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: 8149122
• 负责人: Patricia Jensen
• 金额: $ 72.7万
• 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/8149122
• 关键词: Attention deficit hyperactivity disorder; Development; Disease; Embryonic Development; Molecular; Neurons; Resolution; noradrenergic

The prefrontal cortex (PFC), the region of the frontal lobe that is involved in cognitive functions, receives a relatively rich innervation of noradrenergic fibers originating from the locus coeruleus. It is thought that noradrenergic signaling in the PFC modulates cognitive functions. Indeed, altered noradrenergic signaling is implicated in the cognitive dysfunction associated with a number of disorders including Rett syndrome, attention-deficit/hyperactivity disorder (ADHD), Parkinsons and Alzheimers disease. To date, much of our understanding about the subpopulation(s) of noradrenergic neurons that project to and modulate PFC circuits comes from non-genetic tract tracing and lesioning studies in postnatal animals. Little is known about the molecular identity of these subpopulations or how altered noradrenergic signaling during embryonic development affects normal brain structure and function because tools with the needed resolution to visualize and manipulate different noradrenergic subtypes during development simply have not existed. To fill this knowledge gap, we are developing a set of recombinase-based genetic tools to permit selective visualization and manipulation of molecularly defined subsets of noradrenergic neurons in the mouse. These tools will provide, for the first time, a means to gain genetic access to subsets of noradrenergic neurons during embryonic development and the ability to determine how genetic and environmental alterations in noradrenergic signaling during development results in disrupted PFC function.

前额叶皮质（PFC）是额叶中参与认知功能的区域，接受来自蓝斑的去甲肾上腺素能纤维的相对丰富的神经支配。据认为，PFC中的去甲肾上腺素能信号调节认知功能。事实上，改变的去甲肾上腺素能信号传导涉及与许多病症相关的认知功能障碍，所述病症包括Rett综合征、注意力缺陷/多动障碍（ADHD）、帕金森病和阿尔茨海默病。 到目前为止，我们对投射和调节PFC回路的去甲肾上腺素能神经元亚群的了解大多来自出生后动物的非遗传束追踪和损伤研究。关于这些亚群的分子身份或胚胎发育过程中去甲肾上腺素能信号的改变如何影响正常的脑结构和功能，我们知之甚少，因为在发育过程中，具有可视化和操纵不同去甲肾上腺素能亚型所需分辨率的工具根本不存在。 为了填补这一知识空白，我们正在开发一套基于重组酶的遗传工具，以允许选择性可视化和操纵小鼠中去甲肾上腺素能神经元的分子定义的子集。这些工具将首次提供一种在胚胎发育过程中获得去甲肾上腺素能神经元亚群的遗传途径的手段，并能够确定在发育过程中去甲肾上腺素能信号传导的遗传和环境改变如何导致PFC功能中断。