Central Noradrenergic Neuron Subtype Development and Function

前额叶皮质(PFC)是额叶中参与认知功能的区域，它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。PFC中的去甲肾上腺素能信号被认为对认知功能有调节作用。事实上，去甲肾上腺素能信号的改变与许多疾病相关的认知功能障碍有关，包括雷特综合征、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(S)的大部分了解来自于对出生后动物的非遗传道追踪和损伤研究。关于这些亚群的分子身份，或者胚胎发育过程中去甲肾上腺素信号的变化如何影响正常的大脑结构和功能，人们知之甚少，因为在发育过程中，根本不存在具有所需分辨率的工具来可视化和操纵不同的去甲肾上腺素亚型。 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，以允许选择性地可视化和操纵小鼠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手段，在胚胎发育期间获得去甲肾上腺素能神经元亚群的遗传途径，并能够确定发育期间去甲肾上腺素能信号的遗传和环境变化如何导致PFC功能中断。

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.