Chemical Anatomy and Synaptology of Vestibulo-Sympathetic Pathways

前庭交感神经通路的化学解剖学和突触学

• 批准号: 7467791
• 负责人: Gay R Holstein
• 金额: $ 34.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467791
• 关键词: Address; Admission activity; Adrenergic Receptor; Adult; Adverse effects; Affinity; Age; Am 80; American; Amino Acid Neurotransmitters; Anatomy; Antihypertensive Agents; Architecture; Autonomic nervous system disorders; Baroreflex; Binding; Biological Models; Blood Pressure; Brain; Brain Stem; Cardiovascular system; Cell physiology; Cells; Cessation of life; Chemicals; Citrulline; Clinical Research; Clonidine; Complex; Dendrites; Development; Direct Costs; Disease; Distal; Dizziness; Dopamine; Drug Delivery Systems; Elderly; Epinephrine; Fall prevention; Financial cost; Force of Gravity; Functional disorder; Glutamates; Goals; Homeostasis; Hospitals; Human; IAA-RP; Imidazole; Immunofluorescence Immunologic; Inferior; Injection of therapeutic agent; Injury; Interneurons; Joints; Label; Lead; Ligands; Link; Literature; Location; Mediating; Methods; Mixed Function Oxygenases; Motor; Movement; Neural Pathways; Neurons; Neurotransmitters; Nitric Oxide; Norepinephrine; Nuclear; Nucleus solitarius; Organ; Orthostatic Hypotension; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phaseolus vulgaris leucoagglutinin; Phenotype; Phenylethanolamine N-Methyltransferase; Population; Posture; Pressoreceptors; Presynaptic Terminals; Process; Public Health; Rattus; Rattus norvegicus; Reflex action; Regulation; Relative (related person); Reporting; Research; Signal Transduction; Site; Societies; Source; Spinal Cord; Sympathetic Nervous System; Synapses; System; Testing; Thoracic spinal cord structure; Tissues; Tracer; Trauma; Vertigo; Vestibular nucleus structure; base; blood pressure regulation; falls; gamma-Aminobutyric Acid; imidazoleacetic acid ribotide; immunoreactivity; interest; medial vestibular nucleus; moxonidine; neurochemistry; neuronal cell body; noradrenergic; receptor; research study; rilmenidine; young adult

DESCRIPTION (provided by applicant): It is currently understood that arterial baroreceptors control sympathetic nervous system tone, while vestibular end organs provide afferent input to a vestibulo-sympathetic reflex that normally augments the compensatory baroreflex. However, the chemical anatomy, connectivity and synaptology of the neural pathways underlying this integration remain largely unknown. The overall goal of the proposed project is to identify the neurotransmitters and modulators involved in mediating vestibulo-autonomic synaptic interactions. The four aims address the chemoanatomy and synaptology of these vestibular projections in adult rats and evaluate the overall hypothesis that different transmitter/modulator signatures and distinct synaptic architectural arrangements are utilized by vestibular projections to the caudal and rostral ventrolateral medulla (CVLM and RVLM, respectively). Aim 1 is to identify the locations of vestibulo-medullary and medullo- sympathetic projection neurons, determine the relative proportions of vestibular projections to CVLM and RVLM, identify the primary amino acid neurotransmitter(s) utilized by these pathways and determine whether these projections terminate on glutamatergic and/or GABAergic neurons in CVLM and RVLM. Aim 2 is to determine whether vestibular terminals in CVLM and RVLM co-express IAA-RP and/or L-citrulline. Aim 3 is to conduct a qualitative analysis of the main neurotransmitters and modulators of vestibulo-recipient cells in RVLM and CVLM, to test the hypothesis that glutamatergic vestibular afferents terminate on interneurons and on distal dendrites of GABAergic/IAA-RP-containing CVLM neurons, GABAergic and noradrenergic dendrites in RVLM, and directly on the somata of glutamatergic/IAA-RP-containing RVLM neurons with direct projections to the spinal cord. Aim 4 is to visualize and quantify parameters of vestibulo-sympathetic synaptology, and will test the hypothesis that the synaptology of vestibular terminals in RVLM involves complex interactions among multiple transmitter systems, whereas the synaptology of vestibulo-sympathetic terminals in CVLM reflects direct axo-dendritic contacts with CVLM output neurons. Throughout the project, the vestibulo-sympathetic pathways will be identified using anterograde and retrograde tract-tracing in tissue that will be further processed using additional immunofluorescent tags to identify transmitters and modulators of interest. Ultrastructural studies will employ immunogold labels to identify and quantify terminals and synaptic contacts. These studies will characterize the neurotransmitters, modulators and synaptic articulations utilized by vestibular projections to sympathetic pre-motor medullary neuron pools and will yield qualitative analyses and quantitative estimates of parameters of their synaptic architecture. This information does not currently exist in the literature, and is important for the development of evidence-based pharmacotherapeutics for the treatment of vestibulo-autonomic disorders such as orthostatic hypotension, as well as the development of more specific anti-hypertensive medications that do not elicit disabling vestibular side-effects such as dizziness and vertigo. PUBLIC HEALTH RELEVANCE: Orthostatic hypotension and vestibular side effects of drugs targeting the sympathetic nervous system (e.g. anti-hypertensive medications) impact large populations, especially the elderly. However, little is known about the neurochemical organization of vestibulo-sympathetic pathways. This project will provide fundamental information about the chemoanatomic and synaptic organization of vestibular projections to cardiovascular neurons in the ventrolateral medulla, may suggest new drug therapies to ameliorate orthostatic hypotension and intolerance, and may lead to the development of more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.

描述（由申请人提供）：目前可以理解，动脉压力感受器控制交感神经系统的音调，而前庭终端器官为前庭交照反射提供了传入的输入，通常会增强补偿性baroreflex。然而，这种整合的神经途径的化学解剖学，连通性和突触学仍然在很大程度上未知。拟议项目的总体目标是识别涉及介导前桥自主突触相互作用的神经递质和调节剂。这四个目的涉及成年大鼠这些前庭投影的化学解剖学和突触学，并评估总体假设，即不同的发射机/调节剂特征和独特的突触建筑布置可通过前庭投射到尾骨和鼻腹侧髓质（分别为CVLM和RVLM）。 Aim 1 is to identify the locations of vestibulo-medullary and medullo- sympathetic projection neurons, determine the relative proportions of vestibular projections to CVLM and RVLM, identify the primary amino acid neurotransmitter(s) utilized by these pathways and determine whether these projections terminate on glutamatergic and/or GABAergic neurons in CVLM and RVLM. AIM 2是确定CVLM和RVLM中的前庭终端是否共表达IAA-RP和/或L-Citrulline。目的3是对RVLM和CVLM中前神经递质细胞的主要神经递质和调节剂进行定性分析，以测试谷氨酸疗法的前庭传入对中间神经元和远端树突终止于Gabaergic/iaa-rp-contres cobagagient/iaa-rp-contriens inerrics inerrics neerrics and neuricsdend neerricsdend denerricsdend的假说，GAB RVLM，直接在谷氨酸/IAA-RP的RVLM神经元的somata上，直接投射到脊髓。 Aim 4 is to visualize and quantify parameters of vestibulo-sympathetic synaptology, and will test the hypothesis that the synaptology of vestibular terminals in RVLM involves complex interactions among multiple transmitter systems, whereas the synaptology of vestibulo-sympathetic terminals in CVLM reflects direct axo-dendritic contacts with CVLM output neurons.在整个项目中，将使用在组织中的顺行和逆行路追踪确定前庭交照途径，这些途径将使用其他免疫荧光标签进一步处理，以识别感兴趣的发射器和调节剂。超微结构研究将采用免疫金标签来识别和量化末端和突触接触。这些研究将表征前庭投影所利用的神经递质，调节剂和突触关节，用于交感神经前髓质神经元库，并将产生定性分析和对其突触结构参数的定量估计。该信息目前尚不存在于文献中，对于开发基于循证的药物治疗药，以治疗前庭自主疾病，例如原位性低血压，以及开发出更具体的抗高血压药物，这些药物不会导致无法引起的缺乏前庭的副作用，例如发呆和视觉和Vertigo。公共卫生相关性：针对交感神经系统（例如抗高血压药物）的药物的体位性低血压和前庭副作用会影响大量人群，尤其是老年人。然而，对于前庭交照途径的神经化学组织知之甚少。该项目将提供有关腹外侧髓质中前庭预测的化学解剖和突触组织的基本信息，可能建议提出新的药物疗法以改善定位性低血压和不耐受性，并可能导致更具体的抗高级药物的发展，使更精致的副作用产生伴随效果。