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.

翻译后摘要：急性压力和威胁产生生理焦虑，以促进规划，并允许 生物体调整行为以探索环境，从而促进过度觉醒， 焦虑样行为和回避（即厌恶反应）。压力也直接与许多 精神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已涉及许多应激相关的 情感障碍包括焦虑、过度觉醒和消极情感。LC-NE系统是一个关键的 整合压力诱导的回避。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，电路和功能的多样性（即多态性），而不是神经元。 以前认为。假设通过LC-NE操作的这些各种模式，输出到 下游电路、GPCR和行为受到严格的调控。我们建议分离并定义 调节LC-NE功能的分子细胞、生理和神经药理学机制 对显著刺激和压力的反应。我们小组和其他人最近的证据也表明LC-NE 操作模式受到局部GABA能神经元群体以及许多未知的 分子和神经药理学成分。今后五年，我们将集中力量， 分子细胞、神经药理学、成像和行为方法的对齐，以更好地定义 LC-NE系统在回避、唤醒和“焦虑样”反应中的会聚特征。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2 p/1 p钙成像方法来定义特定的细胞，电路， 以及介导压力诱导的行为回避和“焦虑样”的LC系统内的受体。 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 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 部分决定BLA和HPC中NE的释放;和独特的LC细胞类型，和离散的神经肽/GPCR， 严格调节LC-NE操作和行为回避。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)目的：明确LC-NE神经元活动的调控过程中，LC-NE周围GABA能神经元的动态作用。 急性应激和回避。3)利用分子分析与电生理学，传感器， 神经药理学，以破译遗传定义的LC细胞类型的压力的影响。这种融合 LC-NE功能的分子细胞、神经药理学、生理学和行为学分析将提供 一个有价值的框架，了解复杂的去甲肾上腺素能功能的交叉点， 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