Brainstem GABAergic Neuron Development and Function

描述（由申请人提供）：本项目旨在定义脑干GABAergic （γ -氨基丁酸（GABA）产生）呼吸神经元的发育基因表达及其在呼吸控制中的最终功能。小鼠模型系统中可用的强大遗传工具将用于描述GABAergic亚型的分子，并在此图谱上描述和绘制功能特性。我们假设，脑干下部的gaba能呼吸神经元亚型是由双形起源组织的，导致回路模块能够调节不同的呼吸参数，如呼吸量、频率和形状，当被破坏时，可能在先天性呼吸异常（如SIDS）中发挥作用，SIDS是美国新生儿后期婴儿死亡的主要原因。以及Rett综合征——导致年轻女孩发育障碍的主要原因。本研究计划拟利用Dymecki实验室开发的工具，1)将呼吸gabaergy神经元的命运定义为发育基因表达的功能，2)确定这些基因定义的gabaergy神经元亚型在调节呼吸稳态中所起的作用。通过将早期基因表达与具有不同命运和功能的gaba能神经元组联系起来，我们将发现可用于模拟人类呼吸缺陷的候选发育途径。

DESCRIPTION (provided by applicant): This project aims to define brainstem GABAergic (Gamma-aminobutryc acid (GABA) - producing) respiratory neurons in terms of their developmental gene expression and ultimately their function in respiratory control. Powerful genetic tools available in the mouse model system will be used to delineate GABAergic subtypes molecularly and upon this map, functional properties will then be delineated and plotted. We hypothesize that GABAergic respiratory neuron subtypes in the lower brainstem are organized by rhombomeric origin, resulting in circuit modules capable of regulating distinct respiratory parameters such as respiratory volume, frequency and shape, and that when disrupted, may play a role in congenital respiratory abnormalities such as SIDS - the leading cause of post-neonatal infant mortality in the United States, and Rett syndrome - the leading cause of developmental disabilities in young girls. This research program proposes to use tools developed in the Dymecki lab to 1) define the fates of respiratory GABAergic neurons as a function of developmental gene expression, and 2) determine the role played by these genetically-defined GABAergic neuron subtypes in regulating respiratory homeostasis. By linking early gene expression to groups of GABAergic neurons with distinct fates and functions, we will uncover candidate developmental pathways that can be used to model respiratory defects seen in humans. PUBLIC HEALTH RELEVANCE: Relevance to public health: The proposed studies will contribute to building and applying a genetic system for defining and delineating neural mechanisms important to the control of breathing. The resulting findings will lead to a deeper understanding of respiratory function and dysfunction, including that associated with many common and debilitating, even life-threatening disorders, such as the respiratory abnormalities associated with infant prematurity, with Retts syndrome, Joubert syndrome, and sudden infant death syndrome,