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: 7859442
• 负责人: Gay R Holstein
• 金额: $ 27.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859442
• 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; 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; 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; evidence base; falls; gamma-Aminobutyric Acid; imidazoleacetic acid ribotide; immunoreactivity; interest; medial vestibular nucleus; moxonidine; neurochemistry; neuronal cell body; noradrenergic; receptor; research study; rilmenidine; young adult

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. Project Narrative - Holstein 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.

目前理解的是，动脉压力感受器控制交感神经系统张力，而 前庭终末器官向前庭交感神经反射提供传入输入，该前庭交感神经反射通常增强前庭终末器官的功能。 代偿性压力反射然而，神经元的化学解剖、连接和突触学 这种整合的潜在途径在很大程度上仍然未知。拟议项目的总体目标是 识别参与调节前庭-自主神经突触相互作用的神经递质和调节剂。 这四个目标涉及成年大鼠这些前庭投射的化学解剖学和突触学， 评估不同的发射器/调制器签名和不同的突触的总体假设， 前庭投射到延髓的尾侧和头侧腹外侧， (CVLM和RVLM）。目的1明确前庭延髓和延髓的位置， 交感神经投射神经元，决定前庭投射到CVLM的相对比例， RVLM，鉴定这些通路利用的主要氨基酸神经递质，并确定是否 这些投射终止于CVLM和RVLM中的谷氨酸能和/或GABA能神经元。目标二是 确定CVLM和RVLM中的前庭末梢是否共表达IAA-RP和/或L-瓜氨酸。目标3是 对前庭受体细胞的主要神经递质和调节剂进行定性分析， RVLM和CVLM，以检验前庭神经传入终止于中间神经元的假设， 在含有GABA能/IAA-RP的CVLM神经元的远端树突上，GABA能和去甲肾上腺素能树突 在RVLM中，以及直接在具有直接投射的含多巴胺能/IAA-RP的RVLM神经元的胞体上 到脊髓。目的4是可视化和量化前庭交感神经突触学参数， 测试RVLM中前庭终末的突触学涉及以下因素之间复杂的相互作用的假设： 多个递质系统，而CVLM中前庭交感神经末梢的突触学反映了 与CVLM输出神经元的直接轴-树突接触。在整个项目中，前庭交感神经系统 将使用组织中的顺行和逆行追踪来识别通路， 使用另外的免疫荧光标记进行处理以鉴定感兴趣的递质和调节剂。 超微结构研究将采用免疫金标记来识别和量化终端和突触接触。 这些研究将描述神经递质，调制器和突触关节利用， 前庭投射到交感运动前髓神经元池，并将产生定性分析， 它们的突触结构的参数的定量估计。此信息目前不存在于 文献，并为治疗的循证药物治疗的发展是重要的 前庭自主神经紊乱，如直立性低血压，以及更具体的发展， 抗高血压药物，不会引起致残前庭副作用，如头晕和眩晕。项目叙述-荷斯坦 针对交感神经系统的药物的直立性低血压和前庭副作用（例如， 抗高血压药物）影响大量人群，尤其是老年人。然而，人们对 前庭交感神经通路的神经化学组织。该项目将提供基本的 关于前庭投射到心血管的化学解剖学和突触组织的信息 延髓腹外侧区神经元，可能提示新的药物疗法，以改善直立性低血压， 不耐受，并可能导致开发更具体的抗高血压药物， 使人丧失前庭功能的副作用，如头晕和眩晕。