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.

目前可以理解，动脉压力受体控制交感神经系统的音调，而 前庭端器官为前庭反射提供了传入的输入，通常会增加 赔偿性巴罗雷诺夫。但是，神经的化学解剖学，连通性和突触学 这种整合的途径在很大程度上仍然未知。拟议项目的总体目标是 识别涉及介导前庭自治相互作用的神经递质和调节剂。 这四个目的涉及成年大鼠的前庭投影的化学解剖学和突触学 评估总体假设，即不同的发射器/调制器签名和独特的突触 前庭投影用于尾骨和腹侧外侧延髓 （分别为CVLM和RVLM）。目的1是确定前庭 - 甲壳虫和髓质的位置 同情投射神经元，确定前庭投影与CVLM和 RVLM，识别这些途径使用的主要氨基酸神经递质（S），并确定是否确定是否 这些预测终止于CVLM和RVLM中的谷氨酸能和/或GABA能神经元。目标2是 确定CVLM和RVLM中的前庭端子是否共表达IAA-RP和/或L-Citrulline。目标3是 对前庭递质细胞的主要神经递质和调节剂进行定性分析 RVLM和CVLM，以检验以下假设：谷氨酸毛的前庭传入终止于中间神经元和 在含GABA能/IAA-RP的CVLM神经元的远端树突上 在RVLM中，直接在谷氨酸/IAA-RP的RVLM神经元中直接投影 到脊髓。 AIM 4是可视化和量化前庭交通突触的参数，并将 检验RVLM前庭末端的突触术的假设涉及复杂的相互作用 多个发射器系统，而CVLM中前路交照终端的突触术反映 直接与CVLM输出神经元的直接轴突树突接触。在整个项目中，前卫 - 同情 将使用在组织中使用顺行和逆行路追踪来识别途径，这将进一步 使用其他免疫荧光标签进行处理，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。 这些研究将表征由神经递质，调节剂和突触关节的特征 对交感性前髓质神经元池的前庭预测，将产生定性分析， 其突触体系结构参数的定量估计。此信息当前不存在 文献，对于开发基于证据的药物治疗非常重要 前庭自主疾病（例如体位性低血压）以及更具体的发展 不会引起残障前庭副作用（例如头晕和眩晕）的抗高血压药物。项目叙述 - 荷斯坦 针对交感神经系统的药物的体位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。但是，对 前庭交照途径的神经化学组织。该项目将提供基本 有关心血管的前庭预测的化学生物和突触组织的信息 腹外侧延髓中的神经元可能建议新的药物疗法减轻体位性低血压和 不宽容，并可能导致开发不引起的更具体的抗高血压药物 致残前庭副作用，例如头晕和眩晕。