Decoding Locus Coeruleus Neural Circuits and Signaling in Negative Affect

翻译后摘要：压力已直接与许多心理健康疾病。患者压力增加 疼痛是抑郁症和焦虑症的发病率，并且是一个主要的关注和日益严重的健康问题。焦虑 这些疾病目前影响着18%的美国人口。蓝斑（LC）去甲肾上腺素（NE）系统具有 与许多情感障碍有关，包括压力引起的焦虑。此外，有些人 LC-NE系统也是整合应激诱导的焦虑样 通过其升高的活动和输出到下游电路的反应。此外，最近的证据显示， 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， 压力期间LC的调节。在这个建议中，我们专注于进一步解剖这个假定的收敛 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 杏仁核通过检查电路和受体介导的信号通路参与厌恶和 焦虑在这里，我们使用多学科的方法，包括药理学，化学遗传学，光遗传学， 和体内成像方法，以确定特定的细胞，电路和受体与去甲肾上腺素能LC 调节压力引起的焦虑的系统。这项研究的核心假设是，一个LC- 杏仁核回路是负性情绪行为协调的关键性聚合部位 压力为了更好地理解这个系统在行为中的作用，我们提出了3个目标：1）解剖 CeA -蓝斑（LC）-神经回路在压力诱导的厌恶和焦虑控制中的功能， 2）确定蓝斑- BLA的必要性和充分性 神经回路，细胞类型，肾上腺素能受体及其信号通路在应激诱导的控制 厌恶和焦虑样行为和3）确定和解码特定BLA的网络动力学 神经元群体对应激的反应，上游化学发生调节，以及药理学 受体信号传导的中断。总之，这个项目和所描述的实验可以提供新颖的， 关于去甲肾上腺素能功能和负面影响与压力的交叉的重要信息。

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.