Decoding Locus Coeruleus Neural Circuits and Signaling In Negative Affect

解码蓝斑神经回路和消极情绪中的信号传导

• 批准号: 10518981
• 负责人: Michael R. Bruchas
• 金额: $ 57.96万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-24 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518981
• 关键词: Affect; Affective; Anatomy; Anxiety; Arousal; Behavior; Behavioral; Biological Assay; Biosensor; Blood Pressure; Brain; Calcium; Carrier Proteins; Cells; Characteristics; Control Locus; Data; Development; Disease; Dissociation; Electrophysiology (science); Environment; Exhibits; Exposure to; Fiber; Frequencies; G-Protein-Coupled Receptors; Gene Expression Profile; Genetic Transcription; Heart Rate; Heterogeneity; Hippocampus (Brain); Image; In Situ Hybridization; Individual; Light; Link; Literature; Location; Machine Learning; Measures; Mediating; Mental Health; Mental disorders; Molecular; Molecular Profiling; Mood Disorders; National Institute of Mental Health; Nature; Neurons; Neuropeptides; Neuropharmacology; Neurosciences; Norepinephrine; Organism; Outcome; Output; Pathway interactions; Pharmacology; Phase; Photometry; Physiological; Play; Population; Process; Property; Publishing; Receptor Signaling; Regulation; Reporting; Respiration; Rewards; Risk; Role; Series; Signal Transduction; Signal Transduction Pathway; Slice; Stimulus; Stress; System; Testing; acute stress; anxiety-like behavior; avoidance behavior; behavior influence; behavior measurement; behavioral response; beta-adrenergic receptor; cell type; differential expression; experimental study; gamma-Aminobutyric Acid; imaging approach; in vivo; interdisciplinary approach; locus ceruleus structure; negative affect; neural circuit; neurotransmission; new therapeutic target; noradrenergic; operation; optogenetics; peptide G; receptor; relating to nervous system; response; sensor; stressor; therapeutically effective; therapy development

Abstract: Acute stress and threat produce physiological anxiety to facilitate planning and allow for organisms to tune behavior for exploration of the environment, thus serving to promote hyperarousal, anxiogenic-like behavior and avoidance (i.e. aversive responses). Stress is also directly linked to numerous mental health diseases and these disorders currently affect ~30% of the US population. The locus coeruleus (LC) noradrenergic (NE) system and its related GPCRs have been implicated in numerous stress-related affective disorders including, anxiety, hyperarousal and negative affect. The LC-NE system is a critical component for integration of stress-induced avoidance. Our recent evidence and the literature suggests that LC-NE neurons exhibit more molecular, cellular, circuit and functional diversity (i.e. are polymorphic) than previously thought. It is hypothesized that through these various modes of LC-NE operation, output to downstream circuits, GPCRs, and behavior are tightly regulated. We propose to isolate and define the unique molecular-cellular, physiological and neuropharmacological mechanisms regulating LC-NE function in response to salient stimuli and stress. Recent evidence from our group and others also suggests that LC-NE soperational modes are tightly regulated by a local GABAergic neuron population alongside a host of unknown molecular and neuropharmacological components. In the next five years we will focus on a comprehensive alignment of molecular-cellular, neuropharmacological, imaging, and behavioral approaches to better define converging characteristics of the LC-NE system in avoidance, arousal and “anxiety-like” responses. Here we use a multi-disciplinary approach that includes molecular-cellular approaches, neuropharmacology, NE- biosensors, optogenetics, and in vivo 2p/1p calcium imaging approaches to define the specific cells, circuits, and receptors within the LC system that mediate stress-induced behavioral avoidance and “anxiety-like” behaviors. Our central hypothesis to be tested is that the LC-NE system and it’s distinct neurons have diverse stress/stimuli-responsive molecular and physiological modes in vivo. We predict that LC-NE neuron activity - in part - determines release NE in BLA and HPC; and unique LC cell types, and discrete neuropeptide/GPCRs, tightly regulate LC-NE operation and behavioral avoidance. We propose 3 aims: 1) To determine how stress- induced activation of LC-NE neurons alters encoding and norepinephrine release in the hippocampus and BLA 2) To define the dynamic role of peri-LC GABAergic neurons in the control of LC-NE neuron activity during acute stress and avoidance. 3) To utilize molecular profiling alongside electrophysiology, sensors, and neuropharmacology, to decipher genetically defined LC cell types impacted by stress. This confluence of molecular-cellular, neuropharmacological, physiological and behavioral analysis of LC-NE function will provide a valuable framework for understanding the complexity of noradrenergic function at the intersection of negative affect and stress.

摘要：严重的压力和威胁会产生生理性焦虑，以促进计划并允许 生物为了探索环境而调整行为，从而促进过度唤醒， 类似焦虑的行为和回避(即厌恶反应)。压力也直接与许多 心理健康疾病和这些障碍目前影响着大约30%的美国人口。蓝斑 (LC)去甲肾上腺素(NE)系统及其相关的GPCRs与许多应激相关 情感障碍包括焦虑、过度觉醒和消极情绪。LC-NE系统是一个关键 用于整合压力诱导的回避的组件。我们最近的证据和文献表明 LC-NE神经元表现出更多的分子、细胞、电路和功能多样性(即多态)。 之前的想法是。假设通过LC-NE运行的这些不同模式，输出到 下游电路、GPCR和行为受到严格控制。我们建议分离和定义唯一的 大鼠LC-NE功能调节的分子-细胞、生理和神经药理学机制 对显著刺激和压力的反应。来自我们小组和其他人的最新证据也表明LC-NE 工作模式受到局部GABA能神经元群体的严格调控，同时还有一系列未知的 分子和神经药理成分。未来五年，我们将重点推进全面的 分子-细胞、神经药理学、成像和行为方法的一致性，以更好地定义 LC-NE系统在回避、觉醒和类焦虑反应中的汇聚特征。在这里我们 使用多学科方法，包括分子细胞方法、神经药理学、NE- 生物传感器、光遗传学和体内2P/1P钙成像方法，以确定特定的细胞、电路、 和LC系统中介导应激诱导的行为回避和“类焦虑”的受体 行为。我们要检验的中心假设是，LC-NE系统及其不同的神经元具有不同的 体内应激/刺激反应的分子和生理模式。我们预测LC-NE神经元的活动 部分决定BLA和HPC中NE的释放；独特的LC细胞类型，以及离散神经肽/GPCRs， 严格规范LC-NE操作和行为回避。我们提出了三个目标：1)确定压力如何- 诱导激活LC-NE神经元改变海马和脑白质中去甲肾上腺素的编码和释放 2)明确LC周围GABA能神经元在控制LC-NE神经元活动中的动态作用。 严重的压力和回避。3)与电生理学、传感器和 神经药理学，破译受压力影响的遗传定义的LC细胞类型。这一汇合 对LC-NE功能的分子细胞、神经药理学、生理和行为分析将提供 一个有价值的框架，用来理解去甲肾上腺素能函数在负值的交点上的复杂性 影响和压力。