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

基本信息

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
项目类别：
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

项目摘要

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，焦虑样行为和回避（即厌恶反应）也与许多压力直接相关。目前，心理健康疾病和这些疾病影响着约 30% 的美国人口。 (LC) 去甲肾上腺素能 (NE) 系统及其相关 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 系统是一个关键因素。我们最近的证据和文献表明，整合压力引起的回避的组成部分。 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）先前的想法是，通过 LC-NE 操作的这些不同模式，输出到。我们建议隔离和定义独特的下游电路、GPCR 和行为。调节 LC-NE 功能的分子细胞、生理和神经药理学机制我们小组和其他人的最新证据也表明 LC-NE 的反应。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未来五年我们将重点关注全面的分子和神经药理学成分。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”反应中的聚合特征。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”的受体我们要测试的中心假设是 LC-NE 系统及其独特的神经元具有多样性。我们预测体内 LC-NE 神经元的应激/刺激响应分子和生理模式。部分 - 确定 BLA 和 HPC 中的 NE 释放；以及独特的 LC 细胞类型和离散神经肽/GPCR，我们提出了 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 3) 将分子分析与电生理学、传感器和技术结合起来。神经药理学，破译受压力影响的遗传定义的 LC 细胞类型。 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

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders.

剖析神经发育障碍的神经元基础的当代策略。

DOI：
发表时间：
2019
期刊：
影响因子：
2.7
作者：
Seo, Dong;Motard, Laura E;Bruchas, Michael R
通讯作者：
Bruchas, Michael R

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

臂旁阿片样物质对视前下丘脑的投射介导行为和生理热防御。

DOI：
发表时间：
2021-03-05
期刊：
影响因子：
7.7
作者：
Norris, Aaron J;Shaker, Jordan R;Cone, Aaron L;Ndiokho, Imeh B;Bruchas, Michael R
通讯作者：
Bruchas, Michael R

Activity-dependent constraints on catecholamine signaling.

儿茶酚胺信号传导的活动依赖性限制。

DOI：
发表时间：
2023-03-31
期刊：
影响因子：
0
作者：
Li, Li;Rana, Akshay;Li, Esther M;Feng, Jiesi;Li, Yulong;Bruchas, Michael R
通讯作者：
Bruchas, Michael R

Wireless optoelectronic photometers for monitoring neuronal dynamics in the deep brain.

用于监测大脑深部神经元动态的无线光电光度计。

DOI：
发表时间：
2018-02-13
期刊：
影响因子：
11.1
作者：
Lu, Luyao;Gutruf, Philipp;Xia, Li;Bhatti, Dionnet L;Wang, Xinying;Vazquez;Ning, Xin;Shen, Xinru;Sang, Tian;Ma, Rongxue;Pakeltis, Grace;Sobczak, Gabriel;Zhang, Hao;Seo, Dong;Xue, Mantian;Yin, Lan;Chanda, Debashis;Sheng
通讯作者：
Sheng

Defining circuit-specific roles for G protein-coupled receptors in aversive learning.

定义 G 蛋白偶联受体在厌恶学习中的特定电路作用。