释放因子和去甲肾上腺素能神经回路在LC中的作用及其向基底外侧的输出 杏仁核通过检测涉及厌恶和厌恶的电路和受体介导的信号通路 焦虑。这里我们使用多学科的方法，包括药理学，化学遗传学，光遗传学， 以及体内成像方法，以确定去甲肾上腺素能LC的特定细胞、回路和受体 调节压力引起的焦虑的系统。这项研究建议的中心假设是，LC- 杏仁核回路是负性情绪行为协调反应的关键部位 来施加压力。为了更好地理解这一系统在行为中的作用，我们提出了三个目标：1)剖析 CEA蓝斑(LC)神经回路在控制应激引起的厌恶和焦虑中的作用 2)确定蓝斑(LC)-BLA的必要性和充分性 应激诱导调控中的神经回路、细胞类型、肾上腺素能受体及其信号通路 厌恶和焦虑样行为，以及3)确定和解码特定BLA的网络动态 应激反应、上游化学发生调控和药理学中的神经元群体 受体信号的中断。总而言之，这个项目和所描述的实验可以提供新颖和 关于去甲肾上腺素功能以及负面情绪和压力的交集的重要信息。

Abstract: Stress has been directly linked to numerous mental health diseases. In patients stress increases pain incidence of depression and anxiety, and are a major concern and a growing health problem. Anxiety disorders currently affect 18% of the US population. The locus coeruleus (LC) noradrenergic (NE) system has been implicated in numerous affective disorders including stress-induced anxiety. Additionally, some have reported that the LC-NE system is also a critical component for integration of stress-induced anxiety-like responses through its elevated activity and output to downstream circuits. In addition, recent evidence suggests that the central amygdala corticotropin-releasing factor positive cells may provide discrete input and regulation of the LC during stress. In this proposal we focus on further dissection of this putative convergent role of corticotropin-release factor and noradrenergic neural circuits in the LC, and its output to the basolateral amygdala by examining the circuits and receptor-mediated signaling pathways involved in aversion and anxiety. Here we use a multi-disciplinary approach that includes pharmacology, chemogenetics, optogenetics, and in vivo imaging approaches to define the specific cells, circuits, and receptors with the noradrenergic LC system that mediate stress-induced anxiety. The central hypothesis of this research proposal is that an LC- amygdala circuit is a key site of convergence for the coordination of the negative affective behavior in response to stress. In order to better understand the role of this system in behavior we propose 3 aims: 1) To dissect the function of the CeA - locus coeruleus (LC) –neural circuit in the control of stress-induced aversion and anxiety- like behavioral responses; 2) to determine the necessity and sufficiency of the locus coeruleus (LC) – BLA neural circuit, cell types, adrenergic receptors, and their signaling pathways in the control of stress-induced aversion and anxiety-like behaviors and 3) to determine and decode the network dynamics of specific BLA neuronal populations in response to stress, chemogenetic modulation upstream, and pharmacological disruption of receptor signaling. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and stress.