Central Noradrenergic Neuron Subtype Development and Function

中枢去甲肾上腺素能神经元亚型的发育和功能

• 批准号: 8336658
• 负责人: Patricia Jensen
• 金额: $ 124.25万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336658
• 关键词: Affect; Alzheimer' s Disease; Anxiety; Attention; Attention deficit hyperactivity disorder; Behavior; Biological Models; Brain; Cells; Cellular Morphology; Clinical; Desire for food; Development; Disease; Down Syndrome; Environmental Risk Factor; Genetic; Goals; Heterogeneity; Imagery; Individual; Knowledge; Learning; Location; Memory; Mental Depression; Moods; Mus; Nervous system structure; Neuronal Dysfunction; Neurons; Neuropeptides; Norepinephrine; Parkinson Disease; Pattern; Peripheral Nervous System; Play; Population; Post-Traumatic Stress Disorders; Role; Series; Signal Transduction; Stress; Structure; System; Time; Variant; base; critical period; in vivo; molecular marker; nervous system disorder; noradrenergic; novel; recombinase; research study; tool

Noradrenergic (NA) neurons, the cells of nervous system that actively synthesize norepinephrine, play an essential role in circuits involving attention, mood, appetite, memory, anxiety and stress, as well as providing pivotal support for autonomic function in the peripheral nervous system. As such, abnormal function of NA neurons is implicated in a broad spectrum of neurological disorders such as depression, Post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinsons Disease, Alzheimers Disease and Down Syndrome. The wide variation in clinical features associated with these disorders is paralleled by mounting evidence that unique subpopulations of NA neurons are selectively affected. Heterogeneity among NA neurons is further illustrated by their different anatomical location, cell morphology, axonal projection pattern, neuropeptide expression and vulnerability to environmental factors. Mechanisms that determine these differences are unknown and presently no molecular markers have been identified which are capable of distinguishing individual NA neuron subtypes. Understanding how heterogeneity arises within the NA system is a key step in determining the mechanism of selective neuronal dysfunction following genetic or environmental insult and to gaining genetic access to particular NA neuron subpopulations for experimental study. To fill this knowledge gap, we are developing a set of novel genetic tools to study the development and function of the NA system in vivo. These tools will provide, for the first time, a means to gain genetic access to subsets of NA neurons and the ability to determine the effect of altered NA signaling during critical periods of development on circuits underlying behaviors such as attention and learning & memory.

去甲肾上腺素能 (NA) 神经元是神经系统中积极合成去甲肾上腺素的细胞，在涉及注意力、情绪、食欲、记忆、焦虑和压力的回路中发挥着重要作用，并为周围神经系统的自主功能提供关键支持。 因此，NA 神经元的异常功能与多种神经系统疾病有关，例如抑郁症、创伤后应激障碍 (PTSD)、注意力缺陷多动障碍 (ADHD)、帕金森病、阿尔茨海默病和唐氏综合症。与这些疾病相关的临床特征存在巨大差异，同时越来越多的证据表明 NA 神经元的独特亚群受到选择性影响。 NA神经元之间的异质性通过其不同的解剖位置、细胞形态、轴突投影模式、神经肽表达和对环境因素的脆弱性进一步说明。决定这些差异的机制尚不清楚，目前尚未鉴定出能够区分各个 NA 神经元亚型的分子标记。了解 NA 系统内异质性是如何产生的，是确定遗传或环境损伤后选择性神经元功能障碍的机制以及获得特定 NA 神经元亚群的遗传途径以进行实验研究的关键步骤。 为了填补这一知识空白，我们正在开发一套新颖的遗传工具来研究体内 NA 系统的发育和功能。这些工具将首次提供一种获得 NA 神经元子集的遗传途径的方法，并能够确定在发育关键时期改变的 NA 信号对注意力、学习和记忆等行为基础回路的影响。