Neurochemical Organization of Brain Stem Respiratory Nuclei

脑干呼吸核团的神经化学组织

基本信息

批准号：
7356411
负责人：
MARGARET TT WONG-RILEY
金额：
$ 24.65万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356411
关键词：
AMPA Receptors Age Animal Model Animals Antibodies Behavioral Biological Assay Birth Brain Brain Stem Breathing CDKN1A gene Carbon Dioxide Carotid Body Cell Nucleus Cells Complementary DNA Complex Conscious Cranial Nerves Daily Denervation Depth Development Developmental Process Drops Energy Metabolism Enzymes Event Exhibits Foundations Future GABA Receptor Gene Expression Generations GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Glycine Glycine Receptors Goals Growth Human Hypercapnia Hypoxia In Situ In Situ Hybridization In Vitro Incidence Individual Infant Knowledge Label Laboratories Life Literature Litter Size Lung Mammals Measurement Mediating Mediator of activation protein Messenger RNA Metabolic Modeling Molecular Probes Motor Neurons N-Methyl-D-Aspartate Receptors N-Methylaspartate NR2A NMDA receptor Neonatal Neuromodulator Neurons Neurotransmitter Receptor Neurotransmitters Nuclear Nucleus solitarius Numbers Optics Organism Pathology Pattern Pattern Formation Permeability Physiological Predisposition Principal Investigator Process Pump Rat Strains Rattus Reaction Reporting Research Research Personnel Respiration Respiratory Muscles Risk Rodent Serotonin Serotonin Receptors 5-HT-3 Solid Spinal Cord Staging Structure of nucleus cuneatus Structure of phrenic nerve Sudden infant death syndrome Synapses System Testing Time Tryptophan 5-monooxygenase Ventral thoracic nerve structure Week base cDNA Library critical developmental period cytochrome c oxidase day enzyme activity experience falls gamma-Aminobutyric Acid neurochemistry neurotransmission nucleus ambiguus oncoprotein p21 postnatal programs raphe nuclei receptor relating to nervous system research study respiratory response serotonin 5 receptor serotonin receptor serotonin transporter stressor trend vector

项目摘要

DESCRIPTION (provided by applicant): Respiratory control is multifaceted and complex. In mammals, a network of brain stem nuclei is essential for rhythm generation, pattern formation, and respiratory modulation. The mediators of respiratory neural processing are diverse sets of excitatory and inhibitory neurotransmitters, neuromodulators, and their receptors. Respiratory control differs between different stages of development. The assumption is that growth is progressive and the maturation of respiratory control follows a straight path. This may prove not to be the case, as the incidence of Sudden Infant Death Syndrome suggests that the peak of susceptibility is not at birth, but between the 2nd and 4th months after birth. Physiological studies of responses to hypoxia, hypercapnia, and other insults also suggest critical periods of postnatal development in animals. If such periods exist, the neurochemical bases underlying them need to be explored. When the development of several key neurochemicals in the rat brain stem was analyzed daily from postnatal day (P) 0 to 21, we found that, despite general trends of increasing or decreasing expressions with age, there is a distinct fall in the expression of excitatory neurotransmitters and receptors and a prominent rise in the expression of inhibitory neurotransmitters and receptors at P12. These events suggest a transient period of neurochemical imbalance, during which the system is under stronger inhibitory than excitatory drive, concomitant with a sudden drop in metabolic enzyme activity at P12. Remarkably, an apparent switch in subunit dominance of GABAA receptors from oc3 to a1 also occurs around P12 in the rat pre-Botzinger complex, suggesting that the same neurotransmitter may have different physiological effects before and after the subunit switch. The goal of the present proposal is to test our hypothesis that receptor subunit switching is a common theme for a number of neurotransmitter receptors during the presumed critical period of development in rats. Specifically, we will investigate in several key brain stem nuclei by quantitative immunohistochemical assays the developmental expressions of: 1) GABAA receptor subunits a1, a2, and a3; 2) glutamate receptors, including NMDA receptor subunits 2A and 2B, and AMPA receptor subunits GluR1 and GluR2; and 3) serotonin receptors 5-HT1A, 1B, 2A, 2C, and 3, tryptophan hydroxylase (TPH) and serotonin transporter (SERT). Finally, 4) the possibility that switches occur at the mRNA level will be explored using isolated cDNA fragments and in situ hybridization of subunit-specific riboprobes for GABA, NMDA, and 5-HT receptors. These studies will provide a solid anatomical and neurochemical foundation regarding the temporal events during postnatal development of brain stem respiratory nuclei, so that future physiological and behavioral studies may extend such knowledge toward a more complete understanding of respiratory control in neonatal and early postnatal animals.

描述（由申请人提供）：呼吸控制是多方面且复杂的。在哺乳动物中，脑干核网络对于节律产生、模式形成和呼吸调节至关重要。呼吸神经处理的介质是多种兴奋性和抑制性神经递质、神经调节剂及其受体。不同发育阶段的呼吸控制有所不同。假设生长是渐进的，呼吸控制的成熟遵循一条直线路径。事实可能并非如此，因为婴儿猝死综合症的发病率表明，易感性的高峰期并不在出生时，而是在出生后的第2个月至第4个月之间。对缺氧、高碳酸血症和其他损伤的反应的生理研究也表明动物出生后发育的关键时期。如果存在这样的时期，则需要探索它们背后的神经化学基础。当从出生后第 0 天（P）到第 21 天每天分析大鼠脑干中几种关键神经化学物质的发育时，我们发现，尽管表达随着年龄的增长而增加或减少，但兴奋性神经化学物质的表达却明显下降。神经递质和受体的表达增加，并且抑制性神经递质和受体的表达在 P12 时显着增加。这些事件表明存在短暂的神经化学失衡时期，在此期间系统处于比兴奋驱动更强的抑制状态，同时伴随着 P12 时代谢酶活性的突然下降。值得注意的是，在大鼠前Botzinger复合体中，GABAA受体的亚基优势从oc3到a1的明显转变也发生在P12周围，这表明相同的神经递质在亚基转变之前和之后可能具有不同的生理效应。本提案的目的是检验我们的假设，即在假定的大鼠发育关键时期，受体亚基转换是许多神经递质受体的共同主题。具体来说，我们将通过定量免疫组织化学分析研究几个关键脑干核中以下各项的发育表达：1) GABAA 受体亚基 a1、a2 和 a3； 2)谷氨酸受体，包括NMDA受体亚基2A和2B，以及AMPA受体亚基GluR1和GluR2； 3) 血清素受体 5-HT1A、1B、2A、2C 和 3、色氨酸羟化酶 (TPH) 和血清素转运蛋白 (SERT)。最后，4) 将使用分离的 cDNA 片段和 GABA、NMDA 和 5-HT 受体亚基特异性核糖核酸探针的原位杂交来探索在 mRNA 水平发生转换的可能性。这些研究将为脑干呼吸核出生后发育过程中的时间事件提供坚实的解剖学和神经化学基础，以便未来的生理和行为研究可以扩展这些知识，以更全面地了解新生儿和出生后早期动物的呼吸控制。