SEROTONIN AND GABA NEURON SUBTYPES- THEIR DEVELOPMENT AND FUNCTION

基于对SIDS病例脑干组织的观察，我们假设，作为一个程序， SIDS重要亚群是由5-羟色胺（5-HT）产生神经元和相关的髓质缺陷引起的 神经递质系统，如GABA。有证据表明，这些缺陷出现在怀孕期间， 影响特定亚型的5-HT神经元，而不是所有的5-HT神经元。由此，我们推断，SIDS是一个胚胎， 影响髓质5-HT和/或GABA神经元特定亚型的发育障碍。朝向 了解小岛屿发展中国家的差异基础，我们提出了旨在解码的实验， 延髓5-HT和GABA内不同神经元亚型的发育和分子起源 神经系统的小鼠，并确定这些亚型的具体性质， 自我平衡控制这些实验是通过最近的，强大的进步成为可能：1） 成熟脑干5-HT系统的发育图，首次将系统分解为 分子上可分离的，因此遗传上可接近的5-HT神经元亚型; 2）鉴定 对不同GABA能命运有指导意义的胚胎遗传程序， 在发育中的髓质中;和3）具有足够特异性的工具以扰乱（例如， “沉默”）选择活小鼠中的5-HT或GABA亚型。使用这些工具，我们将绘制细胞功能 5-HT和GABA神经元的发育图 亚型（分别为目标1和3）。因为我们的目标是识别出最相关的神经元亚型 在SIDS的病理生理学方面，我们将重点关注髓质的5-HT和GABA神经元亚型及其 与感知酸中毒和/或缺氧有关的特性（与项目4合作）及其功能 与呼吸、心率、血压和反射性呼吸暂停的控制有关（与项目 2）。这些功能如果受损，可能会导致猝死。此外，我们建议 研究调节5-HT神经元产生的可能机制，我们的目标是破译 SIDS病例中5-HT神经元数量增加的基础。重新定义髓内5-HT和 GABA神经元亚型及其生产基于一系列标准-分子，发育， 电生理学和功能-是这个建议和计划的主要力量和创新。

Based on observations from brainstem tissue of SIDS cases, we hypothesize, as a program, that an important subset of SIDS result from medullary defects in serotonin (5-HT)-producing neurons and related neurotransmitter systems such as GABA. Evidence suggests that these defects arise during gestation and affect specific subtypes of, as opposed to all, 5-HT neurons. From this, we reason that SIDS is an embryonic developmental disorder affecting specific subtypes of 5-HT and/or GABA neurons of the medulla. Towards understanding the differential basis for SIDS, we propose experiments designed to decode the developmental and molecular origins of different neuron subtypes within the medullary 5-HT and GABA neural systems in the mouse, and determine the specific properties of these subtypes as relates to homeostatic control. These experiments are made possible via recent, powerful advances: 1) a developmental map of the mature brainstem 5-HT system that, for the first time, resolves the system into molecularly separable, and therefore genetically accessible, 5-HT neuron subtypes; 2) the identification of embryonic genetic programs that are instructive for different GABAergic fates and which are likely employed in the developing medulla; and 3) tools with sufficient specificity to perturb the activity of (for example, "silence") select 5-HT or GABA subtypes in the living mouse. Using these tools, we will plot cellular functions and electrophysiological properties onto the developmental maps of medullary 5-HT and GABA neuron subtypes (Aims 1 and 3, respectively). Because our goal is to identify neuron subtypes most relevant pathophysiologically to SIDS, we will focus on 5-HT and GABA neuron subtypes of the medulla and their properties as relates to sensing acidosis and/or hypoxia (in collaboration with Project 4) and their functions as relates to control of breathing, heart rate, blood pressure and reflex apnea (in collaboration with Project 2). These are functions which, if impaired, might plausibly contribute to sudden death. Further, we propose investigating a possible mechanism for regulating 5-HT neuron production, our goal being to decipher the basis for the increased number of 5-HT neurons in SIDS cases. The ability to redefine medullary 5-HT and GABA neuron subtypes and their production based on a constellation of criteria - molecular, developmental, electrophysiological, and functional- is a major strength and innovation of this proposal and program.