Decoding Locus Coeruleus Neural Circuits and Signaling In Negative Affect

解码蓝斑神经回路和负面情绪中的信号传导

• 批准号: 10676944
• 负责人: Michael R. Bruchas
• 金额: $ 55.74万
• 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/10676944
• 关键词: Affect; Affective; Anatomy; Anxiety; Arousal; Behavior; Behavioral; Biological Assay; Biosensor; Blood Pressure; Brain; Calcium; Cells; Characteristics; Control Locus; Darkness; 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; Holography; 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; Peptides; Phase; Photometry; Physiological; Play; Population; Process; Property; Publishing; 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; neural circuit; neurotransmission; new therapeutic target; noradrenergic; operation; optogenetics; pharmacologic; receptor; 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：急性压力和威胁会产生生理焦虑，以促进计划并允许 生物体调整探索环境的行为，从而促进过度兴奋， 类似焦虑的行为和回避（即厌恶反应）。压力也与许多因素直接相关 心理健康疾病和这些疾病目前影响约 30% 的美国人口。蓝斑 (LC) 去甲肾上腺素能 (NE) 系统及其相关的 GPCR 与许多应激相关的疾病有关。 情感障碍包括焦虑、过度警觉和负面情绪。 LC-NE 系统是一个关键 用于集成压力诱导回避的组件。我们最近的证据和文献表明 LC-NE 神经元比其他神经元表现出更多的分子、细胞、回路和功能多样性（即多态性） 之前以为。假设通过 LC-NE 操作的这些不同模式，输出到 下游电路、GPCR 和行为受到严格监管。我们建议隔离并定义独特的 调节 LC-NE 功能的分子细胞、生理和神经药理学机制 对显着刺激和压力的反应。我们小组和其他人的最新证据也表明 LC-NE 操作模式受到局部 GABA 神经元群以及许多未知的神经元的严格调节 分子和神经药理学成分。未来五年我们将重点全面推进 分子细胞、神经药理学、成像和行为方法的结合，以更好地定义 LC-NE 系统在回避、唤醒和“类焦虑”反应方面的趋同特征。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 钙成像方法来定义特定的细胞、电路、 LC系统内介导压力诱发的行为回避和“类焦虑”的受体 行为。我们要测试的中心假设是 LC-NE 系统及其不同的神经元具有不同的特征 体内应激/刺激响应分子和生理模式。我们预测 LC-NE 神经元活动 - 在 部分 - 确定 BLA 和 HPC 中的释放 NE；和独特的 LC 细胞类型，以及离散的神经肽/GPCR， 严格规范 LC-NE 操作和行为规避。我们提出 3 个目标：1）确定压力如何- LC-NE 神经元的诱导激活改变海马和 BLA 中的编码和去甲肾上腺素释放 2）定义LC周围GABA能神经元在控制LC-NE神经元活动过程中的动态作用 急性应激和回避。 3) 将分子分析与电生理学、传感器和 神经药理学，破译受压力影响的基因定义的 LC 细胞类型。这种汇合 LC-NE 功能的分子细胞、神经药理学、生理学和行为分析将提供 一个有价值的框架，用于理解负交点去甲肾上腺素能功能的复杂性 影响和压力。

项目成果

Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses.

胫旁阿片能前视下丘脑的神经传导介导行为和生理热防御。

• DOI: 10.7554/elife.60779
• 发表时间: 2021-03-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Norris AJ;Shaker JR;Cone AL;Ndiokho IB;Bruchas MR
• 通讯作者: Bruchas MR

Activity-dependent constraints on catecholamine signaling.

儿茶酚胺信号传导的活动依赖性限制。

• DOI: 10.1101/2023.03.30.534970
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Li,Li;Rana,Akshay;Li,EstherM;Feng,Jiesi;Li,Yulong;Bruchas,MichaelR
• 通讯作者: Bruchas,MichaelR

Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders.

• DOI: 10.1016/j.nlm.2018.03.015
• 发表时间: 2019-11
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Seo DO;Motard LE;Bruchas MR
• 通讯作者: Bruchas MR

A locus coeruleus to dentate gyrus noradrenergic circuit modulates aversive contextual processing.

• DOI: 10.1016/j.neuron.2021.05.006
• 发表时间: 2021-07-07
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Seo DO;Zhang ET;Piantadosi SC;Marcus DJ;Motard LE;Kan BK;Gomez AM;Nguyen TK;Xia L;Bruchas MR
• 通讯作者: Bruchas MR