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: 7570038
• 负责人: Gay R Holstein
• 金额: $ 34.4万
• 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/7570038
• 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

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）：目前已知动脉压力感受器控制交感神经系统张力，而前庭终末器官为前庭交感神经反射提供传入输入，该反射通常增强补偿性压力反射。然而，这种整合背后的神经通路的化学解剖学、连接性和突触学仍然很大程度上未知。该项目的总体目标是确定参与介导前庭自主突触相互作用的神经递质和调节剂。这四个目标解决了成年大鼠中这些前庭投射的化学解剖学和突触学问题，并评估了前庭投射到尾侧和头端腹外侧髓质（分别为 CVLM 和 RVLM）利用不同的递质/调制器特征和不同的突触结构排列的总体假设。目标 1 是确定前庭髓质和髓质交感神经投射神经元的位置，确定前庭投射到 CVLM 和 RVLM 的相对比例，识别这些通路利用的主要氨基酸神经递质，并确定这些投射是否终止于 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 中的前庭末梢是否共同表达 IAA-RP 和/或 L-瓜氨酸。目标 3 是对 RVLM 和 CVLM 中前庭受体细胞的主要神经递质和调节剂进行定性分析，以检验谷氨酸前庭传入细胞终止于中间神经元和含有 GABA 能/IAA-RP 的 CVLM 神经元、GABA 能和去甲肾上腺素能树突的假设。 RVLM，并直接作用于含有谷氨酸/IAA-RP的RVLM神经元的体体，并直接投射到脊髓。目标 4 是可视化和量化前庭交感神经突触的参数，并将检验以下假设：RVLM 中前庭末梢的突触涉及多个递质系统之间的复杂相互作用，而 CVLM 中前庭交感神经末梢的突触反映了与 CVLM 输出神经元的直接轴突接触。在整个项目中，将使用组织中的顺行和逆行束追踪来识别前庭交感神经通路，并使用额外的免疫荧光标签对其进行进一步处理，以识别感兴趣的发射器和调节器。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射到交感前运动髓质神经元池所利用的神经递质、调节剂和突触关节，并将对其突触结构的参数进行定性分析和定量估计。目前文献中尚不存在该信息，但对于开发用于治疗前庭自主神经紊乱（例如直立性低血压）的循证药物治疗方法以及开发不会引起头晕和眩晕等致残性前庭副作用的更具体的抗高血压药物非常重要。公共卫生相关性：直立性低血压和针对交感神经系统的药物（例如抗高血压药物）的前庭副作用影响大量人群，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知之甚少。该项目将提供有关前庭投射到腹外侧延髓心血管神经元的化学解剖学和突触组织的基本信息，可能会建议改善直立性低血压和不耐受的新药物疗法，并可能导致开发更特异性的抗高血压药物，这些药物不会引起头晕和眩晕等致残前庭副作用。