Mapping the developmental, genetic, and functional organization of noradrenergic respiratory neural circuits

 描述（由申请人提供）本项目的目标是将不同的呼吸功能映射到脑干去甲肾上腺素能神经元上。包括SIDS、Rett综合征和CCHS在内的几种呼吸病理生理学均以呼吸紊乱为特征，并与脑干去甲肾上腺素能系统异常相关，去甲肾上腺素能信号传导似乎在阻塞性睡眠呼吸暂停中很重要。在多模型系统中，中枢NA系统已被证明参与呼吸控制。然而，先前的实验技术，包括损伤、基因敲除和药理学操作，已经受到这些技术中固有的不精确性的阻碍。为了清楚地描绘和访问NA亚型，我们正在使用交叉遗传学细分NA神经元的起源菱形。我们推测，早期发育的基因表达程序内在的每个菱形的组织NA系统到不同的功能模块与中央呼吸网络的基础。在每个NA菱形亚群内，我们将使用新的小鼠交叉遗传工具在解剖学上、功能上和分子上映射电路组织。我们建议在三个不同的目标来测试我们的假设。在目的1中，我们将解剖映射NA菱形亚型投影到已知的脑干呼吸中心，以确定来自NA神经元的信息流。在目标2中，我们将使用药物遗传学（恐惧）神经元操作结合全身气压体积描记术分配不同的呼吸功能NA亚型。在目标3中，我们将通过分子分析在分子水平上检验早期发育的菱形亚部进入成年脑干的假设。由此产生的综合框架的解剖，功能和分子特征的菱形NA亚型将增加清晰的中央NA神经元组织和它的作用呼吸系统疾病的理解。最终，我们希望这种方法能够开发出针对所需作用部位的高度靶向的诊断和治疗方法，对NA系统所服务的其他行为和生理功能的副作用最小。

 DESCRIPTION (provided by applicant) the goal of this project is to map distinct respiratory functions onto brainstem noradrenergic neurons. Several respiratory pathophysiologies including SIDS, Rett syndrome, and CCHS feature both disordered breathing and are associated with brainstem noradrenergic system abnormalities and, noradrenergic signaling appears to be important in obstructive sleep apnea. In multiple model systems, the central NA system has been shown to be involved in respiratory control. However, prior experimental techniques, including lesions, gene knockouts, and pharmacological manipulations have been hampered by the imprecision inherent in these techniques. To clearly delineate and access NA subtypes, we are using intersectional genetics to subdivide NA neurons by rhombomere of origin. We hypothesize that the early developmental gene expression programs intrinsic to each rhombomere underlie the organization of the NA system into distinct functional modules with in the central respiratory network. Within each NA rhombomeric subset, we will use new mouse intersectional genetic tools to anatomically, functionally, and molecularly map circuit organization. We propose to test our hypothesis in three separate Aims. In Aim 1, we will anatomically map NA rhombomeric subtype projections to known brainstem respiratory centers to determine the flow of information from NA neurons. In Aim 2, we will use pharmacogenetic (Dreadd) neuron manipulations in combination with whole body barometric plethysmography to assign distinct respiratory functions to NA subtypes. In Aim 3, we will test the hypothesis that early developmental rhombomeric subdivisions carry into the adult brainstem at the molecular level through molecular profiling. The resulting integrated framework of anatomical, functional, and molecular characterizations across rhombomeric NA subtypes will add clarity to our understanding of central NA neuron organization and its role respiratory disorders. Ultimately, we expect this approach to enable the development of highly targeted diagnostics and therapeutics that are directed to the required sites of action with minimal side effects on the other behavioral and physiological functions served by the NA system.