The role of Dbx1-derived medullary neurons for rhythm generation in the intact respiratory network

Dbx1 衍生的髓质神经元在完整呼吸网络中节律生成中的作用

• 批准号: 9352686
• 负责人: Nathan Andrew Baertsch
• 金额: $ 5.92万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352686
• 关键词: Animals; Area; Basic Science; Behavior; Bilateral; Biological Neural Networks; Brain Stem; Breathing; Calcium; Cells; Central Nervous System Diseases; Complex; Coupled; Data; Development; Electrophysiology (science); Frequencies; Generations; Goals; Imaging Techniques; In Vitro; Lesion; Life; Mammals; Mental Depression; Modeling; Mus; Neurons; Neurotransmitters; Pharmacology; Phase; Population; Preparation; Refractory; Respiration; Role; Sleep; Slice; Techniques; Testing; Theoretical Studies; Thinness; Time; Transgenic Mice; base; clinically significant; excitatory neuron; experimental study; expiration; in vivo; insight; interest; neural circuit; novel; optogenetics; preBotzinger complex; presynaptic; receptor expression; relating to nervous system; respiratory; synaptic depression; transcription factor

1: PROJECT SUMMARY Breathing is a complex behavior that is fundamental for life in all mammals. Disturbances in the function and coordination of breathing are common in many disorders of the central nervous system. Thus, the study of specific neural populations that underlie this behavior is not only of great basic science interest, but holds high clinical significance. Lesion experiments and in-vitro studies using transverse brainstem slices have defined the minimal circuitry that is necessary and sufficient for the inspiratory phase of breathing, a small “kernel” of neurons in the ventrolateral medulla termed the preBötzinger Complex (preBötC). Excitatory neurons derived from cells expressing the transcription factor Dbx1 are thought to form the rhythmogenic “core” of the preBötC. However, a “refractory period” for Dbx1 stimulation following each breath limits the ability these neurons to drive a high frequency rhythm in-vitro. The role of this specific population of neurons in controlling the wide range of breathing frequencies common in-vivo is unknown. In this project we will use novel in-vivo and in-vitro approaches conducted in parallel to investigate the role of Dbx1 neurons in the generation of inspiration when embedded in the wider medullary network. Based on our preliminary data, we hypothesize that the inspiratory neural network functions as a distributed column, and is not limited to a defined “core” region. Inhibition of excitatory Dbx1 neurons effectively drives the inspiratory rhythm through post-inhibitory rebound. And, the refractory period for Dbx1 can be reduced in the distributed inspiratory network to allow faster breathing frequencies by modulating mechanisms of short-term synaptic depression. These hypotheses will be tested using powerful optogenetic, electrophysiological, pharmacological and imaging techniques in anesthetized and freely behaving mice (Aim1) and in a novel horizontal brainstem slice preparation that preserves the wider medullary network bilaterally (Aim2). We expect that integration of these preparations will provide a unique perspective to examine issues that remain unresolved in the field of respiratory rhythm generation.

1：项目摘要 呼吸是一种复杂的行为，对所有哺乳动物的生命都是基础的。功能的干扰和 呼吸协调在中枢神经系统的许多疾病中都是常见的。那，研究 这种行为的基础的特定神经种群不仅具有巨大的基础科学兴趣，而且具有很高的 临床意义。使用横向脑干切片的病变实验和体外研究已定义 对于呼吸的吸气阶段所需和足够的最小电路，一个小的“内核” 腹外侧髓质中的神经元称为Prebötzinger综合体（Prebötc）。兴奋性神经元得出 从表达转录因子的细胞中，dbx1被认为形成了prebötc的节奏“核心”。 但是，每次呼吸之后DBX1模拟的“难治时期”限制了这些神经元的能力 驱动高频节奏。这种特定的神经元人群在控制范围方面的作用 呼吸频率范围常见的体内尚不清楚。在这个项目中，我们将使用新颖的体内和视野 并行进行的方法，以研究DBX1神经元在灵感产生中的作用 嵌入在更广泛的髓网络中。根据我们的初步数据，我们假设灵感 神经网络充当分布式列，不限于定义的“核心”区域。抑制 兴奋性DBX1神经元通过抑制后反弹有效地驱动了灵感节奏。而且， DBX1的难治期可以在分布式的灵感网络中减少，以更快地呼吸 通过调节短期突触抑制的机制来频率。这些假设将进行测试 在麻醉和 自由表现的小鼠（AIM1）和一种新颖的水平脑干切片制剂，以保存野外 双侧髓网络（AIM2）。我们希望这些制剂的整合将提供独特的 研究呼吸节奏产生领域尚未解决的问题的观点。